Understanding Hispanic/Latino Participation in Clinical Trials and Observational Studies, and Strategies to Increase Participation: A Targeted Literature Review.

Hispanic/Latino representation in medical research remains poor. We describe factors affecting rates of recruitment, participation, adherence, and retention of Hispanics/Latinos in clinical studies in the United States and characterize proposed strategies to improve these rates. A targeted literature review was conducted. Relevant studies were identified from Embase, MEDLINE®, and CENTRAL from January 1, 2010 to September 4, 2020. Sixty-eight studies were included. Key facilitators to research involvement were establishing trust between research staff and participants, incorporating familism, and using culturally appropriate language. Common elements of successful strategies for improving research involvement included incorporating community partners, bilingual and culturally competent research staff, continuous engagement and building relationships between participants and staff, and incorporating Hispanic/Latino cultural values. There is no universal strategy to improve research involvement of Hispanics/Latinos. The best strategy is likely a combination of key elements from several strategies, tailored to each unique study population. Further research is needed.

Dronedarone versus sotalol in patients with atrial fibrillation: A systematic literature review and network meta-analysis.

BACKGROUND: There are limited comparative data on safety and efficacy within commonly used Vaughan-Williams (VW) class III antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in adults with atrial fibrillation (AF). HYPOTHESIS: We hypothesized that dronedarone and sotalol, two commonly prescribed VW class III AADs with class II properties, have different safety and efficacy effects in patients with nonpermanent AF. METHODS: A systematic literature review was conducted searching MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to June 15, 2021 (NCT05279833). Clinical trials and observational studies that evaluated safety and efficacy of dronedarone or sotalol in adults with AF were included. Bayesian random-effects network meta-analysis (NMA) was used to quantify comparative safety and efficacy. Where feasible, we performed sensitivity analyses by including only randomized controlled trials (RCTs). RESULTS: Of 3581 records identified through database searches, 37 unique studies (23 RCTs, 13 observational studies, and 1 nonrandomized trial) were included in the NMA. Dronedarone was associated with a statistically significantly lower risk of all-cause death versus sotalol (hazard ratio [HR] = 0.38 [95% credible interval, CrI: 0.19, 0.74]). The association was numerically similar in the sensitivity analysis (HR = 0.46 [95% CrI: 0.21, 1.02]). AF recurrence and cardiovascular death results were not significantly different between dronedarone and sotalol in all-studies and sensitivity analyses. CONCLUSION: The NMA findings indicate that, across all clinical trials and observational studies included, dronedarone compared with sotalol was associated with a lower risk of all-cause death, but with no difference in AF recurrence.

Digital Devices for Assessing Motor Functions in Mobility-Impaired and Healthy Populations: Systematic Literature Review.

BACKGROUND: With the advent of smart sensing technology, mobile and wearable devices can provide continuous and objective monitoring and assessment of motor function outcomes. OBJECTIVE: We aimed to describe the existing scientific literature on wearable and mobile technologies that are being used or tested for assessing motor functions in mobility-impaired and healthy adults and to evaluate the degree to which these devices provide clinically valid measures of motor function in these populations. METHODS: A systematic literature review was conducted by searching Embase, MEDLINE, CENTRAL (January 1, 2015, to June 24, 2020), the United States and European Union clinical trial registries, and the United States Food and Drug Administration website using predefined study selection criteria. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. RESULTS: A total of 91 publications representing 87 unique studies were included. The most represented clinical conditions were Parkinson disease (n=51 studies), followed by stroke (n=5), Huntington disease (n=5), and multiple sclerosis (n=2). A total of 42 motion-detecting devices were identified, and the majority (n=27, 64%) were created for the purpose of health care-related data collection, although approximately 25% were personal electronic devices (eg, smartphones and watches) and 11% were entertainment consoles (eg, Microsoft Kinect or Xbox and Nintendo Wii). The primary motion outcomes were related to gait (n=30), gross motor movements (n=25), and fine motor movements (n=23). As a group, sensor-derived motion data showed a mean sensitivity of 0.83 (SD 7.27), a mean specificity of 0.84 (SD 15.40), a mean accuracy of 0.90 (SD 5.87) in discriminating between diseased individuals and healthy controls, and a mean Pearson r validity coefficient of 0.52 (SD 0.22) relative to clinical measures. We did not find significant differences in the degree of validity between in-laboratory and at-home sensor-based assessments nor between device class (ie, health care-related device, personal electronic devices, and entertainment consoles). CONCLUSIONS: Sensor-derived motion data can be leveraged to classify and quantify disease status for a variety of neurological conditions. However, most of the recent research on digital clinical measures is derived from proof-of-concept studies with considerable variation in methodological approaches, and much of the reviewed literature has focused on clinical validation, with less than one-quarter of the studies performing analytical validation. Overall, future research is crucially needed to further consolidate that sensor-derived motion data may lead to the development of robust and transformative digital measurements intended to predict, diagnose, and quantify neurological disease state and its longitudinal change.

