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Many treatments have been proposed for adult obstructive sleep apnea (OSA), but no comprehensive comparison of all interventions has been performed. We aimed to compare and rank the effectiveness of all minimally invasive treatments for adult OSA in a systematic review and network meta-analysis. Literature was searched within Ovid MedLine, EMBASE Classic+Embase, Cochrane library, and Cochrane Database of Systematic Reviews from inception to Aug 9th, 2016 for randomized controlled trials comparing minimally invasive treatments for adult OSA. The outcomes were the changes in apnea-hypopnea index (AHI) and Epworth sleepiness scale (ESS). Frequentist approach to network meta-analysis was used and treatment hierarchy was summarized according to the surfaces under the cumulative ranking curves. Eighty-nine randomized controlled trials comprising 6346 adult OSA participants and comparing 18 different interventions were included. In comparison with no treatment, positive airway pressure (PAP) was most effective in reducing AHI (23.28 [weighted mean difference]; 95% confidence interval: 19.20-27.35). PAP was ranked first followed by mandibular advancement device (MAD) in reducing AHI. Exercise was ranked first followed by cervico-mandibular support collar in reducing ESS. Considering the effectiveness in reducing both AHI and ESS, PAP was ranked the best, followed by MAD and positional therapy, while lifestyle modification alone was the least effective intervention. Interventions that are highly effective in reducing objective laboratory-derived AHI do not demonstrate equivalent effectiveness in improving patients' subjective sleepiness. Future improvement of the interventions is necessary to simultaneously improve both objective and subjective outcomes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical- and cost-effectiveness at 2-year follow-up of providing individual, supervised exercise physiotherapy and/or manual physiotherapy in addition to usual medical care.Method: People with hip or knee osteoarthritis meeting the American College of Rheumatology clinical diagnostic criteria were randomised (1:1, concealed, assessor-blinded) to four groups: usual medical care; supervised exercise physiotherapy; manual physiotherapy; or combined exercise and manual physiotherapy. Physiotherapy group participants were provided 10 50-min treatment sessions including booster sessions at 4 and 13 months, in addition to usual care. The primary outcome at 2-year follow-up was incremental cost-utility ratio (ICUR) of each physiotherapy intervention in addition to usual care, compared with usual care alone, from the health system and societal perspectives. To allow interpretation of negative ICURs, we report incremental net benefit (INB). The primary clinical outcome was the Western Ontario and McMaster Osteoarthritis Index (WOMAC).Results: Of 206 patients, 186 (90·3%) were retained at 2-year follow-up. Exercise physiotherapy and manual physiotherapy dominated usual care, demonstrating cost savings; combined therapy did not. Exercise therapy had the highest incremental net benefits (INBs), statistically significant at all willingness-to-pay (base-case: societal New Zealand (NZ)$6,312, 95%CI 334 to 12,279; health system NZ$8,065, 95%CI 136 to 15,994). Clinical improvements were superior to usual care only in the exercise physiotherapy group (-28.2 WOMAC points, 95%CI -49.2 to -7.1). No serious adverse events were recorded.Conclusion: Individually supervised exercise therapy is cost-effective and clinically effective in addition to usual medical care at 2-year follow-up, and leads to cost savings for the health system and society.Trial Registration: Prospectively registered with the Australian NZ Clinical Trials Registry, reference ACTRN12608000130369. [ABSTRACT FROM AUTHOR]

Background Hospitalized patients with cancer experience a high symptom burden, which is associated with poor health outcomes and increased health care utilization. However, studies investigating symptom monitoring interventions in this population are lacking. We conducted a pilot randomized trial to assess the feasibility and preliminary efficacy of a symptom monitoring intervention to improve symptom management in hospitalized patients with advanced cancer. Patients and methods We randomly assigned patients with advanced cancer who were admitted to the inpatient oncology service to a symptom monitoring intervention or usual care. Patients in both arms self-reported their symptoms daily (Edmonton Symptom Assessment System and Patient Health Questionnaire-4). Patients assigned to the intervention had their symptom reports presented graphically with alerts for moderate/severe symptoms during daily team rounds. The primary end point of the study was feasibility. We defined the intervention as feasible if >75% of participants hospitalized >2 days completed >2 symptom reports. We observed daily rounds to determine whether clinicians discussed and developed a plan to address patients' symptoms. We used regression models to assess intervention effects on patients' symptoms throughout their hospitalization, readmission risk, and hospital length of stay (LOS). Results Among 150 enrolled patients (81.1% enrollment), 94.2% completed >2 symptom reports. Clinicians discussed 60.4% of the symptom reports and developed a plan to address the symptoms highlighted by the symptom reports 20.8% of the time. Compared with usual care, intervention patients had a greater proportion of days with lower psychological distress (B  =   0.12, P  =   0.008), but no significant difference in the proportion of days with improved Edmonton Symptom Assessment System-physical symptoms (B  =   0.07, P  =   0.138). Intervention patients had lower readmission risk (hazard ratio = 0.68, P  =   0.224), although this difference was not significant. We found no significant intervention effects on hospital LOS (B  =   0.16, P  =   0.862). Conclusions This symptom monitoring intervention is feasible and demonstrates encouraging preliminary efficacy for improving patients' symptoms and readmission risk. ClinicalTrials.gov identifier NCT02891993 [ABSTRACT FROM AUTHOR]

Abstract Background aims Cytokine-induced killer (CIK) cells are the most commonly used cellular immunotherapy for multiple tumors. To further confirm whether chemotherapy with CIK cells improves clinical effectiveness and to reveal its optimal use in non–small cell lung cancer (NSCLC), we systematically reevaluated all relevant studies. Methods We collected all studies about chemotherapy with CIK cells for NSCLC from the Medline, Embase, Web of Science, China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journals Full-Text Database (VIP), Wanfang Data, China Biological Medicine Database (CBM), Cochrane Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and U.S. clinical trials. We evaluated their quality according to the Cochrane evaluation handbook of randomized controlled trials (RCTs) (version 5.1.0), extracted the data using a standard data extraction form, synthesized the data using meta-analysis and finally rated the evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Thirty-two RCTs with 2250 patients were included, and most trials had unclear risk of bias. The merged risk ratios values and their 95% confidence intervals of meta-analysis for objective response rate, disease control rate, 1- and 2-year overall survival rates, 1- and 2-year progression-free survival rates were as following: 1.45 (1.31–1.61), 1.26 (1.16–.37), 1.42 (1.23–1.63), 2.06 (1.36–3.12), 1.93 (1.38–2.69) and 3.30 (1.13–9.67). Compared with chemotherapy alone, all differences were statistically signif i cant. CIK cells could increase the CD3+ T cells, CD3+ CD4+ T cells, NK cells and the ratio of CD4+/CD8+ T cells. The chemotherapy with CIK cells had a lower risk of hematotoxicity, gastrointestinal toxicity, liver injury and a higher fever than that of chemotherapy alone. The evidence quality was "moderate" to "very low." Conclusions The available moderate evidences indicate that chemotherapy with CIK cells, especially autologous CIK cells, can significantly improve the tumor responses, 1- and 2-year overall and progression-free survival rates in patients with advanced NSCLC. This treatment does have a high risk of fever. The optimal use may be treatment with one or two cycles and in combination with vinorelbine and cisplatin, paclitaxel and cisplatin, or docetaxel and cisplatin. [ABSTRACT FROM AUTHOR]

