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Background Limited evidence supports the common public health guideline that children >2 y of age should consume dairy with reduced fat content. Objectives We aimed to investigate the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity and biomarkers of cardiometabolic risk in healthy 4- to 6-y-old children. Methods The Milky Way Study enrolled 49 children (mean ± SD age: 5.2 ± 0.9 y; 47% girls) who were habitual consumers of whole-fat dairy, then randomly assigned them in a double-blind fashion to remain on whole-fat dairy or switch their dairy consumption to reduced-fat products for 3 mo. Primary endpoints included measures of adiposity, body composition, blood pressure, fasting serum lipids, blood glucose, glycated hemoglobin (HbA1c), and C-reactive protein (CRP) and were assessed at baseline and study end. Pre- and postintervention results were compared using linear mixed models, adjusted for growth, age, and sex. Results Dairy fat intake was reduced by an adjusted (mean ± SEM) 12.9 ± 4.1 g/d in the reduced-fat compared with the whole-fat dairy group (95% CI: –21.2, –4.6 g/d; P  = 0.003), whereas dietary energy intakes remained similar (P  = 0.936). We found no significant differential changes between dairy groups in any measure of adiposity, body composition, blood pressure, or fasting serum lipids, glucose, HbA1c, and CRP. Conclusions Our results suggest that although changing from whole-fat to reduced-fat dairy products does reduce dairy fat intake, it does not result in changes to markers of adiposity or cardiometabolic disease risk in healthy children. This trial was registered at www.anzctr.org.au as ACTRN12616001642471. [ABSTRACT FROM AUTHOR]

Background Although there is growing evidence on the role of preconception nutrition for birth outcomes, very few studies have evaluated the long-term effects of nutrition interventions during the preconception period on offspring cognitive outcomes. Objective We evaluate the impact of preconception weekly multiple micronutrients (MMs) or iron and folic acid (IFA) supplementation compared with folic acid (FA) alone on offspring intellectual functioning at age 6–7 y. Methods We followed 1599 offspring born to women who participated in a double-blinded randomized controlled trial of preconception supplementation in Vietnam. Women received weekly supplements containing either 2800 μg FA only, 60 mg iron and 2800 μg FA, or MMs (15 micronutrients including IFA) from baseline until conception, followed by daily prenatal IFA supplements until delivery. We used the Wechsler Intelligence Scale for Children to measure full-scale IQ (FSIQ) and 4 related domains of intellectual functioning [Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores] at 6–7 y. Group comparisons were done using ANOVA tests for all children and the subgroup born to women who consumed the supplements ≥26 wk before conception (per-protocol analyses). Results The final sample with data at 6–7 y (n  = 1321) was similar for baseline maternal and offspring birth characteristics and age at follow-up by treatment group. Compared with the offspring in the FA group, those in the MM group had higher FSIQ (β = 1.7; 95% CI: 0.1, 3.3), WMI (β = 1.7; 95% CI: 0.2, 3.2), and PSI (β = 2.5; 95% CI: 0.9, 4.1). Similar findings were observed in the per-protocol analyses. There were no significant differences by treatment group for VCI and PRI. Conclusions Preconception supplementation with MMs improved certain domains of intellectual functioning at age 6–7 y compared with FA. These findings suggest the potential for preconception micronutrient interventions to have long-term benefits for offspring cognition. [ABSTRACT FROM AUTHOR]

Background: The potential of a ketone monoester (β-hydroxybutyrate; KEβHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEβHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown.Objectives: The primary objective was to investigate the effect of KEβHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides.Methods: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of β-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEβHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [β-hydroxybutyrate (βHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time.Results: Blood βHB concentrations increased to 3.5 mmol/L within 30 minutes after KEβHB supplementation. Plasma glucose AUC was significantly lower after KEβHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEβHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1.Conclusions: Ingestion of the KEβHB-supplemented drink acutely increased the blood βHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEβHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210. [ABSTRACT FROM AUTHOR]

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. Results Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: −57.0 g/d; 95% CI: −77.9, −39.5 g/d; and −38.8 μmol/d; 95% CI: −91.2, −10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P  < 0.001 and P  = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: −0.7% point, 95% CI: −2.0, −0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. Conclusions Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group. This trial was registered at clinicaltrials.gov as NCT03067428. [ABSTRACT FROM AUTHOR]