Risk Factors for Contracting Invasive Meningococcal Disease and Related Mortality: A Systematic Literature Review and Meta-analysis.

OBJECTIVES: To describe risk factors (RFs) and quantify their effects in invasive meningococcal disease (IMD) and associated mortality across all age groups based on the available published literature. METHODS: A systematic literature review (SLR) was conducted via MEDLINE® and Embase. Study selection, data extraction, and quality assessment were performed by two independent reviewers. Associations between RFs and outcomes were quantified via a meta-analysis (MA). RESULTS: Seventy-four studies (date range 1950 - 2018) were included in the SLR. Statistically significant RFs for contracting IMD identified from the SLR (within-study) included previous IMD infection and young age (0 - 4 years). MA indicated that significant RFs for contracting IMD (11 studies) were: HIV-positive status, passive smoke exposure, and crowded living space. In the MA for IMD-related mortality risk (11 studies), age 25 - 45 years (vs. 0 - 5 years) and serogroup C (vs. serogroup B) were significantly associated with increased risk. CONCLUSIONS: Previous findings of higher risk for IMD contraction with smoke exposure and crowded living conditions in children/adolescents have been extended by this SLR/MA to all age groups. We provide strong evidence for higher risk of IMD in HIV-positive individuals, and confirm previous findings of higher IMD-related mortality risk in adults aged 25 - 45.

Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence.

Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials (n = 7 studies), long-lasting effects (up to 6 months; n = 3), and substantial variation of placebo effect sizes across populations (n = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration (n = 6) and dilution of inflammatory mediators (n = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection versus oral; n = 4) and patient expectations (n = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects (n = 9), discontinuation of intra-articular saline as an appropriate placebo (n = 5), and inclusion of 'no treatment' or sham injection as a control (n = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.

A fresh look at the role of spiramycin in preventing a neglected disease: meta-analyses of observational studies.

PURPOSE: We aimed to investigate the effect of antepartum treatment with spiramycin with or without subsequent pyrimethamine-sulfonamide-folinic acid, compared to no treatment, on the rate of mother-to-child transmission (MTCT) of Toxoplasma gondii (T. gondii) and incidence/severity of sequelae in the offspring. METHODS: Embase and PubMed were searched for literature on spiramycin in pregnant women suspected/diagnosed with T. gondii infection. Meta-analyses were performed using random-effects model. RESULTS: Thirty-three studies (32 cohorts and 1 cross-sectional study), with a total of 15,406 mothers and 15,250 offspring, were pooled for analyses. The MTCT rate for all treated patients was significantly lower than the untreated [19.5% (95% CI 14-25.5%) versus 50.7% (95% CI 31.2-70%), p < 0.001]. The transmission rate in patients on spiramycin monotherapy was also significantly lower than untreated [17.6% (95% CI 9.9-26.8%) versus 50.7% (95% CI 31.2-70%), p < 0.001]. CONCLUSION: Results indicate significant reduction in MTCT rates following spiramycin treatment of suspected/diagnosed maternal T. gondii infection.

Cardiovascular Safety and Hemostatic Efficacy of Topical Epinephrine in Children Receiving Zirconia Crowns.