Abstract Objectives To compare immunogenicity, reactogenicity and acceptability of high- and standard-dose trivalent inactivated influenza vaccine (HDTIV, SDTIV) in 18- to 64-year-olds. Methods We randomized 18- to 64-year-olds to HDTIV or SDTIV in two consecutive years. We collected serum on days 0 and 21, measured haemagglutination inhibition geometric mean titres (GMT) and compared seroconversion, day 21 titres, seroprotection, reactogenicity and acceptability. Results Immunogenicity was evaluable in 42 of 47 2014 participants, all 33 both-year participants and 87 of 90 2015-only participants. First-dose HDTIV recipients experienced seroconversion more frequently than SDTIV recipients to A(H3N2) in 2014 (13/21, 62% vs. 4/21, 19%, p 0.01) and to all vaccine strains in 2015: (A(H1N1): 24/42, 57% vs. 15/59, 25%; A(H3N2): 42/42, 100% vs. 47/59, 80%; B: 25/42, 60% vs. 13/59, 22%; all p <0.01). Day 21 haemagglutination inhibition GMT were higher in first and two sequential-year HDTIV vs. SDTIV recipients: A(H1N1): GMT 749 and 768 vs. 384 (p <0.0001, p 0.002); A(H3N2): 1238 and 956 vs. 633 (p 0.0003, p 0.1); and B: 1113 and 1086 vs. 556 (p 0.0005, p 0.02). HDTIV was more reactogenic (local pain score 3 vs. 1 of 10 on day 0/1, p 0.0003), but recipients were equally willing to be revaccinated (HDTIV: 76/83 (92%); SDTIV: 76/80 (95%), p 0.54). The ratios of day 21 GMT in SDTIV recipients vaccinated in 0 to 4 prior years to those in SDTIV and HDTIV recipients vaccinated in 15 or more prior years were A(H1N1): 3.73 and 1.38; A(H3N2) 3.07 and 1.16; and B: 2.01 and 1.21. Conclusions HDTIV is more immunogenic and reactogenic and as acceptable as SDTIV in 18- to 64-year-olds. [ABSTRACT FROM AUTHOR]

Abstract Objectives To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. Methods We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. Results Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9–13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45–0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. Conclusions Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women. [ABSTRACT FROM AUTHOR]

Background Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Methods We carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0–10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference −0.8, 95% confidence interval, −1.3 to −0.4, P  < 0.01) and when compared with the HR+RMSTD group (difference −0.6, −1.1 to −0.1, P  = 0.05). In all, 47.2% (42.7%−51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results. [ABSTRACT FROM AUTHOR]

The design of clinical trials on Hepatic Encephalopathy (HE) is not an easy task, in fact there are several issues related to the performance of clinical trials in HE that have impeded progress in the field, mainly because most of the studies on HE therapy were performed before the era of rigorous Randomized Controlled Trials (RCTs). In this review we discuss the major problems affecting previously published trials on HE treatments aiming to provide evidences, suggestions and indications to prepare well designed RCTs in three different settings: (1) management of hospitalized patients with episodic HE; (2) secondary prophylaxis in patients following an episode of HE; and (3) management of minimal/covert HE. [ABSTRACT FROM AUTHOR]

Highlights • There is a close interaction between insomnia and pain severity/disability. • CBT-I can improve sleep and pain interference in chronic spinal pain. • Clinical implication 1: combined approach may improve pain, sleep and function. • Clinical implication 2: may lead to new treatment guidelines for professionals. Abstract Background Insomnia is a highly prevalent and debilitating comorbidity that is often not addressed in therapy for chronic spinal pain (CSP). Given the close interaction between insomnia and CSP severity and related disability, targeting sleep problems during therapy could improve treatment outcomes in these patients. Objective Can cognitive behavioral therapy for insomnia (CBT-I) combined with the modern neuroscience approach (i.e. pain neuroscience education and cognition-targeted exercise therapy) reduce pain and improve sleep, physical activity and function in people with CSP and comorbid insomnia? Methods Participants: One-hundred-twenty participants with chronic spinal pain and comorbid insomnia Intervention: CBT-I combined with the modern neuroscience approach (experimental) compared to the modern neuroscience approach alone (control). Both interventions start with three sessions of pain neuroscience education, followed by six sessions of CBT-I and nine sessions of cognition-targeted exercise therapy in the experimental group, or 15 sessions of cognition-targeted exercise therapy in the control group. Measurements Primary outcome measure: self-reported pain severity (Brief Pain Inventory). Secondary outcome measures: pain sensitivity (pressure pain thresholds, and online questionnaires), sleep-related outcomes (home-based polysomnography and online questionnaires), physical activity (actigraphy), and function (online questionnaires). Online questionnaires will be completed at baseline, directly post-treatment, and at 3, 6 and 12 months post-treatment. Polysomnography, pressure pain thresholds and actigraphy will be carried out at baseline, post-treatment and at 12 months follow-up. Discussion Findings may provide (1) a novel therapeutic approach for people with CSP and comorbid insomnia to improve pain, sleep, physical activity and function, and (2) new treatment guidelines for professionals. Trial registration Clinicaltrials.gov NCT03482856 (https://clinicaltrials.gov/ct2/show/NCT03482856). [ABSTRACT FROM AUTHOR]

Background: Vitamin D insufficiency is common in older people and may lead to increased bone resorption, bone loss, and increased falls and fractures. However, clinical trials assessing the effect of vitamin D supplementation on bone mineral density (BMD) have yielded conflicting results. Objectives: This study examined the effect of vitamin D supplementation on BMD at the hip, using dual-energy X-ray absorptiometry. Methods: A total of 379 adults aged ≥70 y (48% women; mean age: 75 y) from the northeast of England were randomly allocated to 1 of 3 doses of vitamin D3 [12,000 international units (IU), 24,000 IU, or 48,000 IU] given once a month. The primary outcome was change in BMD (ΔBMD) at the hip. Secondary endpoints comprised the dose effects on femoral neck BMD, falls, circulating calciotropic hormones, bone turnover markers, and adverse events. Results: The mean ± SD baseline plasma 25-hydroxyvitamin D [25(OH)D] concentration was 40.0 ± 20.1 nmol/L, which increased after 12 mo to a mean 25(OH)D of 55.9, 64.6, or 79.0 nmol/L for participants receiving a monthly dose of 12,000, 24,000, or 48,000 IU, respectively (P < 0.01 for difference). There was no between-group difference in ΔBMD. However, parathyroid hormone concentrations decreased in all 3 groups, with a significantly greater decrease in the 48,000-IU group compared with the 12,000-IU group (P < 0.01). There were no differences in any adverse events between groups, with 3 cases of hypercalcemia, none of nephrolithiasis, and 249 falls observed. Conclusions: There was no difference in change in BMD over 12 mo between the 3 doses of vitamin D, suggesting no effect of the intervention or a similar attenuation of the anticipated decrease in BMD over 12 mo. The treatment was safe and effective in increasing plasma 25(OH)D concentrations, with no dose-related adverse events [ABSTRACT FROM AUTHOR]

Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4-24.8 μg/L) increase in CSF selenium, distributed across selenoproteins and inorganic species. Reclassifying subjects as either responsive or non-responsive based on elevation in CSF selenium concentrations revealed that responsive group did not deteriorate in Mini-Mental Status Examination (MMSE) as non-responsive group (p = 0.03). Pooled analysis of all samples revealed that CSF selenium could predict change in MMSE performance (Spearman's rho = 0.403; p = 0.023). High-dose sodium selenate supplementation is well tolerated and can modulate CNS selenium concentration, although individual variation in selenium metabolism must be considered to optimize potential benefits in AD. The Vel002 study is listed on the Australian and New Zealand Clinical Trials Registry ( http://www.anzctr.org.au /), ID: ACTRN12611001200976. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9-100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ.Methods: This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated.Results: No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status.Conclusion: The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method. [ABSTRACT FROM AUTHOR]