Background: Obesity accelerates age-related cognitive decline, which is partly mediated by vascular dysfunction.Objective: The aim was to test the hypothesis that supplementation with fish oil and curcumin can enhance cognitive performance by improving cerebral circulatory function in overweight or obese middle-aged to older adults.Methods: In a 16-wk double-blind, placebo-controlled intervention trial, adults [50-80 y; BMI (kg/m2): 25-40] were randomly assigned to either fish oil (2000 mg/d DHA + 400 mg/d EPA), curcumin (160 mg/d), or a combination. Effects on cerebrovascular function (primary outcome) and cardiovascular risk factors were reported previously. Effects on cognitive performance and cerebrovascular responsiveness (CVR) to cognitive stimuli are reported herein. One-factor ANOVA with post hoc analyses was conducted between groups in the whole cohort and in males and females separately. Two-factor ANOVA was conducted to assess independent effects of fish oil and curcumin and a potential interaction. Correlations between outcomes (those obtained herein and previously reported) were also examined.Results: Compared with placebo, fish oil improved CVR to a processing speed test (4.4% ± 1.9% vs. -2.2% ± 2.1%; P = 0.023) and processing speed in males only (Z-score: 0.6 ± 0.2 vs. 0.1 ± 0.2; P = 0.043). Changes in processing speed correlated inversely with changes in blood pressure (R = -0.243, P = 0.006) and C-reactive protein (R = -0.183, P = 0.046). Curcumin improved CVR in a working memory test (3.6% ± 1.2% vs. -0.2% ± 0.2%, P = 0.026) and, in males only, performance of a verbal memory test compared with placebo (Z-score: 0.2 ± 0.1 vs. -0.5 ± 0.2, P = 0.039). Combining fish oil with curcumin did not produce additional benefits.Conclusions: Improvements in processing speed following fish-oil supplementation in middle-aged to older males might be mediated by improvements in circulatory function. Mechanisms underlying the cognitive benefit seen with curcumin are unknown. As cognitive benefits were found in males only, further evaluation of sex differences in responsiveness to supplementation is warranted. This trial was registered at the Australian and New Zealand Clinical Trial Register at https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370788 as ACTRN12616000732482p. [ABSTRACT FROM AUTHOR]

Context: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated.Objectives: Does oxycodone reduce chronic breathlessness compared with placebo?Methods: A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms Days 5-7. Secondary end points were average and worst breathlessness, quality of life, function, and harms.Results: Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001).Conclusion: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness. [ABSTRACT FROM AUTHOR]

Background Comparative studies suggest that DHA may have stronger serum triglyceride–lowering effects than EPA; however, the molecular basis for this differential effect remains unexplored in humans. Differential regulation of lipogenesis and triglyceride clearance are 2 possible mechanisms of action. Objectives We compared the effects of EPA and DHA supplementation on serum triglycerides, markers of lipogenesis, and lipoprotein lipase (LPL) activity in adults participating in a double-blind, multiarm, placebo-controlled parallel-group randomized trial. Lipogenesis was assessed with the lipogenic index and compound specific isotope analysis (CSIA). Methods Young, healthy normolipidemic men and women (n  = 89; 21.6 ± 0.23 y; mean ± SEM) were randomly allocated into 1 of 3 supplement groups for 12 wk: 1) olive oil, 2) ∼3 g EPA/d, and 3) ∼3 g DHA/d. Omega-3 supplements were provided in triglyceride form. Blood was collected before and after supplementation for the analysis of fatty acids and preheparin LPL activity. Variations in the 13C:12C ratio (δ13C) of palmitate (16:0) and linoleate (18:2n–6) were measured by CSIA. Results DHA supplementation reduced blood triglycerides (0.85 ± 0.04 mmol/L to 0.65 ± 0.03 mmol/L; P  < 0.01), with no change seen with EPA supplementation. DHA supplementation did not change the lipogenic index or δ13C-16:0, whereas EPA supplementation increased the lipogenic index by 11% (P  < 0.01) and δ13C-16:0 (P  = 0.03) from −23.2 ± 0.2 to −22.8 ± 0.2 milliUrey ± SEM. Conclusions Reduced triglyceride concentrations after DHA supplementation are associated with increased LPL activity, whereas the null effect of EPA supplementation on blood triglycerides may stem from the concomitant increases in lipogenesis and LPL activity. Further investigation of the differential triglyceride-lowering effects of EPA and DHA is warranted in both normolipidemic and hyperlipidemic individuals. This trial was registered at clinicaltrials.gov as NCT03378232. [ABSTRACT FROM AUTHOR]

