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Objectives: To evaluate the effect of a single 10-minute session of Chinese head massage on the activity of the cardiac autonomic nervous system via measurement of heart rate variability (HRV). Design: In this pilot randomized crossover trial, each participant received both head massage and the control intervention in a randomized fashion. Settings/Location: The study was conducted at Children's & Women's Health Centre of British Columbia between June and November 2014. Participants: Ten otherwise healthy adults (6 men and 4 women) were enrolled in this study. Interventions: The intervention comprised 10 minutes of head massage therapy (HMT) in a seated position compared with a control intervention of sitting quietly on the same chair with eyes closed for an equal amount of time (no HMT). Outcome measures: The primary outcome measures were the main parameters of HRV, including total power (TP), high frequency (HF), HF as a normalized unit, pre-ejection period, and heart rate (HR). Results: A single short session (10 minutes) of head massage demonstrated an increase in TP continuing up to 20 minutes after massage and reaching statistical significance at 10 minutes after massage (relative change from baseline, 66% for HMT versus −6.6% for no HMT; p = 0.017). The effect on HF also peaked up to 10 minutes after massage (59.4% for HMT versus 4% for no HMT; p = 0.139). Receiving head massage also decreased HR by more than three-fold compared to the control intervention. Conclusion: This study shows the potential benefits of head massage by modulating the cardiac autonomic nervous system through an increase in the total variability and a shift toward higher parasympathetic nervous system activity. Randomized controlled trials with larger sample size and multiple sessions of massage are needed to substantiate these findings. [ABSTRACT FROM AUTHOR]

To evaluate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) using aggregate-level data from resectable esophageal or gastroesophageal junction cancer (EC/GEJC) trials assessing therapies in (neo)adjuvant and perioperative settings. A systematic literature review was conducted to identify trials reporting OS and DFS, or compatible progression-free survival (PFS). Bivariate random-effects meta-analysis was used to estimate correlation between the treatment effects on DFS/PFS and OS, and weighted linear regression models assuming trial sample sizes as weights were used to estimate surrogacy equations. The primary analysis consisted of trials across all treatment settings, and secondary analysis consisted of trials only in the adjuvant setting. Leave-one-out cross-validation (LOOCV) was performed to measure the stability and predictive accuracy of the surrogacy equations while surrogate threshold effects (STE)—the minimum treatment effect on DFS/PFS that would translate into a positive OS benefit—were derived to measure their usefulness. The primary analysis included 26 trials. The estimated correlation coefficient between the hazard ratio (HR) of DFS/PFS (HR DFS/PFS) and HR of OS (HR OS) was 0.83 (95% confidence interval [CI]: 0.70–0.90). The estimated surrogacy equation was log(HR OS) = 0.80 × log(HR DFS/PFS) with a corresponding STE of 0.82. Reported HR OS was within the 95% prediction interval of the predicted HR OS from the model for more than 95% of the trials in the LOOCV, indicating a valid model. Secondary analysis included 7 trials with an estimated correlation coefficient of 0.76 (95% CI: 0.18–0.95). Through LOOCV, the surrogacy equation in the adjuvant setting was deemed valid. Our meta-analysis suggests that HR DFS/PFS —where DFS/PFS is defined as time from resection to disease recurrence (local, locoregional, or distant) or death—is correlated to HR OS , and a valid and useful surrogate predictor for HR OS in the neoadjuvant, perioperative, or adjuvant settings. • First published DFS/OS surrogacy analysis spanning all treatment settings in EC/GEJ. • Meta-analysis of 26 trials suggests correlated hazard ratios for DFS and OS. • DFS can be a valid and useful surrogate for OS in resectable EC/GEJ. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of iGlarLixi, a fixed‐ratio combination of basal insulin glargine 100 U/mL and lixisenatide (glucagon‐like peptide‐1 receptor agonist) versus IDegAsp, a co‐formulation of basal insulin degludec 100 U/mL with rapid‐acting insulin aspart. Materials and Methods: A systematic literature search of randomized controlled trials (RCTs) was performed. Outcomes from eligible RCTs were compared by an indirect treatment comparison using a Bayesian framework. Subanalyses of Japanese and international trials were performed. Results: Eight RCTs (duration 26‐30 weeks) were included. Mean difference in HbA1c change with iGlarLixi exceeded that for IDegAsp: −0.64 (95% credible interval −1.01, −0.28) %‐units (−7.0 [−11.0, −3.1] mmol/mol) for all trials, −0.39 (−0.55, −0.23) %‐units (−4.3 [−6.0, −2.5] mmol/mol) for international, and −0.88 (−1.11, −0.64) %‐units (−9.6 [−12.1, −7.0] mmol/mol) for Japanese trials. HbA1c target achievement (<7.0%‐units [<53 mmol/mol]) was greater for iGlarLixi in all trials (odds ratio 2.50 [1.06, 5.56]) and Japanese trials (2.17 [1.27, 3.70]), but not in international trials (2.17 [0.42, 11.11]). Analyses suggesting differences in mean postmeal self‐measured plasma glucose were significantly lower by 1.0‐2.0 mmol/L (18‐36 mg/dL) with iGlarLixi in all analyses. Bodyweight change was more favourable (1‐2 kg) for iGlarLixi versus IDegAsp for all analyses (P < 0.05). Comparisons of hypoglycaemia were inconclusive owing to differences in definitions between studies. Adverse events were more frequent with iGlarLixi because of gastrointestinal intolerance. Conclusions: iGlarLixi appears to offer clinical benefit in glucose control and bodyweight change in people needing both basal and meal‐time intervention. [ABSTRACT FROM AUTHOR]