OBJECTIVE: The primary aim of this study was to determine the cardiovascular safety of topical racemic epinephrine pellets by measuring heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure in children receiving dental care under general anesthesia. The secondary aim was to assess clinical efficacy by measuring time to reach adequate hemostasis. METHODS: For this pilot study utilizing a split-mouth randomized design, 13 patients requiring prefabricated zirconia crowns on both primary maxillary first molars were recruited. Patients received continuous infusions of propofol and remifentanil with 50-70% inhaled nitrous oxide and oxygen. After randomization and tooth preparation, either saline pellets (control) or racemic epinephrine pellets (experimental) were applied directly to gingival tissue. Vital signs were recorded for 5 minutes. The procedure was repeated on the contralateral side using the alternative (control or experimental) treatment. RESULTS: Topical racemic epinephrine compared to saline produced a significantly larger decrease in mean diastolic blood pressure (-11.1% vs -3.9%; P < .01) and mean arterial pressure (-8.1% vs -2.1%; P < .01), although all noted decreases in cardiovascular variables were clinically insignificant. All experimental treatment teeth achieved adequate hemostasis after 2.2 minutes. Only 5 of the 13 control treatment teeth achieved adequate hemostasis during the 5-minute observation period (1.6 vs 4.2 minutes; P = .01). CONCLUSION: Overall, we conclude that use of topical racemic epinephrine pellets did not result in adverse cardiovascular effects and hemostasis was reached more quickly and predictably compared to saline pellets.

Cardiovascular Disease in Rheumatoid Arthritis: Risk Factors, Autoantibodies, and the Effect of Antirheumatic Therapies.

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.

Health state utility values by cancer stage: a systematic literature review.

OBJECTIVES: Cancer diagnoses at later stages are associated with a decrease in health-related quality of life (HRQOL). Health state utility values (HSUVs) reflect preference-based HRQOL and can vary based on cancer type, stage, treatment, and disease progression. Detecting and treating cancer at earlier stages may lead to improved HRQOL, which is important for value assessments. We describe published HSUVs by cancer type and stage. METHODS: A systematic review was conducted using Embase, MEDLINE®, EconLit, and gray literature to identify studies published from January 1999 to September 2019 that reported HSUVs by cancer type and stage. Disutility values were calculated from differences in reported HSUVs across cancer stages. RESULTS: From 13,872 publications, 27 were eligible for evidence synthesis. The most frequent cancer types were breast (n = 9), lung (n = 5), colorectal (n = 4), and cervical cancer (n = 3). Mean HSUVs decreased with increased cancer stage, with consistently lower values seen in stage IV or later-stage cancer across studies (e.g., - 0.74, - 0.44, and - 0.51 for breast, colorectal, and cervical cancer, respectively). Disutility values were highest between later-stage (metastatic or stage IV) cancers compared to earlier-stage (localized or stage I-III) cancers. CONCLUSIONS: This study provides a summary of HSUVs across different cancer types and stages that can inform economic evaluations. Despite the large variation in HSUVs overall, a consistent decline in HSUVs can be seen in the later stages, including stage IV. These findings indicate substantial impairment on individuals' quality of life and suggest value in early detection and intervention.

Efficacy and safety of a single intra-articular injection of 6 ml Hylan G-F 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis : C-SOUND study, a 26-week multicenter double-blind randomized placebo-controlled trial in China.