Background Thiamin, a water-soluble B-complex vitamin, functions as a coenzyme in macronutrient oxidation and in the production of cellular ATP. Data suggest that thiamin depletion occurs in heart failure (HF). Therefore, thiamin supplementation in HF patients may improve cardiac function. Objective We sought to determine whether oral thiamin supplementation improves left ventricular ejection fraction (LVEF), exercise tolerance, and quality of life among patients with HF and reduced LVEF. Methods In this prospective, multicenter, double-blind, placebo-controlled randomized trial, eligible ambulatory patients with HF and reduced LVEF were recruited from 4 academic and community hospitals between 2010 and 2015. Participants were randomly assigned to receive either 200 mg oral thiamin mononitrate per day or placebo for 6 mo. Results Sixty-nine patients (mean ± SD age: 64 ± 12 y; 83% men; LVEF: 37% ± 11%) were randomly assigned: 34 received placebo and 35 received thiamin supplementation. Erythrocyte thiamin pyrophosphate and urine thiamin concentrations were significantly higher in the supplemented group than in the placebo group at 6 mo (P  = 0.02 and <0.001, respectively). At 6 mo, LVEF was significantly higher in the placebo group than in the thiamin group (38%; 95% CI: 36%, 39% compared with 35%; 95% CI: 33%, 37%, P  = 0.047) after adjusting for baseline measurements. There were no significant differences in Minnesota Living with Heart Failure score, distance walked in 6 min, and N-terminal prohormone of brain natriuretic peptide concentrations between the 2 groups. One patient (2.9%) in the thiamin-supplemented group and none in the control group died at 6 mo. Conclusions In ambulatory patients with HF and reduced LVEF, thiamin supplementation for 6 mo did not improve LVEF, quality of life, or exercise capacity, despite increases in thiamin concentrations. These findings do not support routine thiamin supplementation in the treatment of HF and reduced LVEF. This trial was registered at clinicaltrials.gov as NCT00959075. [ABSTRACT FROM AUTHOR]

Context: The optimal dose of fentanyl sublingual spray (FSS) for exertional dyspnea has not been determined.Objectives: We examined the effect of two doses of prophylactic FSS on exertional dyspnea.Methods: In this parallel, dose-finding, double-blind randomized clinical trial, opioid-tolerant cancer patients completed a shuttle walk test at baseline. Patients completed a second shuttle walk test 10 minutes after a single dose of FSS equivalent to either 35%-45% (high dose) or 15%-25% (low dose) of the total daily opioid dose. The primary outcome was change in modified dyspnea Borg scale (0-10) between the first and second shuttle walk tests. Secondary outcomes included adverse events as well as changes in walk distance, vital signs, and neurocognitive function.Results: Thirty of the 50 enrolled patients completed the study. High-dose FSS (n = 13) resulted in significantly lower dyspnea (mean change -1.42; 95% CI -2.37, -0.48; P = 0.007) and greater walk distance (mean change 44 m; P = 0.001) compared to baseline. Low-dose FSS (n = 17) resulted in a nonsignificant reduction in dyspnea (mean change -0.47; 95% CI -1.26, 0.32; P = 0.24) and significant increase in walk distance (mean change 24 m; P = 0.01) compared to baseline. Global evaluation showed high-dose group was more likely to report at least somewhat better improvement (64% vs. 24%; P = 0.06). No significant adverse events or detriment to vital signs or neurocognitive function was detected.Conclusion: Prophylactic FSS was well tolerated and demonstrated a dose-response relationship in improving both dyspnea and walk distance. High-dose FSS should be tested in confirmatory trials. [ABSTRACT FROM AUTHOR]

Context: Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails.Objectives: We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy.Methods: A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]-Item 5) ≥ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases.Results: Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P = 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 0.002).Conclusion: Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine. [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]