Little is known about the long-term outcomes of emerging Internet-delivered pain management programs. The current study reports the 12- and 24-month follow-up data from a randomized controlled trial (n = 490) of an Internet-delivered pain management program, the Pain Course. The initial results of the trial to the 3-month follow-up have been reported elsewhere. There were significant improvements in disability, depression, anxiety, and pain levels across 3 treatment groups receiving different levels of clinician support compared with a treatment as the usual control. No marked or significant differences were found between the treatment groups either after treatment or at the 3-month follow-up. The current study obtained long-term follow-up data from 78% and 79% of participants (n = 397) at the 12-month and 24-month follow-up marks, respectively. Clinically significant decreases (average percent reduction; Cohen's d effect sizes) were maintained at the 12- and 24-month follow-ups for disability (average reduction ≥27%; d ≥ .67), depression (average reduction ≥36%; d ≥ .80), anxiety (average reduction ≥38%; d ≥ .66), and average pain levels (average reduction ≥21%; d ≥ .67). No marked or consistent differences were found among the 3 treatment groups. These findings suggest that the outcomes of Internet-delivered programs may be maintained over the long term. PERSPECTIVE: This article presents the long-term outcome data of an established Internet-delivered pain management program for adults with chronic pain. The clinical improvements observed during the program were found to be maintained at the 12- and 24-month follow-up marks. This finding indicates that these programs can have lasting clinical effects. [ABSTRACT FROM AUTHOR]

Background: In recent years, berberine has become widely used as an effective alternative to treat dyslipidaemias; much clinical evidence has emerged. It is important to systematically and critically evaluate the existing evidence.Purpose: This study aims to evaluate the efficacy and safety of berberine in patients with dyslipidaemias.Study Design: A systematic review and meta-analysis of randomized clinical trials.Methods: Five electronic databases were searched up to Apr 15, 2018 to identify randomized controlled trials (RCTs) of berberine in treatment of dyslipidaemias. The outcomes were lipid profile parameters and adverse events. Study selection, data collection, risk of bias assessment, data analyses and interpretations were conducted according to the Cochrane handbook.Results: Sixteen trials with total of 2147 participants were judged to be eligible and were included in the meta-analysis. The included trials were assessed to be of high clinical heterogeneity. The methodological quality of the majority of the trials was generally low in terms of random sequence generation, allocation concealment, blinding and incomplete outcome data. Thus, selection bias, performance bias, detection bias, attrition bias and confounding bias might exist. Meta-analysis showed that berberine significantly reduced levels of total cholesterol (TC) (MD = -0.47  mmol/l 95% CI [-0.64, -0.31], p < 0.00001), low-density lipoprotein cholesterol (LDL-C) (MD =-0.38  mmol/l 95% CI [-0.53, -0.22], p < 0.00001) and triglycerides (TG) (MD = -0.28  mmol/l 95% CI [-0.46, -0.10], p = 0.002). Berberine also increased the level of high-density lipoprotein cholesterol (HDL-C) when used alone (MD = 0.08  mmol/l 95% CI [0.03, 0.12], p = 0.001). No significant differences were found between groups in terms of incidence of adverse events (RR = 0.64 95% CI [0.31, 1.30], p = 0.22). No severe adverse effects were reported in either group.Conclusion: Berberine improves lipid profiles in dyslipidaemias with satisfactory safety. Nevertheless, these findings should be interpreted with caution because of the high clinical heterogeneity and high risk of bias in the included trials. Rigorous clinical trials should be carried out to provide more reliable evidence. [ABSTRACT FROM AUTHOR]

Introduction: Prolonged fatigue is common among adults, yet only a small percentage of affected individuals seek medical attention. Following findings that complementary and alternative medicine can be effective strategies for improving fatigue, we evaluated the effect of an herbal tea regimen on prolonged fatigue.Methods: In this pilot randomized controlled trial, participants with prolonged fatigue were randomly allocated to either a tea (n = 20) or control (n = 20) group. The tea group consumed herbal tea consisting of Astragali Radix, Angelicae gigantis Radix, and Zizyphi Fructus twice daily for 4 weeks, whereas the control group received no intervention. Outcomes were assessed at baseline and 4 and 8 weeks. The primary outcome was fatigue severity, measured using the Chalder Fatigue Scale. Secondary outcomes included sleep quality, depression symptoms, and quality of life.Results: Among the 40 individuals screened, 35 completed the study. Fatigue severity was significantly lower in the tea group than the control group at 4 weeks, and within the tea group, fatigue severity and sleep quality improved at the 4- and 8-week follow-ups vs. baseline in the tea group. Depression also significantly improved in the tea group at 8 weeks. There were no changes within the control group on any measure.Conclusion: The findings suggest that our herbal tea formulation reduces fatigue severity and improves sleep quality in adults with prolonged fatigue. [ABSTRACT FROM AUTHOR]

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Researchers and practitioners of online education have consistently emphasized the importance of facilitating peer interaction and mutual support to create a sense of community, which in turn may enhance motivation, promote extrinsic accountability, and improve learning outcomes. Despite these assertions, experimental evidence on the effects of peer support in college online courses is limited. To address this gap, we conducted a randomized controlled trial to examine the impact of a study-together group intervention on students' academic and non-cognitive outcomes in a for-credit online course at a public four-year college. Our findings indicate that students who were offered a study-together group reported a higher sense of belonging than those who were not. Additionally, students with lower academic preparation and lower baseline motivation demonstrated improved academic performance as a result of this intervention, while students who preferred passive interaction reported increased motivation. However, for students with higher baseline motivation and those who preferred active interaction, the intervention appeared to negatively influence their time management. • An RCT that examines the impact of study-together groups in a college online course. • Intervention improves students' group study behaviors and sense of belonging. • Intervention improves course grades for low-achieving and less-motivated students. • Intervention improves motivation for students who prefer passive interaction. • Negative effects on time management for highly motivated and outgoing students. [ABSTRACT FROM AUTHOR]

Electricity as a clean cooking fuel is economically and environmentally efficient compared to other cooking fuels, and induction stoves are among the most efficient that could contribute to the sustainable energy transition. Nepal is rich in water resources, having resources four times higher than the global average. With increasing hydroelectricity generation, promoting induction stoves for cooking is a viable way to reduce the use of traditional fuels and Liquified Petroleum Gas imported from other countries. This study aims to identify the underlying product-specific factors influencing households' preference for electric cooking using induction stoves and assess the impact of awareness about the benefits of induction stoves on choice probability. We used a randomized conjoint experiment along with a randomized controlled trial collecting primary data of 9500 choice responses from 950 households in the Nuwakot district of central Nepal to achieve the objective. Among the six product-specific factors considered in the conjoint analysis, monthly expenses and supply of electricity were found to be significant determinants for choosing electric induction cooking, while cooking time, sickness rate, and environmental conditions also had a certain degree of influence, whereas the effect of installation cost was found to be statistically insignificant. The lower bound of households' willingness to pay for electric induction cooking was found to be as high as 4% of their monthly income. The information treatment increases the uptake rate of the induction package by 5% and willingness to pay by 9.58%. This indicates the role of awareness and behavior change in driving a sustainable energy transition, highlighting the need for policymakers to promote cleaner cooking technologies through the effective dissemination of information The results of this study will enable policymakers to make informed decisions to promote the use of induction stoves as the primary cooking fuel, thereby contributing to efforts toward climate change mitigation. • Promoting clean cooking fuel transition is essential for addressing global sustainability challenges. • However, prospects of the adoption of clean cooking fuels are uncertain. • We identify determinants of household preferences for clean cooking fuel transition. • Nepal government is prioritizing the provision of free induction stoves to households. • Instead, reducing monthly expenses and regular supply of electricity should be prioritized. [ABSTRACT FROM AUTHOR]

Context: Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.Objectives: This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.Methods: Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness "right now"-morning and evening-measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).Results: Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness "right now" was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = -0.22 (-0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = -0.33 (-0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation.Conclusion: This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms. [ABSTRACT FROM AUTHOR]