Objective: To scope the current published evidence on cardiovascular risk factors in rheumatoid arthritis (RA) focusing on the role of autoantibodies and the effect of antirheumatic agents. Methods: Two reviews were conducted in parallel: A targeted literature review (TLR) describing the risk factors associated with cardiovascular disease (CVD) in RA patients; and a systematic literature review (SLR) identifying and characterizing the association between autoantibody status and CVD risk in RA. A narrative synthesis of the evidence was carried out. Results: A total of 69 publications (49 in the TLR and 20 in the SLR) were included in the qualitative evidence synthesis. The most prevalent topic related to CVD risks in RA was inflammation as a shared mechanism behind both RA morbidity and atherosclerotic processes. Published evidence indicated that most of RA patients already had significant CV pathologies at the time of diagnosis, suggesting subclinical CVD may be developing before patients become symptomatic. Four types of autoantibodies (rheumatoid factor, anti-citrullinated peptide antibodies, anti-phospholipid autoantibodies, anti-lipoprotein autoantibodies) showed increased risk of specific cardiovascular events, such as higher risk of cardiovascular death in rheumatoid factor positive patients and higher risk of thrombosis in anti-phospholipid autoantibody positive patients. Conclusion: Autoantibodies appear to increase CVD risk; however, the magnitude of the increase and the types of CVD outcomes affected are still unclear. Prospective studies with larger populations are required to further understand and quantify the association, including the causal pathway, between specific risk factors and CVD outcomes in RA patients. [ABSTRACT FROM AUTHOR]

Background: Direct injection of corticosteroids into the joint is a standard treatment for knee osteoarthritis (OA). However, the treatment is somewhat controversial with regard to the benefit of both single and repeated injections; evidence that they are beneficial comes from small studies that show only modest improvements. The aim of this study was to estimate the short- and long-term clinical efficacy and safety of hylan G-F 20 versus intra-articular corticosteroids (IACS) for the treatment of pain in knee OA using Bayesian network meta-analysis. Methods: Based on a pre-specified protocol, MEDLINE, Embase, and CENTRAL were searched from inception to June 2018 to identify randomized controlled trials. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used to assess the included studies. Hylan G-F 20 and IACS were compared using Bayesian network meta-analysis. Efficacy was evaluated at 1, 3, and 6 months, and at the final follow-up for safety outcomes. A pain hierarchy was used to select 1 pain outcome per study. Results: Forty-two trials were included for analysis. The network meta-analysis of pain showed that hylan G-F 20 may be equivalent to IACS in the short-term, but by 6 months the benefit relative to IACS was statistically significant, standardized mean difference (95% credible interval): –0.13 (–0.26, –0.01). There were no statistical differences in adverse events. Conclusions: Hylan G-F 20 may perform better in relieving pain at 6 months post-injection compared to IACS. Both agents were relatively well tolerated, with no clear differences in safety. [ABSTRACT FROM AUTHOR]

Aims: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. Materials and Methods: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. Results: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was -0.36 (95% credible intervals -0.58, -0.14) % [-3.9 (-6.3, -1.5) mmol/mol] for HbA1c and -1.0 (-1.6, -0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial selfmonitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/ L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). Conclusions: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches. [ABSTRACT FROM AUTHOR]

Background: Direct injection of corticosteroids into the joint is a standard treatment for knee osteoarthritis (OA). However, the treatment is somewhat controversial with regard to the benefit of both single and repeated injections; evidence that they are beneficial comes from small studies that show only modest improvements. The aim of this study was to estimate the short- and long-term clinical efficacy and safety of hylan G-F 20 versus intra-articular corticosteroids (IACS) for the treatment of pain in knee OA using Bayesian network meta-analysis. Methods: Based on a pre-specified protocol, MEDLINE, Embase, and CENTRAL were searched from inception to June 2018 to identify randomized controlled trials. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used to assess the included studies. Hylan G-F 20 and IACS were compared using Bayesian network meta-analysis. Efficacy was evaluated at 1, 3, and 6 months, and at the final follow-up for safety outcomes. A pain hierarchy was used to select 1 pain outcome per study. Results: Forty-two trials were included for analysis. The network meta-analysis of pain showed that hylan G-F 20 may be equivalent to IACS in the short-term, but by 6 months the benefit relative to IACS was statistically significant, standardized mean difference (95% credible interval): –0.13 (–0.26, –0.01). There were no statistical differences in adverse events. Conclusions: Hylan G-F 20 may perform better in relieving pain at 6 months post-injection compared to IACS. Both agents were relatively well tolerated, with no clear differences in safety. [ABSTRACT FROM AUTHOR]