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]

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: 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]

Question Among people admitted for inpatient rehabilitation, is usual care plus standing balance circuit classes more cost-effective than usual care alone? Design Cost-effectiveness study embedded within a randomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. Participants 162 rehabilitation inpatients from a metropolitan hospital in Sydney, Australia. Intervention The experimental group received a 1-hour standing balance circuit class, delivered three times a week for 2 weeks, in addition to usual therapy. The circuit classes were supervised by one physiotherapist and one physiotherapy assistant for up to eight patients. The control group received usual therapy alone. Outcome measures Costs were estimated from routinely collected hospital use data in the 3 months after randomisation. The functional outcome measure was mobility measured at 3 months using the Short Physical Performance Battery administered by a blinded assessor. An incremental analysis was conducted and the joint probability distribution of costs and outcomes was examined using bootstrapping. Results The median cost savings for the intervention group was AUD4,741 (95% CI 137 to 9,372) per participant; 94% of bootstraps showed that the intervention was both effective and cost saving. Conclusions Two weeks of additional standing balance circuit classes delivered in addition to usual therapy resulted in decreased healthcare costs at 3 months in hospital inpatients admitted for rehabilitation. There is a high probability that this intervention is both cost saving and effective. Registration ACTRN12611000412932. [Treacy D, Howard K, Hayes A, Hassett L, Schurr K, Sherrington C (2018) Two weeks of additional standing balance circuit classes during inpatient rehabilitation are cost saving and effective: an economic evaluation. Journal of Physiotherapy 64: 41–47] [ABSTRACT FROM AUTHOR]

Question Among women in labour, does sequential application of non-pharmacological interventions relieve labour pain, shorten labour, and delay pharmacological analgesia use? Design Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Participants Eighty women admitted in labour at the end of a low-risk pregnancy. Intervention Participants in the experimental group received three interventions for up to 40 minutes each in particular stages of labour: exercise on a Swiss ball at 4 to 5 cm of cervical dilation; lumbosacral massage at 5 to 6 cm dilation; and a warm shower at >7 cm dilation. Participants in the control group received usual maternity unit care. Participants in both groups were encouraged to try not to avoid or delay use of pharmacological analgesia. Outcome measures Pain severity was reported on a visual analogue scale. Maternal and neonatal data were collected from official birth records. Satisfaction with care was recorded with a questionnaire. Results Some participants took analgesic medication before the study was complete, so pain was analysed with a last observation carried forward approach. In this analysis, the experimental group had significantly lower pain severity immediately after: exercises (MD 24 mm, 95% CI 15 to 34), massage (14 mm, 95% CI 4 to 25), and showering (17 mm, 95% CI 5 to 29), which allowed delayed and reduced use of analgesic medication. Other significant benefits included: faster expulsion (MD 18 minutes, 95% CI 5 to 30), improved neonatal status, and higher maternal satisfaction. No adverse effects were identified. Conclusion This sequence of non-pharmacological interventions significantly reduced labour pain from 4 cm to beyond 7 cm of cervical dilation, as reflected in decreased and delayed use of analgesic medication. Women in labour could be encouraged to use these interventions, especially if they seek to minimise or delay use of analgesic medication. Trial registration NCT01389128. [Gallo RBS, Santana LS, Marcolin AC, Duarte G, Quintana SM (2018) Sequential application of non-pharmacological interventions reduces the severity of labour pain, delays use of pharmacological analgesia, and improves some obstetric outcomes: a randomised trial. Journal of Physiotherapy 64: 33–40] [ABSTRACT FROM AUTHOR]