BACKGROUND: Single 6 ml Hylan G-F 20 injection, is indicated for knee osteoarthritis patients who have failed to respond to non-pharmacologic therapy and/or simple analgesics. To obtain more thorough understanding of the clinical efficacy and safety, a randomized clinical trial was conducted comparing intra-articular (IA) administration of single 6 ml Hylan G-F 20 injection versus placebo in knee OA patients of Chinese ethnicity. METHODS: This was a randomized, multi-center, double-blind, placebo-controlled clinical trial conducted in 21 centers across China. Four hundred forty adults with knee OA received a single 6 ml Hylan G-F 20 or placebo injection and were evaluated for clinical efficacy and safety outcomes over 26 weeks. Western Ontario and McMaster Universities OA (WOMAC) A1 index, treatment-emergent adverse events (TEAEs) and standard safety parameters were measured at pre-injection, and at weeks 1, 4, 8, 12, 16, 20 and 26 post-injection. RESULTS: Four hundred forty patients (male: 98 [22.3%]; female: 342 [77.7%]) were randomized. The mean age [standard deviation (SD)] was 61.5 (7.9) years. All patients were of East Asian ethnicity. Mean WOMAC A1 score at baseline was 5.3 (1.2) and 5.2 (1.3) in single 6 ml Hylan G-F 20 injection and placebo groups, respectively. Significant reductions of WOMAC A1 score were observed in both treatment groups when compared to baseline at 26 weeks post-injection, with the mean reduction of [standard error (SE)/percentage] -2.146 (0.108)/- 40.5% and - 2.271 (0.110) /- 43.7% in the single 6 ml Hylan G-F 20 injection and the placebo groups, respectively. Additionally, clinically important reductions in pain at 26 weeks was reported in 67.0 and 68.2% in single 6 ml Hylan G-F 20 injection and placebo groups (p = 0.36). Regarding safety, TEAEs were similar between the two treatment groups (hylan G-F 20 single: 61.5%; placebo: 64.5%). CONCLUSIONS: While the magnitude of the effect of a single 6 ml Hylan G-F 20 injection in this study is consistent with previously published literature with respect to the efficacy and safety of the drug, the current study shows a strong IA placebo effect and did not established superiority of single 6 ml Hylan G-F 20 injection over IA placebo in Chinese knee OA patients. TRIAL REGISTRATION: Prospectively registered Jun 16, 2017 at www.clinicaltrials.gov ( NCT03190369 ).

Rheumatoid arthritis-associated interstitial lung disease: epidemiology, risk/prognostic factors, and treatment landscape.

OBJECTIVES: To summarise the epidemiology, risk and prognostic factors, and treatment landscape of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: Targeted and systematic literature reviews were conducted to characterise the epidemiology and treatment landscape associated with RA-ILD, respectively. MEDLINE®, Embase, and CENTRAL were searched via OvidSP in March 2019 and December 2018. The results were narratively summarised. RESULTS: A total of 24 and 20 publications were captured through targeted and systematic literature review, respectively. No randomised controlled trials were identified; publications were observational cohort studies, cross-sectional, or case-control. Unadjusted incidence of interstitial lung disease (ILD) ranged from 1.3/1,000 person-years for interstitial pneumonia-type ILD to 5.0/1,000 person-years for 'probable or definite ILD'. Prevalence of ILD ranged from 1.8% to 67% (median: 24.9%) and varied with case definition and sample size. Few publications identified the same risk and prognostic factors; age, male sex, duration of disease, and antibodies to cyclic citrullinated peptides were the most frequently reported risk factors for development of RA-ILD, and age was the most common predictor of mortality. Despite identification of a variety of pharmacotherapeutic interventions, assessment of the comparative efficacy and safety of the available treatments were difficult due to heterogenous reporting of outcomes and small sample size. CONCLUSIONS: A wide range of estimates were identified for incidence and prevalence of RA-ILD. Further, there was no consensus on risk and prognostic factors. Sufficiently powered clinical trials are needed to confirm the findings of the observational studies with respect to efficacy and safety of current treatments.