Introduction: No head-to-head trials compare iGlarLixi, a fixed-ratio combination of basal insulin (BI) and glucagon-like peptide-1 receptor agonist, with IDegAsp, a co-formulation of BI analog and meal-time insulin. Methods: A systematic literature search of randomized controlled trials (RCTs) of iGlarLixi and IDegAsp vs. comparators was carried out. Studies were compared by an ITC using a Bayesian framework. Results are given for all trials, Japanese trials, and international trials. Results: Eight RCTs (duration 24-30 weeks) were included. Change in HbA1c with iGlarLixi was greater, and bodyweight trajectory was more favorable than with IDegAsp for all analyses (Figure). A greater percentage of people achieved HbA1c target (<7.0 % [<53 mmol/mol]) with iGlarLixi in all trials (odds ratio [95% credible interval] 2.50 [1.06, 5.56]) and Japanese trials (2.17 [1.27, 3.70]), but was not confirmed in international trials (2.17 [0.42, 11.11]). Exploratory analysis suggested favorable differences in change in pre-meal self-measured plasma glucose (SMPG; all trials and international trials) and post-meal SMPG (all analyses) with iGlarLixi vs. IDegAsp. Hypoglycemia comparisons were inconclusive due to different definitions. Conclusion: iGlarLixi offers clinical benefit in glycemic control and weight change vs. IDegAsp in those requiring both basal plus meal-time insulin interventions. Disclosure: P. Home: Consultant; Self; American Diabetes Association, Kriya Technologies, Sanofi, Other Relationship; Self; Association of British Clinical Diabetologists, AstraZeneca, Novartis Malaysia, Sanofi, Research Support; Self; Sanofi. R. Mehta: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Speaker's Bureau; Self; Abbott, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc. K. Hafidh: None. O. Gurova: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, STADA, Takeda Pharmaceutical Co. A. Alvarez: Employee; Self; Sanofi. P. Serafini: Other Relationship; Self; Sanofi. M. Pourrahmat: Other Relationship; Self; Sanofi. Funding: Sanofi [ABSTRACT FROM AUTHOR]

In people with type 2 diabetes uncontrolled by GLP-1 RAs, fixed-ratio combination (FRC; basal insulin + GLP-1 RA) is a recommended option. A PICO-framework systematic review of RCTs followed by an ITC was performed to compare the efficacy and safety of the FRCs iGlarLixi (insulin glargine 100 U/mL + lixisenatide) and IDegLira (insulin degludec + liraglutide) in this population. A fixed effects model was used on the two eligible RCTs. Outcomes: change from baseline to week 26 in HbA1c, clinic fasting plasma glucose (FPG), self-monitored plasma glucose (SMPG), and body weight; proportion achieving HbA1c <6.5 or <7.0 %; hypoglycemia incidence. Baseline characteristics were similar across studies. Significant mean differences were seen in change in HbA1c and FPG favoring IDegLira, but not pre- or postprandial SMPG (breakfast or daily average) or weight (Table). Similar proportions achieved HbA1c targets. Hypoglycemia comparisons suffered from varying definitions, sulfonylurea (SU) use and eligibility, and few events in the GLP-1 RA arms (incidence: 32% [confirmed ≤3.1 mmol/L, 28% without SU] with IDegLira and 9% or 28% [symptomatic <3.0 or ≤3.9 mmol/L] with iGlarLixi). This ITC shows similar FRC HbA1c glycemic target achievement but suggests divergent differences in other glycemia results and hypoglycemia, likely due to different study design and titration application. Disclosure: P. Home: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Mundipharma International, Novartis AG, Sanofi. Research Support; Self; GlaxoSmithKline plc., Merck & Co., Inc., Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH. V.R. Aroda: Consultant; Self; Duke, Novo Nordisk Inc., Sanofi. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Applied Therapeutics, Fractyl Laboratories, Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; IMNE, Medscape. M. Fazeli: None. C. Whittington: Employee; Self; Sanofi US. H. Goswami: None. A. Shaunik: None. M. Pourrahmat: Other Relationship; Self; Sanofi US. L. Blonde: Advisory Panel; Self; AstraZeneca, Gilead Sciences, Inc. Consultant; Self; Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Janssen Scientific Affairs, LLC., Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Sanofi. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. Funding: Sanofi [ABSTRACT FROM AUTHOR]