Background: There are conflicting views in the literature as to whether vitamin D2 and vitamin D3 are equally effective in increasing and maintaining serum concentrations of 25-hydroxyvitamin D [25(OH)D], particularly at lower doses of vitamin D. Objectives: We aimed to investigate whether vitamin D2 or vitamin D3 fortified in juice or food, at a relatively low dose of 15 μg/d, was effective in increasing serum total 25(OH)D and to compare their respective efficacy in South Asian and white European women over the winter months within the setting of a large randomized controlled trial. Design: A randomized, double-blind, placebo-controlled food-fortification trial was conducted in healthy South Asian and white European women aged 20-64 y (n = 335; Surrey, United Kingdom) who consumed placebo, juice supplemented with 15 μg vitamin D2, biscuit supplemented with 15 μg vitamin D2, juice supplemented with 15 μg vitamin D3, or biscuit supplemented with 15 μg vitamin D3 daily for 12 wk. Serum 25(OH)D was measured by liquid chromatography-tandem mass spectrometry at baseline and at weeks 6 and 12 of the study. Results: Postintervention in the 2 ethnic groups combined, both the vitamin D3 biscuit and the vitamin D3 juice groups showed a significantly greater absolute incremental change (Δ) in total 25(OH)D when compared with the vitamin D2 biscuit group [Δ (95% CI): 15.3 nmol/L (7.4, 23.3 nmol/L) (P < 0.0003) and 16.0 nmol/L (8.0, 23.9 nmol/L) (P < 0.0001)], the vitamin D2 juice group [Δ (95% CI): 16.3 nmol/L (8.4, 24.2 nmol/L) (P < 0.0001) and 16.9 nmol/L (9.0, 24.8 nmol/L) (P < 0.0001)], and the placebo group [Δ (95% CI): 42.3 nmol/L (34.4, 50.2 nmol/L) (P < 0.0001) and 42.9 nmol/L (35.0, 50.8 nmol/L) (P < 0.0002)]. Conclusions: With the use of a daily dose of vitamin D relevant to public health recommendations (15 μg) and in vehicles relevant to food-fortification strategies, vitamin D3 was more effective than vitamin D2 in increasing serum 25(OH)D in the wintertime. Vitamin D3 may therefore be a preferential form to optimize vitamin D status within the general population. [ABSTRACT FROM AUTHOR]

Background: Green tea has been suggested to improve cardiovascular disease risk factors, including circulating lipid variables. However, current evidence is predominantly based on small, short-term randomized controlled trials conducted in diverse populations. Objective: The aim of this study was to examine the efficacy and impact of green tea extract (GTE) supplementation high in epigallocatechin gallate (EGCG) on blood lipids in healthy postmenopausal women. Design: This was an ancillary study of a double-blind, randomized, placebo-controlled, parallel-arm trial investigating the effects of a GTE supplement containing 1315 mg catechins (843 mg EGCG) on biomarkers of breast cancer risk. Participants were randomly assigned to receive GTE (n = 538) or placebo (n = 537) and were stratified by catechol-O-methyltransferase (COMT) genotype activity (high COMT compared with low or intermediate COMT genotype activity). They consumed either 4 GTE or identical placebo capsules daily for 12 mo. A total of 936 women completed this substudy. Circulating lipid panels including total cholesterol (TC), HDL cholesterol, and triglycerides were measured at baseline and at months 6 and 12. Results: Compared with placebo, 1-y supplementation with GTE capsules resulted in a significant reduction in circulating TC (-2.1% compared with 0.7%; P = 0.0004), LDL cholesterol (-4.1% compared with 0.9%; P < 0.0001) and non-HDL cholesterol (-3.1% compared with 0.4%; P = 0.0032). There was no change in HDL-cholesterol concentration, but triglyceride concentrations increased by 3.6% in the GTE group, whereas they decreased by 2.5% in the placebo group (P = 0.046). A significant reduction in TC was observed only among women with high (i.e., ≥200 mg/dL) baseline TC concentrations (P-interaction = 0.01) who consumed GTE capsules. The effect of GTE on the increase in triglycerides was mainly observed among obese women and statin users (P-interaction = 0.06). Conclusion: Supplementation with GTE significantly reduced circulating TC and LDL-cholesterol concentrations, especially in those with elevated baseline TC concentrations. This trial was registered at clinicaltrials.gov as NCT00917735. [ABSTRACT FROM AUTHOR]