Efficacy and Safety of Antiplatelet Therapies in Symptomatic Peripheral Artery Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Clopidogrel monotherapy is guideline-recommended in symptomatic peripheral artery disease (PAD). The advent of new antithrombotic strategies prompts an updated analysis of available evidence on antiplatelet therapy for PAD. METHODS: We searched MEDLINE, Embase and CENTRAL through January 2019 for randomised controlled trials and observational studies comparing antiplatelet therapies as monotherapy, dual therapy, or combination with anticoagulants. Efficacy (major adverse cardiovascular events, acute or chronic limb ischaemia, vascular amputation, peripheral revascularisation) and safety (all-cause mortality and overall bleeding) outcomes were evaluated via Bayesian network meta-analyses. RESULTS: We analysed 26 randomised controlled trials. Clopidogrel (hazard ratio, HR, 0.78; 95% credible interval [CrI] 0.65-0.93) and ticagrelor (HR 0.80; 95% CrI 0.65-0.98) significantly reduced major adverse cardiovascular events risk compared with aspirin. No significant difference was observed for dual antiplatelet therapy with clopidogrel and aspirin. Vorapaxar significantly reduced limb ischaemia and revascularisation compared with placebo, while dual antiplatelet therapy with clopidogrel and aspirin showed a trend for reduced risk of amputation compared with aspirin (risk ratio 0.68; 95% CrI 0.43-1.04). For all-cause mortality, picotamide, vorapaxar, dipyridamole with aspirin, and ticlopidine showed a significantly lower risk of all-cause mortality vs aspirin. Clopidogrel and ticagrelor showed similar overall bleeding risk vs aspirin, while dual antiplatelet therapy with clopidogrel and aspirin significantly increased bleeding risk. CONCLUSION: This updated network meta-analysis confirms that clopidogrel significantly decreases the risk of major adverse cardiovascular events compared with aspirin, without increasing bleeding risk. Clopidogrel should remain a mainstay of PAD treatment, at least in patients at higher bleeding risk.

The Effect of Massage on the Cardiac Autonomic Nervous System and Markers of Inflammation in Night Shift Workers: a Pilot Randomized Crossover Trial.

BACKGROUND: Shift work is a necessary part of many industries; however, it can have detrimental effects on health over time. PURPOSE: This study investigated the effect of a massage intervention on the cardiac autonomic activity and blood inflammatory markers of healthy medical residents working night shifts. SETTING: This trial was conducted at British Columbia Children's and Women's Hospital between February 2014 and June 2016. PARTICIPANTS: Included participants were generally healthy medical residents and were working rotating night shifts on a regular basis. RESEARCH DESIGN: This was a randomized, controlled, crossover, open-label trial (NCT02247089). INTERVENTIONS: Participants received either a 30-min massage intervention or reading control after consecutive periods of night shift. MAIN OUTCOME MEASURES: The primary outcome was high frequency, a proxy for the cardiac parasympathetic activity, measured via heart rate variability. Secondary outcomes included other heart rate variability measures, blood markers of inflammation, and blood pressure. RESULTS: Twelve participants were recruited (nine female) with median age of 28 years. There was no significant difference between the massage intervention and the reading control for the primary outcome, (median relative change between pre- and postmassage [interquartile range]: 62% [-1 to 150], pre- and postreading: 14% [-10 to 51], p = .16). Similarly, there was no difference with respect to blood inflammatory markers and blood pressure. Median high frequency significantly increased between pre- and postmassage (185 vs. 358 ms2, p = .04). CONCLUSION: This pilot study found no statistically significant difference between the massage intervention and the reading control; however, we did observe a significant increase in median high frequency from before massage to after massage, indicative of increased parasympathetic activity. This study may help inform planning of larger trials evaluating massage interventions on the activity of the autonomic nervous system and managing shift work stress.

Efficacy and safety of iGlarLixi versus IDegLira in adults with type 2 diabetes inadequately controlled by glucagon-like peptide-1 receptor agonists: a systematic literature review and indirect treatment comparison.

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 self-monitored 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.

Comparative efficacy and safety of current therapies for early rheumatoid arthritis: a systematic literature review and network meta-analysis.