Context: Dyspnea is a common distressing symptom among patients with advanced cancer.Objective: The objective of this study was to determine the effect of fan therapy on dyspnea in patients with terminally ill cancer.Methods: This parallel-arm, randomized controlled trial included 40 patients with advanced cancer from a palliative care unit at the National Cancer Center Hospital in Japan. All patients experienced dyspnea at rest with a score of at least three points on a subjective 0- to 10-point Numerical Rating Scale (NRS), showed peripheral oxygen saturation levels of ≥90%, had an Eastern Cooperative Oncology Group grade of 3 or 4, and were aged 20 years or more. In one group, a fan was directed to blow air on the patient's face for five minutes. This group was compared to a control group wherein air was blown to the patient's legs. Patients were randomly assigned to each group. The main outcome measure was the difference in dyspnea NRS scores between fan-to-face and fan-to-legs groups.Results: No significant differences were seen in baseline dyspnea NRS between groups (mean score, 5.3 vs. 5.1, P = 0.665). Mean dyspnea changed by -1.35 points (95% CI, -1.86 to -0.84) in patients assigned to receive fan-to-face and by -0.1 points (-0.53 to 0.33) in patients assigned to receive fan-to-legs (P < 0.001). The proportion of patients with a one-point reduction in dyspnea NRS was significantly higher in the fan-to-face arm than in the fan-to-legs arm (80% [n = 16] vs. 25% [n = 5], P = 0.001).Conclusion: Fan-to-face is effective in alleviating dyspnea in patients with terminally ill cancer. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases and their risk factors are inheritable. Single nucleotide polymorphisms in the human genome are found in around 1 in 1000 base pairs, and this may affect the genetic variety of individuals. During meiosis, any genetic information is randomized and is independent of other characteristics. In a Mendelian randomization study (MRS), a genetic variant associated with biomarker is used as a proxy for the biomarker, and the outcomes are compared between the groups harboring the effect alleles and a group with the reference allele. An MRS using variants of both rare and modest effect sizes and variants of common and lower effect sizes provides an understanding of risk factors and their causality of cardiovascular disease; for example, an individual possessing an allele associated with lower low-density lipoprotein cholesterol (LDL-C) exhibits lower risk of coronary artery disease (CAD). Moreover, the log-transformed reduction rates of CAD are linearly correlated with the reduction value of LDL-C. High-density lipoprotein (HDL) removes cholesteryl esters from peripheral tissues, including atherosclerotic plaque to the liver. Numerous epidemiological studies have shown that HDL-cholesterol (HDL-C) levels are inversely associated with the frequency of the occurrence of CAD. However, genetic variants, which are only associated with higher HDL-C levels, do not decrease the frequency of myocardial infarction. This fact shows that HDL-C level is not a cause but a biomarker of CAD. Discoveries of rare variants in Mendelian disorders resulted in the successful development of drugs for the general population. An MRS may also predict the pharmacological effectiveness and adverse side effects of novel drugs targeting specific molecules. An MRS could become a standard process to be performed before the development of novel drugs. Furthermore, future guidelines for the prevention of CAD should consider the genetic information of individuals, which will result in precision medicine for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Summary Objectives To compare 2-year outcomes of total knee replacement (TKR) followed by non-surgical treatment to that of non-surgical treatment alone and outcomes of the same non-surgical treatment to that of written advice. Design In two randomized trials, 200 (mean age 66) adults with moderate to severe knee osteoarthritis (OA), 100 eligible for TKR and 100 not eligible for TKR, were randomized to TKR followed by non-surgical treatment, non-surgical treatment alone, or written advice. Non-surgical treatment consisted of 12 weeks of supervised exercise, education, dietary advice, use of insoles, and pain medication. The primary outcome was the mean score of the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales, covering pain, symptoms, activities of daily living (ADL), and quality of life (QOL). Results Patients randomized to TKR had greater improvements than patients randomized to non-surgical treatment alone (difference of 18.3 points (95% CI; 11.3 to 25.3)), who in turn improved more than patients randomized to written advice (difference of 7.0 points (95% CI; 0.4 to 13.5)). Among patients eligible for TKR, 16 (32%) from the non-surgical group underwent TKR during 2 years and among those initially ineligible, seven patients (14%) from the non-surgical group and ten (20%) from the written advice group underwent TKR. Conclusions TKR followed by non-surgical treatment is more effective on pain and function than non-surgical treatment alone, which in turn is more effective than written advice. Two out of three patients with moderate to severe knee OA eligible for TKR delayed surgery for at least 2 years following non-surgical treatment. Trial registration ClinicalTrials.gov numbers NCT01410409 and NCT01535001 . [ABSTRACT FROM AUTHOR]

Background: Inulin-type fructans used in formula have been shown to promote microbiota composition and stool consistency closer to those of breastfed infants and to have beneficial effects on fever occurrence, diarrhea, and incidence of infections requiring antibiotic treatment in infants.Objectives: The primary study aim was to explore whether prophylactic supplementation with prebiotic fructans is able to influence the frequency of infectious diseases in kindergarten children during a winter period. A secondary objective was to ascertain the effect on the intestinal microbiota.Methods: 142 boys and 128 girls aged 3-6 y were randomly allocated to consume 6 g/d fructans or maltodextrin for 24 wk. At baseline, stool samples were collected for microbiota analysis and anthropometric measurements were made. During the intervention period diagnoses were recorded by physicians, whereas disease symptoms, kindergarten absenteeism, dietary habits, and stool consistency were recorded by parents. Baseline measurements were repeated at wk 24.Results: In total 219 children finished the study. Both the relative abundance of Bifidobacterium (P < 0.001) and that of Lactobacillus (P = 0.014) were 19.9% and 7.8% higher, respectively, post data normalization, in stool samples of children receiving fructans as compared with those of controls at wk 24. This was accompanied by significantly softer stools within the normal range in the prebiotic group from wk 12 onwards. The incidence of febrile episodes requiring medical attention [0.65 ± 1.09 compared with 0.9 ± 1.11 infections/(24 wk × child), P = 0.04] and that of sinusitis (0.01 ± 0.1 compared with 0.06 ± 0.25, P = 0.03) were significantly lower in the prebiotic group. The number of infectious episodes and their duration reported by parents did not differ significantly between the 2 intervention groups.Conclusions: Prebiotic supplementation modified the composition of the intestinal microbiota and resulted in softer stools in kindergarten-aged children. The reduction in febrile episodes requiring medical attention supports the concept of further studies on prebiotics in young children. This trial was registered at clinicaltrials.gov as NCT03241355. [ABSTRACT FROM AUTHOR]