Background: Children in northern latitudes are at high risk of vitamin D deficiency during winter because of negligible dermal vitamin D3 production. However, to our knowledge, the dietary requirement for maintaining the nutritional adequacy of vitamin D in young children has not been investigated. Objective: We aimed to establish the distribution of vitamin D intakes required to maintain winter serum 25-hydroxyvitamin D [25(OH)D] concentrations above the proposed cutoffs (25, 30, 40, and 50 nmol/L) in white Danish children aged 4-8 y living at 55°N. Design: In a double-blind, randomized, controlled trial 119 children (mean age: 6.7 y) were assigned to 0 (placebo), 10, or 20 μg vitamin D3/d supplementation for 20 wk. We measured anthropometry, dietary vitamin D, and serum 25(OH)D with liquid chromatography- tandem mass spectrometry at baseline and endpoint. Results: The mean ± SD baseline saum 25(OH)D was 56.7 ± 12.3 nmol/L (range: 28.7-101.4 nmol/L). Serum 25(OH)D increased by a mean ± SE of 4.9 ± 1.3 and 17.7 ± 1.8 nmol/L in the groups receiving 10 and 20 mg vitamin D3/d, respectively, and decreased by 24.1 ± 1.2 nmol/L in the placebo group (P < 0.001). A nonlinear model of serum 25(OH)D as a function of total vitamin D intake (diet and supplements) was fit to the data. The estimated vitamin D intakes required to maintain winter serum 25(OH)D >30 (avoiding deficiency) and >50 nmol/L (ensuring adequacy) in 97.5% of participants were 8.3 and 19.5 μg/d, respectively, and 4.4 μg/d was required to maintain serum 25(OH)D >40 nmol/L in 50% of participants. Conclusions: Vitamin D intakes between 8 and 20 μg/d are required by white 4- to 8-y-olds during winter in northern latitudes to maintain serum 25(OH)D >30-50 nmol/L depending on chosen serum 25(OH)D threshold. This trial was registered at clinicaltrials. gov as NCT02145195. [ABSTRACT FROM AUTHOR]

Background: To date, most studies on the anti-inflammatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in humans have used a mixture of the 2 fatty acids in various forms and proportions. Objectives: We compared the effects of EPA supplementation with those of DHA supplementation (re-esterified triacylglycerol; 90% pure) on inflammation markers (primary outcome) and blood lipids (secondary outcome) in men and women at risk of cardiovascular disease. Design: In a double-blind, randomized, crossover, controlled study, healthy men (n = 48) and women (n = 106) with abdominal obesity and low-grade systemic inflammation consumed 3 g/d of the following supplements for periods of 10 wk: 1) EPA (2.7 g/d), 2) DHA (2.7 g/d), and 3) corn oil as a control with each supplementation separated by a 9-wk washout period. Primary analyses assessed the difference in cardiometabolic outcomes between EPA and DHA. Results: Supplementation with DHA compared with supplementation with EPA led to a greater reduction in interleukin-18 (IL-18) (-7.0% ± 2.8% compared with -0.5% ± 3.0%, respectively; P = 0.01) and a greater increase in adiponectin (3.1% ± 1.6% compared with -1.2% ± 1.7%, respectively; P < 0.001). Between DHA and EPA, changes in CRP (-7.9% ± 5.0% compared with -1.8% ± 6.5%, respectively; P = 0.25), IL-6 (212.0% ± 7.0% compared with 213.4% ± 7.0%, respectively; P = 0.86), and tumor necrosis factor-a (-14.8% ± 5.1% compared with -7.6% ± 10.2%, respectively; P = 0.63) were NS. DHA compared with EPA led to more pronounced reductions in triglycerides (-13.3% ± 2.3% compared with -11.9% ± 2.2%, respectively; P = 0.005) and the cholesterol:HDL-cholesterol ratio (-2.5% ± 1.3% compared with 0.3% ± 1.1%, respectively; P = 0.006) and greater increases in HDL cholesterol (7.6% ± 1.4% compared with -0.7% ± 1.1%, respectively; P < 0.0001) and LDL cholesterol (6.9% ± 1.8% compared with 2.2% ± 1.6%, respectively; P = 0.04). The increase in LDLcholesterol concentrations for DHA compared with EPAwas significant in men but not in women (P-treatment 3 sex interaction = 0.046). Conclusions: DHA is more effective than EPA in modulating specific markers of inflammation as well as blood lipids. Additional studies are needed to determine the effect of a long-term DHA supplementation per se on cardiovascular disease risk. This trial was registered at clinicaltrials.gov as NCT01810003. [ABSTRACT FROM AUTHOR]