OBJECTIVES: This systematic literature review (SLR) and network meta-analysis (NMA) was aimed at comparing the relative efficacy and safety of abatacept (ABA) with other currently recommended therapies for patients with early RA. METHODS: An SLR (January 1998 to June 2018) was conducted including MEDLINE®, Embase, and CENTRAL databases, and grey literature. Population was adults with active RA for ≤2 years treated with biologic DMARDs as monotherapy or in combination with conventional DMARDs. A Bayesian NMA was performed using randomised controlled trials (RCTs) and comparisons for ACR50, DAS28 remission, withdrawal due to adverse events and total withdrawal where reported. RESULTS: Ninety publications pertaining to 69 studies (43 RCTs and 26 observational studies) were identified. Twenty-eight RCTs were eligible to be included in the NMA. ABA as monotherapy was similar to the combination of ABA+methotrexate (MTX) for ACR50 (RR: 0.82 [95% CI 0.51-1.35]), and DAS28 remission (RR: 0.69 [95% CI 0.37-1.3]), as well as for withdrawal due to AEs (RR: 2.35 [95% CI 0.69-7.38]) and all-cause withdrawal (RR: 1.73 [95% CI 0.905-3.35]). ABA as monotherapy and ABA+MTX were both comparable to all other therapies for the main efficacy and safety outcomes. Observational study data reported was congruous with the RCT analysis. CONCLUSIONS: The results of this NMA show similar efficacy and safety between ABA (as monotherapy or in combination with MTX) and other biologics in early RA. Further comparison of different treatment options for early RA is warranted as growing research provides evidence for the application of new novel therapies for RA.

The effects of antimuscarinic agents on the activity of the cardiac autonomic nervous system in children with functional overactive bladder.

BACKGROUND: Functional overactive bladder disorder is one of the most prevalent presentations of bladder and bowel dysfunction in children, and it is associated with lower overall cardiac autonomic and parasympathetic activity. Antimuscarinics are the most frequently used pharmacological agents for treatment of children with functional overactive bladder disorder; however, there is a gap in the literature in describing the effect of antimuscarinics on the autonomic profile of this population. OBJECTIVE: The aim of the study was to assess the cardiac parasympathetic activity before and after 12 weeks of oxybutynin treatment in children with overactive bladder. METHODS: This was a single-institution prospective cohort study. Cardiac autonomic activity was assessed during storage and voiding phases of the bladder function via spectral analysis of heart rate variability and impedance cardiography. The primary outcome measure was high frequency, a proxy for parasympathetic nervous system activity. Parameters of uroflow study, severity of symptoms, and quality of life outcomes were also assessed. RESULTS: Ten children (7 females) diagnosed with overactive bladder with a median age of 10 years (range = 6-14) were followed up for a median treatment duration of 11.8 weeks (range = 6-19.4). After treatment, there was a significant reduction in high frequency during the storage phase (median change = -24.17%, p = 0.047). No change was observed in the other outcome measures except for the overall Symptom Score for Dysfunctional Elimination Syndrome after treatment (5-point decrease, p = 0.034) (Summary Table). DISCUSSION: The findings of the present follow-up study suggest that the use of oxybutynin in children with overactive bladder is associated with a significant reduction in the activity of the parasympathetic nervous system. The clinical implications of this finding are important because similar autonomic profiles (as markers of chronic stress) have been shown to be associated with increased inflammation and are found in major chronic diseases. The authors caution making a clinical connection between the heart rate variability profile of the patients in this study and patients with chronic diseases because oxybutynin is usually not administered as long-term treatment for overactive bladder. CONCLUSION: Use of oxybutynin was associated with reduction in cardiac parasympathetic activity of children with functional overactive bladder. Further investigation into the role of the autonomic nervous system as a treatment target in the management of these children is warranted.

Treatment modifying factors of biologics for psoriatic arthritis: a systematic review and Bayesian meta-regression.

OBJECTIVES: The aim of this study was to explore factors that modify treatment effects of non-conventional biologics versus placebo in patients with psoriatic arthritis. METHODS: A systematic literature review and meta-regression was conducted. The biologics included etanercept, infliximab, adalimumab, golimumab, certolizumab, ustekinumab, tocilizumab, anakinra, abatacept, rituximab, and secukinumab. Outcomes included American College of Rheumatology (ACR) 20 and 50, Psoriasis Area Severity Index (PASI) 75, and 36-Item Short Form Health Survey (SF-36) Physical and Mental Component Summaries (PCS and MCS). RESULTS: Twelve RCTs were eligible for meta-regression. Treatment effects for ACR-20 at 12 weeks were higher in trials with longer disease durations (OR=2.94), and lower in trials enrolling older patients (OR=0.48), and those recently published (OR=0.49). Treatment effects for ACR-50 at 12 weeks were higher in trials with more males (OR=2.27), but lower in trials with high prior anti-TNF use (OR=0.28) and recently published trials (OR=0.37). For PASI-75, trials with more male patients (24 weeks: OR=2.56), and with higher swollen and tender joint counts (12 weeks: OR=8.33; 24 weeks: OR=14.44) showed higher treatment effects, and trials with high prior anti-TNF use had lower effects (OR=0.41). Treatment effects for SF-36 PCS at 24 weeks were higher in trials with longer psoriasis disease durations (OR=2.95) and PsA disease durations (OR=4.76), and those published earlier (OR=4.19). CONCLUSIONS: Our analyses show that differences in baseline characteristics may explain some of the differences in response to biologics versus placebo across different trials. Accounting for these factors in future studies will likely be important.