Background: Low serum 25-hydroxyvitamin D [25(OH)D] has been associated with unfavorable cardiometabolic risk profiles in many observational studies in children, but very few randomized controlled trials have investigated this.Objective: We explored the effect of winter-time cholecalciferol (vitamin D3) supplementation on cardiometabolic risk markers in young, white, 4- to 8-y-old healthy Danish children (55°N) as part of the pan-European ODIN project.Methods: In the ODIN Junior double-blind, placebo-controlled, dose-response trial, 119 children (mean ± SD age: 6.7 ± 1.5 y; 36% male; 82% normal weight) were randomly allocated to 0, 10 or 20 µg/d of vitamin D3 for 20 wk (October-March). Cardiometabolic risk markers including BMI-for-age z score (BMIz), waist circumference, systolic and diastolic blood pressure, serum triglycerides and cholesterol (total, LDL, HDL, and total:HDL), plasma glucose and insulin, and whole-blood glycated hemoglobin were measured at baseline and endpoint as secondary outcomes together with serum 25(OH)D. Intervention effects were evaluated in linear regression models as between-group differences at endpoint adjusted for baseline value of the outcome, and additionally for age, sex, baseline serum 25(OH)D, BMIz, time since breakfast, and breakfast content.Results: Mean ± SD serum 25(OH)D was 56.7 ± 12.3 nmol/L at baseline and differed between groups at endpoint with concentrations of 31.1 ± 7.5, 61.8 ± 10.6, and 75.8 ± 11.5 nmol/L in the 0-, 10-, and 20 µg/d groups, respectively (P < 0.0001). Vitamin D3 supplementation had no effect on any of the cardiometabolic risk markers in analyses adjusted for baseline value of the outcome (all P ≥ 0.05), and additional covariate adjustment did not change the results notably.Conclusions: Preventing the winter decline in serum 25(OH)D with daily vitamin D3 supplementation of 10 or 20 µg had no cardiometabolic effects in healthy 4- to 8-y-old Danish children. This trial was registered at www.clinicaltrials.gov as NCT02145195. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies have supported inverse associations between low serum 25-hydroxyvitamin D [25(OH)D] and cardiometabolic risk markers, but few randomized trials have investigated the effect of vitamin D supplementation on these markers in adolescents.Objective: The objective of this study was to investigate the effect of winter-time cholecalciferol (vitamin D3) supplementation on cardiometabolic risk markers in white, healthy 14- to 18-y-old adolescents in the UK (51°N) as part of the ODIN Project.Methods: In a dose-response trial, 110 adolescents (mean ± SD age: 15.9 ± 1.4 y; 43% male; 81% normal weight) were randomly assigned to receive 0, 10 or 20 μg/d vitamin D3 for 20 wk (October-March). Cardiometabolic risk markers including BMI-for-age z score (BMIz), waist circumference, systolic and diastolic blood pressure, fasting plasma triglycerides, cholesterol (total, HDL, LDL, and total:HDL), and glucose were measured at baseline and endpoint as secondary outcomes, together with serum 25(OH)D. Intervention effects were evaluated in linear regression models as between-group differences at endpoint, adjusted for the baseline value of the outcome variable and additionally for age, sex, Tanner stage, BMIz, and baseline serum 25(OH)D.Results: Mean ± SD baseline serum 25(OH)D was 49.1 ± 12.3 nmol/L and differed between groups at endpoint with concentrations of 30.7 ± 8.6, 56.6 ± 12.4, and 63.9 ± 10.6 nmol/L in the 0, 10, and 20 μg/d groups, respectively (P ≤ 0.001). Vitamin D3 supplementation had no effect on any of the cardiometabolic risk markers (all P > 0.05), except for lower HDL (-0.12 mmol/L; 95% CI: -0.21, 0.04 mmol/L; P = 0.003) and total cholesterol (-0.21 mmol/L; 95% CI: -0.42, 0.00 mmol/L; P = 0.05) in the 20 μg/d than in the 10 μg/d group, which disappeared in the fully adjusted analysis (P = 0.27 and P = 0.30, respectively).Conclusions: Supplementation with vitamin D3 at 10 and 20 μg/d, which increased serum 25(OH)D concentrations during the winter-time, had no effect on markers of cardiometabolic risk in healthy 14- to 18-y-old adolescents. This trial was registered at clinicaltrials.gov as NCT02150122. [ABSTRACT FROM AUTHOR]

Background This study investigated the safety and efficacy of famciclovir compared to acyclovir in patients with herpes zoster, to determine whether the two regimens are equally effective for the treatment of patients with uncomplicated herpes zoster over a period of 7 days. Methods Patients were randomly assigned to receive either famciclovir 500 mg (one tablet) three times daily or acyclovir 800 mg (two capsules) five times daily for 7 days. The primary endpoint was defined as the time to full crusting of herpes zoster lesions. Secondary endpoints were the proportion of patients who achieved complete cure and the change in score of signs/symptoms (pain, vesicular lesions, loss of sensitivity, burning pain, and pruritus) according to the patient diary. This study has been registered at ClinicalTrials.gov (NCT01327144). Results One hundred and seventy-four patients were enrolled and randomized; 151 of these patients completed treatment ( n = 75 famciclovir, n = 76 acyclovir). A similar proportion of patients who received acyclovir (94.74%) and famciclovir (94.67%) achieved complete cure. The mean time to full crusting of herpes zoster lesions was 15.033 days in the acyclovir group and 14.840 days in the famciclovir group (log-rank p -value = 0.820). The most common adverse events in the pooled groups were headache, diarrhea, nausea, back pain, cold, and drowsiness, but none of these was deemed to be clinically important. Conclusions Both interventions obtained high rates of cure and had a similar time to full crusting of lesions. Analysis of the primary efficacy endpoint proved that famciclovir is non-inferior to acyclovir, as the confidence interval for the difference in efficacy did not violate the non-inferior margin. Therefore, the results are not different enough to be clinically relevant. [ABSTRACT FROM AUTHOR]

In this study, 67 participants (95% female) with fibromyalgia (FM) were randomly assigned to an online acceptance and commitment therapy (online ACT) and treatment as usual (TAU; ACT + TAU) protocol or a TAU control condition. Online ACT + TAU participants were asked to complete 7 modules over an 8-week period. Assessments were completed at pre-treatment, post-treatment, and 3-month follow-up periods and included measures of FM impact (primary outcome), depression, pain, sleep, 6-minute walk, sit to stand, pain acceptance (primary process variable), mindfulness, cognitive fusion, valued living, kinesiophobia, and pain catastrophizing. The results indicated that online ACT + TAU participants significantly improved in FM impact, relative to TAU ( P  <   .001), with large between condition effect sizes at post-treatment (1.26) and follow-up (1.59). Increases in pain acceptance significantly mediated these improvements ( P  = .005). Significant improvements in favor of online ACT + TAU were also found on measures of depression ( P  = .02), pain ( P  = .01), and kinesiophobia ( P  = .001). Although preliminary, this study highlights the potential for online ACT to be an efficacious, accessible, and cost-effective treatment for people with FM and other chronic pain conditions. Perspective Online ACT reduced FM impact relative to a TAU control condition in this randomized controlled trial. Reductions in FM impact were mediated by improvements in pain acceptance. Online ACT appears to be a promising intervention for FM. [ABSTRACT FROM AUTHOR]

Objective: To compare changes in knee pain, function, and loading following a 4-month progressive walking program with or without toe-out gait modification in people with medial tibiofemoral knee osteoarthritis.Design: Individuals with medial knee osteoarthritis were randomized to a 4-month program to increase walking activity with (toe-out) or without (progressive walking) concomitant toe-out gait modification. The walking program was similar between the two groups, except that the gait modification group was trained to walk with 15° more toe-out. Primary outcomes included: knee joint pain (WOMAC), foot progression angles and knee joint loading during gait (knee adduction moment (KAM)). Secondary outcomes included WOMAC function, timed stair climb, and knee flexion moments during gait.Results: Seventy-nine participants (40 in toe-out group, 39 in progressive walking group) were recruited. Intention-to-treat analysis showed no between-group differences in knee pain, function, or timed stair climb. However, the toe-out group exhibited significantly greater changes in foot progression angle (mean difference = -9.04° (indicating more toe-out), 95% CI: -11.22°, -6.86°; P < 0.001), late stance KAM (mean difference = -0.26 %BW*ht, 95% CI: -0.39 %BW*ht, -0.12 %BW*ht, P < 0.001) and KAM impulse (-0.06 %BW*ht*s, 95% CI: -0.11 %BW*ht*s, -0.01 %BW*ht*s; P = 0.031) compared to the progressive walking group at follow-up. The only between-group difference that remained at a 1-month retention assessment was foot progression angle, with greater changes in the toe-out group (mean difference = -6.78°, 95% CI: -8.82°, -4.75°; P < 0.001).Conclusions: Though both groups experienced improvements in self-reported pain and function, only the toe-out group experienced biomechanical improvements.Trials Registry Number: NCT02019108. [ABSTRACT FROM AUTHOR]