Background: Severe, persistent inguinal postherniorrhaphy pain (PIPP) is a debilitating condition that develops in 2-5% of patients. PIPP may be neuropathic in nature, yet the lesion in the peripheral nervous system has not been located. Most PIPP-patients demonstrate a tender point (TP) in the medial aspect of the inguinal region that triggers pain upon minimal pressure. As TPs may play a role in the pathophysiology of PIPP, the aim of this trial was to investigate the analgesic effects of local anaesthetic TP-blockade.Methods: A randomized, double-blind, placebo-controlled, crossover trial was performed in 14 PIPP-patients and six healthy volunteers. All participated in two sessions, seven days apart, receiving 10 ml of 0.25% bupivacaine or normal saline via an ultrasound-guided fascial plane block at the TP. The TP-area was used for pain assessments (at rest, on movement, with 100 kPa pressure-algometry) and quantitative sensory testing (pressure pain thresholds, thermal detection/pain thresholds, supra-threshold heat perception), before and after the TP-blockade.Results: The median (95% CI) reduction in pain was 63% (44.1 to 73.6%) after bupivacaine compared with 36% (11.6 to 49.7%; P=0.003) after placebo. Significant increases in cool detection (P=0.01) and pressure pain thresholds (P=0.009) with decreases in supra-threshold heat pain perception (P=0.003) were seen after bupivacaine only. In four out of six volunteers, increased thermal and evoked-pain thresholds after bupivacaine compared with placebo, was demonstrated.Conclusions: This trial demonstrates that peripheral afferent input from the TP-area is important for maintenance of spontaneous and evoked pain in PIPP.Clinical Trial Registration: NCT02065219. [ABSTRACT FROM AUTHOR]

Background: Parenteral nutrition is central to the care of very immature infants. Current international recommendations favor higher amino acid intakes and fish oil-containing lipid emulsions. Objective: The aim of this trial was to compare 1) the effects of high [immediate recommended daily intake (Imm-RDI)] and low [incremental introduction of amino acids (Inc-AAs)] parenteral amino acid delivery within 24 h of birth on body composition and 2) the effect of a multicomponent lipid emulsion containing 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil (SMOF) with that of soybean oil (SO)-based lipid emulsion on intrahepatocellular lipid (IHCL) content. Design: We conducted a 2-by-2 factorial, double-blind, multicenter randomized controlled trial. Results: We randomly assigned 168 infants born at,31 wk of gestation. We evaluated outcomes at term in 133 infants. There were no significant differences between Imm-RDI and Inc-AA groups for non-adipose mass [adjusted mean difference: 1.0 g (95% CI: -108, 111 g; P = 0.98)] or between SMOF and SO groups for IHCL [adjusted mean SMOF:SO ratio: 1.1 (95% CI: 0.8, 1.6; P = 0.58]. SMOF does not affect IHCL content. There was a significant interaction (P = 0.05) between the 2 interventions for nonadipose mass. There were no significant interactions between group differences for either primary outcome measure after adjusting for additional confounders. Imm-RDI infants were more likely than Inc-AA infants to have blood urea nitrogen concentrations >7 mmol/L or >10 mmol/L, respectively (75% compared with 49%, P < 0.01; 49% compared with 18%, P < 0.01). Head circumference at term was smaller in the Imm-RDI group [mean difference: 20.8 cm (95% CI: 21.5, -0.1 cm; P = 0.02)]. There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, incidence of conjugated hyperbilirubinemia, weight, length, mortality, and brain volumes. Conclusion: Imm-RDI of parenteral amino acids does not benefit body composition or growth to term and may be harmful. This trial was registered at www.isrctn.com as ISRCTN29665319 and at eudract.ema.europa.eu as EudraCT 2009-016731-34. [ABSTRACT FROM AUTHOR]