Cardiac Autonomic Function at Baseline and under Stress and Its Relationship to Circulatory Markers of Inflammation in Obese Compared to Nonobese Children: A Pilot Study.

BACKGROUND/AIMS: The autonomic nervous system (ANS) provides neurogenic control of inflammatory reactions. ANS changes in obesity may result in inflammation. This study sought to gain insight into cardiac autonomic dysfunction and inflammation in childhood obesity, and to gather pilot data on the potential relationship between altered ANS and inflammation. METHODS: Fifteen obese children and adolescents without metabolic complications and 15 nonobese controls underwent heart rate variability and impedance cardiography testing during rest, mental stress, and physical stress. Inflammatory cytokines and immune reactivity were measured. RESULTS: There was no statistically significant difference between groups in cardiac ANS testing at rest or in response to stress. Median high-sensitivity C-reactive protein (hsCRP) was higher in the obese group [obese 2.6 mg/l (IQR 1.6-11.9); nonobese 0.3 mg/l (IQR 0.2-0.7); p < 0.001]. Interleukin-6 and tumour necrosis factor-α were similar between groups. Immune reactivity testing (in vitro Toll-like receptor stimulation) revealed a strong, but comparable, inflammatory response in both groups. CONCLUSIONS: Obese children and adolescents without metabolic complications did not have cardiac ANS dysfunction. While hsCRP was elevated, systemic cytokines were not raised. Compared to prior studies, which often focused on children with obesity and its complications, it is encouraging that obese children without metabolic complications may not yet have autonomic dysfunction.

Cardiac Autonomic Nervous System Activity in Children with Bladder and Bowel Dysfunction.

PURPOSE: Bladder and bowel dysfunction is a common reason for referral to pediatric urology. The role of the autonomic nervous system in the pathogenesis of bladder and bowel dysfunction has not been well investigated. We compared autonomic nervous system activity in children with bladder and bowel dysfunction to that in healthy controls. We hypothesized that children with dysfunction have a different autonomic profile as measured by parameters from spectral analysis of heart rate variability and impedance cardiography. MATERIALS AND METHODS: We recruited 40 children, including 25 girls, with a median age of 10 years (range 5 to 18) in whom bladder and bowel dysfunction was clinically diagnosed by a validated questionnaire and 19 healthy controls, including 9 girls, with a median age of 8 years (range 5 to 16). Cardiac autonomic activity was assessed at baseline and during voiding. The primary outcome measures were the main parameters of heart rate variability, including total power and high frequency, as well as pre-ejection period and heart rate. RESULTS: Comparison of outcomes at baseline showed significantly lower total power and high frequency heart rate variability in bladder and bowel dysfunction cases (p = 0.001 and 0.002, respectively). Children with dysfunction also showed a significantly smaller decrease in sympathetic nervous system activity during voiding (p = 0.05). CONCLUSIONS: Our results demonstrate that compared to healthy controls children with bladder and bowel dysfunction show a different cardiac autonomic profile at rest and in response to voiding. This difference may be used in future studies to further clarify the pathophysiology of bladder and bowel dysfunction, and introduce novel treatment targets to manage the condition.

The Effect of Head Massage on the Regulation of the Cardiac Autonomic Nervous System: A Pilot Randomized Crossover Trial.

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.