Background: In the absence of dose-response data, Dietary ReferenceValues for vitaminDin nonpregnant adults are extended to pregnancy. Objective: The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [25(OH)D] in late gestation at a concentration sufficient to prevent newborn 25(OH)D <25-30 nmol/L, a threshold indicative of increased risk of nutritional rickets. Design: We conducted a 3-arm, dose-response, double-blind, randomized placebo-controlled trial in Cork, Ireland (51.9°N). A total of 144 white-skinned pregnant women were assigned to receive 0, 10 (400 IU), or 20 (800 IU) µg vitamin D3/d from ≤18 wk of gestation. Vitamin D metabolites at 14, 24, and 36 wk of gestation and in cord sera, including 25(OH)D3, 3-epi-25(OH)D3, 24,25(OH)2D3, and 25(OH)D2 were quantified by liquid chromatography--tandem mass spectrometry. A curvilinear regression model predicted the total vitamin D intake (from diet and antenatal supplements plus treatment dose) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25-30 nmol/L. Results: Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint (36 wk of gestation) were 12.1 ± 8.0, 21.9 ± 5.3, and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups, respectively; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups, respectively, compared with placebo (P < 0.001). For maternal 25(OH)D concentrations ≥50 nmol/L, 95% of cord sera were ≥30 nmol/L and 99% were >25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5% of women was 28.9 µg/d. Conclusions: Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude, which kept 25(OH)D at >25 nmol/L in 99% and ≥30 nmol/L in 95% of umbilical cord sera. This trial was registered at www.clinicaltrials. gov as NCT02506439. [ABSTRACT FROM AUTHOR]

The gender gap in economics majors (i.e., male students are much more likely to major in economics than are their female counterparts) has remained large, despite narrowing gaps observed in many other fields. This study examines whether mentoring, the provision of additional information, and nudges help reduce the gender gap in economics majors via a randomized controlled experiment conducted in introductory economics classes at a large, public, four-year institution in the United States. The results show that the treatment effects are heterogeneous and have the most significant impact on female students with grades above the median. The treatments increase these female students’ probability of majoring in economics by 5.41–6.27 percentage points. [ABSTRACT FROM AUTHOR]

Objective: New interventions supporting health literacy and a tobacco-free lifestyle in adolescence are needed to narrow the widening gap in existing health inequalities. Health games offer potential and could be utilized for example in school healthcare, but more research is needed to increase the understanding of the effects of game elements in health interventions. The aim of this feasibility study is to determine the short-term effectiveness of the tobacco-related mobile health game Fume and a non-gamified website in comparison with a no-intervention control group, regarding tobacco-related health literacy among 10-13-year-old early adolescents. In addition, we compare the demand for and acceptability of Fume to that of the website.Methods: In total, 151 early adolescents participated in this single-blinded, three-armed cluster randomized trial. The participants from three municipalities in southwest Finland were randomly allocated between a group with access to the health game Fume (n = 61), a group with access to the website (n = 47), and a group with no intervention (n = 43). The intervention groups first participated in a 20-min training session with Fume/the website, and then had two weeks to use Fume/the website based on their own interest. Short-term effectiveness was measured by primary (anti-smoking self-efficacy) and secondary (smoking outcome expectations, attitudes towards tobacco use, tobacco-use motives, motivation to decline tobacco use in the future, and knowledge about tobacco) outcomes derived from the theory-based determinants of tobacco-related health literacy and evaluated with self-assessment questionnaires at baseline and post-intervention (after a two-week follow-up). For evaluating the demand, the actual use of Fume/the website was tracked during the two-week period. Regarding acceptability, the raised interest towards Fume/the website and opinions about the interventions were evaluated post-intervention. Differences were tested with the McNemar, Fisher exact, and non-parametric tests.Results: Statistically significant favorable changes during the study period were found for positive (P = 0.002) and negative (P = 0.02) smoking outcome expectations and attitudes towards cigarette smoking (P = 0.01) within the group using Fume. No statistically significant changes were detected within the website or control groups. Statistically significant differences were not found for the change in outcome variables among the three groups. The number of visits (P < 0.001), number of separate visit days (P < 0.001) and total duration of use (P < 0.001) were larger for the group using Fume than for that using the website. Fume sparked more interest in early adolescents than the website did (P <  0.001). There were no statistically significant differences in opinions about Fume and those regarding the website.Conclusions: The intervention with embedded game elements, the health game Fume, was found to be more feasible as a tobacco-related health education intervention than the non-gamified website among early adolescents in light of demand and acceptability (raised interest). Even though no change in anti-smoking self-efficacy was found, the results of this feasibility study demonstrated favorable short-term changes with Fume in some other theory-based determinants of tobacco-related health literacy. [ABSTRACT FROM AUTHOR]

Limiting milk production for a short period of time in early lactation could be a relevant strategy to prevent hyperketonemia (HYK). From December 2013 to March 2015, 838 multiparous Holstein cows from 13 herds were enrolled in a randomized controlled trial evaluating the effect of incomplete milking in early lactation on ketonemia and its effect on body condition score (BCS) loss. Cows were randomly assigned 4 wk before expected calving date to 1 of 2 treatment groups, (1) a conventional milking protocol (CON) for which cows were completely milked or (2) an incomplete milking protocol (INC) for which a maximum of 10 to 14 kg of milk/d were withdrawn during the first 5 d in milk (DIM). β-Hydroxybutyrate (BHB) concentrations were measured from blood samples collected on each cow 3 times at weekly intervals. Hyperketonemia was defined as BHB ≥1.4 mmol/L. Body condition score variation in the postcalving period was calculated by subtracting BCS assessed at wk 7 from BCS assessed at first week after calving. Effect of treatment on ketonemia and prevalence of HYK were evaluated for 4 specific time periods: 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM. Effect of treatment on ketonemia was investigated using linear mixed models with natural logarithm of BHB measurements as outcome and treatment groups as fixed effect. Generalized linear mixed models with HYK as outcome, using logit link, and treatment groups as fixed effect were used to investigate effect of treatment on odds of HYK. A logistic regression model with BCS loss (<0.75 or ≥0.75) as outcome and treatment groups and herd as fixed effects was used to study effect of INC on odds of having BCS loss ≥0.75. A total of 813 lactations had complete data and were used for statistical analysis of ketonemia and HYK. A total of 709 lactations had complete data and were used for analysis of BCS loss. Geometric means of blood BHB concentrations during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 0.72 (95% confidence interval = 0.66, 0.80), 0.66 (0.60, 0.73), 0.90 (0.80, 1.01), and 0.93 (0.83, 1.05) mmol/L for INC, and 0.65 (0.59, 0.72), 0.79 (0.72, 0.87), 0.94 (0.84, 1.06), and 0.92 (0.82, 1.04) mmol/L for CON. Cows in INC group had lower ketonemia during the 4 to 7 DIM period. Predicted prevalence of HYK during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 2.8 (3.2, 15.1), 4.6 (2.0, 10.0), 13.4 (8.4, 20.0), and 23.0% (17.4, 29.7) for INC and 2.6 (2.5, 13.8), 10.7 (5.6, 19.3), 19.4 (13.0, 27.9), and 21.3% (16.0, 27.8) for CON. The INC treatment reduced the prevalence of HYK during the 4 to 7 and 8 to 17 DIM periods. No association was observed between INC and BCS loss in the postcalving period. Overall, the incomplete milking protocol was effective for reducing ketonemia and prevalence of HYK during the early postpartum period. [ABSTRACT FROM AUTHOR]

Objectives: Uric acid may activate an innate immune response in osteoarthritis (OA), contributing to disease pathology and progression. We evaluated the effectiveness of colchicine on pain and function in symptomatic knee OA (KOA) and the underlying mechanism of action.Methods: Colchicine effectiveness in symptoms and inflammation modification in knee osteoarthritis (COLKOA) was a double-blind, placebo-controlled, randomized trial comparing 16 weeks of treatment with 0.5 mg twice-daily oral colchicine to placebo for knee osteoarthritis (KOA). The primary endpoint was ≥30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary endpoints included improvement in pain (0-10 Likert scales); WOMAC pain; patient global assessment (0-100); physical function; the OARSI-OMERACT response; quality of life; and change in serum, urine, synovial fluid (SF) biomarkers of cartilage metabolism and inflammation, and plasma/SF colchicine concentrations.Results: Of 109 randomly assigned participants, 39% (95% confidence interval (CI) 27-52%) and 49% (95% CI 36-62%) in the colchicine and placebo arms respectively met the primary endpoint at study end (P = 0.284, odds ratio 0.66, 95% CI 0.31-1.41). No strong evidence of treatment differences was identified on clinical secondary endpoints. Treatment significantly reduced mean serum hs-CRP (P = 0.008) and SF CTXI (P = 0.002); treatment tended to reduce inflammatory markers (SF IL-6, IL8, TNFα, CD14 and IL-18), but these differences were not statistically significant.Conclusion: Colchicine (0.5 mg twice-daily orally) reduced inflammation and high bone turnover biomarkers known to be associated with OA severity and progression risk, but did not reduce KOA symptoms over a 16-week study period. A longer-term study to evaluate for slow-acting disease modifying effects is warranted.Trial Registration: The trial has been registered at clinicaltrials.gov as NCT02176460. Date of registration: June 26, 2014. [ABSTRACT FROM AUTHOR]

Background: Individuals with impaired fat taste (FT) sensitivity have reduced satiety responses after consuming fatty foods, leading to increased dietary fat intake. Habitual consumption of dietary fat may modulate sensitivity to FT, with high consumption decreasing sensitivity [increasing fatty acid taste threshold (FATT)] and low consumption increasing sensitivity (decreasing FATT). However, some individuals may be less susceptible to diet-mediated changes in FATT due to variations in gene expression. Objective: The objective of this study was to determine the effect of an 8-wk low-fat or high-fat diet on FATT while maintaining baseline weight (<2.0 kg variation) to assess heritability and to explore the effect of genetics on diet-mediated changes in FATT. Design: A co-twin randomized controlled trial including 44 pairs (mean ± SD age: 43.7 ± 15.4 y; 34 monozygotic, 10 dizygotic; 33 women, 10 men, 1 gender-discordant) was conducted. Twins within a pair were randomly allocated to an 8-wk low-fat (<20% of energy from fat) or high-fat (>35% of energy from fat) diet. FATT was assessed by a 3-alternate forced choice methodology and transformed to an ordinal scale (FT rank) at baseline and at 4 and 8 wk. Linear mixed models were fit to assess diet effect on FT rank and diet effect modification due to zygosity. A variance components model was fit to calculate baseline heritability. Results: There was a significant time x diet interaction for FT rank after the 8-wk trial (P < 0.001), with the same conclusions for the subset of participants maintaining baseline weight (low-fat; n = 32; high-fat: n = 35). There was no evidence of zygosity effect modification (interaction of time x diet x zygosity: P = 0.892). Heritability of baseline FT rank was 8%. Conclusions: There appears to be little to no genetic contribution on heritability of FATT or diet-mediated changes to FATT. Rather, environment, specifically dietary fat intake, is the main influencer of FT sensitivity, regardless of body weight. [ABSTRACT FROM AUTHOR]

Question In people who have undergone cardiac surgery via median sternotomy, does modifying usual sternal precautions to make them less restrictive improve physical function, pain, kinesiophobia and health-related quality of life? Design Two-centre, randomised, controlled trial with concealed allocation, blinded assessors and intention-to-treat analysis. Participants Seventy-two adults who had undergone cardiac surgery via a median sternotomy were included. Intervention Participants were randomly allocated to one of two groups at 4 (SD 1) days after surgery. The control group received the usual advice to restrict their upper limb use for 4 to 6 weeks (ie, restrictive sternal precautions). The experimental group received advice to use pain and discomfort as the safe limits for their upper limb use during daily activities (ie, less restrictive precautions) for the same period. Both groups received postoperative individualised education in hospital and via weekly telephone calls for 6 weeks. Outcome measures The primary outcome was physical function assessed by the Short Physical Performance Battery. Secondary outcomes included upper limb function, pain, kinesophobia, and health-related quality of life. Outcomes were measured before hospital discharge and at 4 and 12 weeks postoperatively. Adherence to sternal precautions was recorded. Results There were no statistically significant differences in physical function between the groups at 4 weeks (MD 1.0, 95% CI –0.2 to 2.3) and 12 weeks (MD 0.4, 95% CI –0.9 to 1.6) postoperatively. There were no statistically significant between-group differences in secondary outcomes. Conclusion Modified (ie, less restrictive) sternal precautions for people following cardiac surgery had similar effects on physical recovery, pain and health-related quality of life as usual restrictive sternal precautions. Similar outcomes can be anticipated regardless of whether people following cardiac surgery are managed with traditional or modified sternal precautions. Trial registration Australian and New Zealand Clinical Trials Registry ANZCTRN12615000968572. [Katijjahbe MA, Granger CL, Denehy L, Royse A, Royse C, Bates R, Logie S, Nur Ayub MA, Clarke S, El-Ansary D (2018) Standard restrictive sternal precautions and modified sternal precautions had similar effects in people after cardiac surgery via median sternotomy (‘SMART’ Trial): a randomised trial. Journal of Physiotherapy 64: 97–106] [ABSTRACT FROM AUTHOR]

Background: Recent evidence has highlighted the prevalence of mild-to-moderate iodine deficiency in women of childbearing age and pregnant women, with important public health ramifications due to the role of iodine, which is required for thyroid hormone production, in neurodevelopment. Cow milk contributes the greatest amount to iodine intakes in several countries.Objective: The objective of this study was to investigate the effect of increased cow milk consumption on iodine status, thyroid hormone concentrations, and selenium status.Methods: A 12-wk randomized controlled trial was conducted in 78 low-moderate milk-consuming (<250 mL/d) healthy women (aged 18-45 y). The intervention group was asked to consume 3 L semiskimmed milk/wk, whereas the control group continued their usual milk consumption (baseline median: 140 mL/d; IQR: 40-240 mL/d). At baseline and weeks 6 and 12, participants provided a spot urine sample [urinary iodine concentration (UIC), creatinine] and a fasting blood sample (thyroid hormone concentrations, serum total selenium, selenoprotein P).Results: At baseline, the median (IQR) UIC of all participants was 78.5 µg/L (39.1-126.1 µg/L). Changes in the median UIC from baseline to week 6 (35.4 compared with 0.6 µg/L; P = 0.014) and week 12 (51.6 compared with -3.8 µg/L; P = 0.045) were significantly greater in the intervention group compared with the control group. However, despite being higher within the intervention group at weeks 6 and 12, the change in the iodine:creatinine ratio from baseline was not significantly different between groups at either week 6 (P = 0.637) or week 12 (P = 0.178). There were no significant differences in thyroid hormone concentrations or selenium status between groups at any time point.Conclusions: The present study shows that the consumption of additional cow milk can significantly increase UIC in women of childbearing age. These results suggest that cow milk is a potentially important dietary source of iodine in this population group. This trial was registered at www.clinicaltrials.gov as NCT02767167. [ABSTRACT FROM AUTHOR]

Background In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). Materials and methods We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Results Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. Conclusion(s) The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. [ABSTRACT FROM AUTHOR]

Objective Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. Methods Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). Results Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2–10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15–7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26–1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. Conclusions The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. Trial registration number at ClinicalTrials.gov NCT01018602 . [ABSTRACT FROM AUTHOR]

Background: Most Canadian children do not meet the recommended dietary intake for vitamin D. Objectives: The aims were to test how much vitamin D from food is needed to maintain a healthy serum 25-hydroxyvitamin D3 [25(OH)D3] status from fall to spring in young children and to examine musculoskeletal outcomes. Design: Healthy children aged 2-8 y (n = 51) living in Montreal, Canada, were randomly assigned to 1 of 2 dietary vitamin D groups (control or intervention to reach 400 lU/d by using vitamin D- fortified foods) for 6 mo, starting October 2014. At baseline and at 3 and 6 mo, anthropometric characteristics, vitamin D metabolites (liquid chromatography-tandem mass spectrometry), and bone biomarkers (IDS-iSYS, Immunodiagnositc Systems; Liaison; Diasorin) were measured and physical activity and food intakes surveyed. At baseline and at 6 mo, bone outcomes and body composition (dual-energy X-ray absorptiometry) were measured. Cross-sectional images of distal tibia geometry and muscle density were conducted with the use of peripheral quantitative computed tomography scans at 6 mo. Results: At baseline, participants were aged 5.2 ± 1.9 (mean ± SD) y and had a body mass index z score of 0.65 ± 0.12; 53% of participants were boys. There were no differences between groups in baseline serum 25(OH)D3 (66.4 ± 13.6 nmol/L) or vitamin D intake (225 ± 74 lU/d). Median (IQR) compliance was 96% (89-99%) for yogurt and 84% (71-97%) for cheese. At 3 mo, serum 25(OH)D3 was higher in the intervention group (P < 0.05) but was not different between groups by 6 mo. Although lean mass accretion was higher in the intervention group (P < 0.05), no differences in muscle density or bone outcomes were observed. Conclusions: The consumption of 400 IU vitamin D/d from fall to spring did not maintain serum 25(OH)D3 concentration or improve bone outcomes. Further work with lean mass accretion as the primary outcome is needed to confirm if vitamin D enhances lean accretion in healthy young children. This trial was registered at www.clinicaltrials.gov as NCT02387892. [ABSTRACT FROM AUTHOR]

Background: Although self-efficacy is a potential determinant of feeding and care behaviors, there is limited empirical analysis of the role of maternal self-efficacy in low- and middle-income countries. In the context of behavior change interventions (BCIs) addressing complementary feeding (CF), it is possible that maternal self-efficacy can mediate or enhance intervention impacts.Objective: In the context of a BCI in Bangladesh, we studied the role of maternal self-efficacy for CF (MSE-CF) for 2 CF behaviors with the use of a theoretically grounded empirical model of determinants to illustrate the potential roles of MSE-CF.Methods: We developed and tested a locally relevant scale for MSE-CF and included it in a survey (n = 457 mothers of children aged 6-24 mo) conducted as part of a cluster-randomized evaluation. Qualitative research was used to inform the selection of 2 intervention-targeted behaviors: feeding green leafy vegetables in the last 24 h (GLV) and on-time introduction of egg (EGG) between 6 and 8 mo of age. We then examined direct, mediated, and potentiated paths of MSE-CF in relation to the impacts of the BCI on these behaviors with the use of regression and structural equation modeling.Results: GLV and EGG were higher in the intensive group than in the nonintensive control group (16.0 percentage points for GLV; P < 0.001; 11.2 percentage points for EGG; P = 0.037). For GLV, MSE-CF mediated (β = 0.345, P = 0.010) and potentiated (β = 0.390, P = 0.038) the effect of the intensive group. In contrast, MSE-CF did not mediate or potentiate the effect of the intervention on EGG.Conclusions: MSE-CF was a significant mediator and potentiator for GLV but not for EGG. The divergent findings highlight the complex determinants of individual specific infant and young child feeding behaviors. The study shows the value of measuring behavioral determinants, such as MSE-CF, that affect a caregiver's capability to adopt intervention-targeted behaviors. [ABSTRACT FROM AUTHOR]

Background Household air pollution (HAP) exposure has been linked to adverse pregnancy outcomes. Objectives A randomized controlled trial was undertaken in Ibadan, Nigeria to determine the impact of cooking with ethanol on pregnancy outcomes. Methods Three-hundred-twenty-four pregnant women were randomized to either the control (continued cooking using kerosene/firewood stove, n = 162) or intervention group (received ethanol stove, n = 162). Primary outcome variables were birthweight, preterm delivery, intrauterine growth restriction (IUGR), and occurrence of miscarriage/stillbirth. Results Mean birthweights for ethanol and controls were 3076 and 2988 g, respectively; the difference, 88 g, (95% confidence interval: − 18 g to 194 g), was not statistically significant (p = 0.10). After adjusting for covariates, the difference reached significance (p = 0.020). Rates of preterm delivery were 6.7% (ethanol) and 11.0% (control), (p = 0.22). Number of miscarriages was 1(ethanol) vs. 4 (control) and stillbirths was 3 (ethanol) vs. 7 (control) (both non-significant). Average gestational age at delivery was significantly (p = 0.015) higher in ethanol-users (39.2 weeks) compared to controls (38.2 weeks). Perinatal mortality (stillbirths and neonatal deaths) was twice as high in controls compared to ethanol-users (7.9% vs. 3.9%; p = 0.045, after adjustment for covariates). We did not detect significant differences in exposure levels between the two treatment arms, perhaps due to large seasonal effects and high ambient air pollution levels. Conclusions Transition from traditional biomass/kerosene fuel to ethanol reduced adverse pregnancy outcomes. However, the difference in birthweight was statistically significant only after covariate adjustment and the other significant differences were in tertiary endpoints. Our results are suggestive of a beneficial effect of ethanol use. Larger trials are required to validate these findings. [ABSTRACT FROM AUTHOR]

Objectives To evaluate if treatment with ceftriaxone and a macrolide, improved patient outcome when compared with monotherapy with ceftriaxone, in hospitalized patients with human immunodeficiency virus/acquired immunodeficient syndrome (HIV/AIDS) with community-acquired pneumonia (CAP). Methods Adult patients with HIV hospitalized due to suspected CAP were randomized to receive one of two regimens, ceftriaxone plus macrolide or ceftriaxone plus placebo, at a 1:1 proportion (Brazilian Clinical Trials Registry: RBR-8wtq2b). The primary outcome was in-hospital mortality and the secondary outcomes were mortality within 14 days, need for vasoactive drugs, need for mechanical ventilation, time to clinical stability and length of hospitalization. Results A total of 227 patients were randomized, two were excluded after randomization; 225 patients were analysed (112 receiving ceftriaxone plus placebo and 113 receiving ceftriaxone plus macrolide). The frequency of the primary outcome, in-hospital mortality, was not statistically different between the regimens: 12/112 (11%) patients who received ceftriaxone plus placebo and 17/113 (15%) who received ceftriaxone plus macrolide died during hospitalization (hazard ratio 1.22, 95% CI 0.57–2.59). We did not find differences between the regimens for any of the secondary outcomes, including mortality within 14 days, which occurred in 5/112 (4%) patients with ceftriaxone plus placebo and in 12/113 (11%) patients with ceftriaxone plus macrolide (relative risk 2.38, 95% CI 0.87–6.53). Conclusions Among hospitalized patients with HIV/AIDS with CAP, treatment with ceftriaxone and a macrolide did not improve patient outcomes, when compared with ceftriaxone monotherapy. [ABSTRACT FROM AUTHOR]

Background: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial.Methods: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner.Results: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network.Conclusions: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism.Clinical Trial Registration: NCT0061015. [ABSTRACT FROM AUTHOR]

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Background: Currently, many studies focus on how the environment can be changed to encourage healthier eating behavior, referred to as choice architecture or "nudging." However, to date, these strategies are not often investigated in real-life settings, such as worksite cafeterias, or are only done so on a short-term basis. Objective: The objective of this study is to examine the effects of a healthy worksite cafeteria ["worksite cafeteria 2.0" (WC 2.0)] intervention on Dutch employees' purchase behavior over a 12-wk period. Design: We conducted a randomized controlled trial in 30 worksite cafeterias. Worksite cafeterias were randomized to either the intervention or control group. The intervention aimed to encourage employees to make healthier food choices during their daily worksite cafeteria visits. The intervention consisted of 14 simultaneously executed strategies based on nudging and social marketing theories, involving product, price, placement, and promotion. Results: Adjusted multilevel models showed significant positive effects of the intervention on purchases for 3 of the 7 studied product groups: healthier sandwiches, healthier cheese as a sandwich filling, and the inclusion of fruit. The increased sales of these healthier meal options were constant throughout the 12-wk intervention period. Conclusions: This study shows that the way worksite cafeterias offer products affects purchase behavior. Situated nudging and social marketing-based strategies are effective in promoting healthier choices and aim to remain effective over time. Some product groups only indicated an upward trend in purchases. Such an intervention could ultimately help prevent and reduce obesity in the Dutch working population. [ABSTRACT FROM AUTHOR]