Background: Unanticipated difficult intubation remains a challenge in anaesthesia. The Simplified Airway Risk Index (SARI) is a multivariable risk model consisting of seven independent risk factors for difficult intubation. Our aim was to compare preoperative airway assessment based on the SARI with usual airway assessment.Methods: From 01.10.2012 to 31.12.2013, 28 departments were cluster-randomized to apply the SARI model or usual airway assessment. The SARI group implemented the SARI model. The Non-SARI group continued usual airway assessment, thus reflecting a group of anaesthetists' heterogeneous individual airway assessments. Preoperative prediction of difficult intubation and actual intubation difficulties were registered in the Danish Anaesthesia Database for both groups. Patients who were preoperatively scheduled for intubation by advanced techniques (e.g. video laryngoscopy; flexible optic scope) were excluded from the primary analysis. Primary outcomes were the proportions of unanticipated difficult and unanticipated easy intubation.Results: A total of 26 departments (15 SARI and 11 Non-SARI) and 64 273 participants were included. In the primary analyses 29 209 SARI and 30 305 Non-SARI participants were included.In SARI departments 2.4% (696) of the participants had an unanticipated difficult intubation vs 2.4% (723) in Non-SARI departments. Odds ratio (OR) adjusted for design variables was 1.03 (95% CI: 0.77-1.38). The proportion of unanticipated easy intubation was 1.42% (415) in SARI departments vs 1.00% (302) in Non-SARI departments. Adjusted OR was 1.26 (0.68-2.34).Conclusions: Using the SARI compared with usual airway assessment we detected no statistical significant changes in unanticipated difficult- or easy intubations.Clinical Trial Registration: NCT01718561. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is fundamental for bone health. A high proportion of Canadian 2- to 8-y-olds do not meet the Estimated Average Requirement (EAR) of 400 IU/d. Objective: The objective was to determine whether vitamin D intakes consistent with the EAR or Recommended Dietary Allowance (RDA), through fortification of additional dairy products, would result in higher vitamin D status in young children. Design: Participants aged 2-8 y (n = 77; Montreal, Canada) were randomly assigned to 1 of 3 dietary vitamin D targets (control; EAR: 400 IU/d; or RDA: 600 IU/d) for 12 wk (January to April 2014). Anthropometric measurements, demographic characteristics, dietary intakes, fasting serum parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], and ionized calcium were compared by using mixed-model ANOVA. Results: Participants' mean ± SD age was 5.1 ± 1.9 y; 54.5% were boys with body mass index z scores of 0.50 ± 0.85. Compliance was 85% overall. No differences were observed in baseline dietary vitamin D intakes or serum 25(OH)D. At 12 wk, the EAR and RDA groups had significantly higher vitamin D intakes [median (IQR): control, 227 (184-305) IU/d; EAR, 410 (363-516) IU/d; and RDA, 554 (493-653) IU/d; P < 0.05] and serum 25(OH)D concentrations (control: 55.8 ± 12.3 nmol/L; EAR: 64.1 ± 10.0 nmol/L; and RDA: 63.7 ± 12.4 nmol/L; P < 0.05) than the control group. Ninety-six percent of children in the EAR and RDA groups and 67% of the control group had 25(OH)D concentrations ≥50 nmol/L. Conclusion: Increasing the vitamin D intakes of young children through fortification of alternative dairy products results in significantly higher serum concentrations of 25(OH)D and a significantly greater proportion of children with serum 25(OH)D ≥50 nmol/L during periods of minimal ultraviolet B radiation exposure. This trial was registered at clinicaltrials.gov as NCT02097160 and had Health Canada Temporary Marketing Authorization Letters for both products (TM-13-0432 and TM-13-0433). [ABSTRACT FROM AUTHOR]

Background: Tuberculosis, including multidrug-resistant tuberculosis (MDR-TB), is a major global health problem. Individuals with tuberculosis disease commonly exhibit vitamin D deficiency, which may adversely affect immunity and the response to therapy. Objective: We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease. Design: The study was a double-blind, randomized, placebo-controlled, intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi, Georgia. Subjects were randomly assigned to receive oral vitamin D3 [50,000 IUs (1.25 mg) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk] or a placebo concomitant with standard first-line antituberculosis drugs. The primary outcome was the time for the conversion of a Mycobacterium tuberculosis (Mtb) sputum culture to negative. Results: Baseline characteristics between groups were similar. Most subjects (74%) were vitamin D deficient (plasma 25-hydroxyvitamin D [25(OH)D] concentration,50 nmol/L). With vitamin D3, plasma 25(OH)D concentrations peaked at ~250 nmol/L by 8 wk and decreased to ~125 nmol/L at week 16. Adverse events and plasma calcium concentrations were similar between groups. In 192 subjects with culture-confirmed tuberculosis, an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [29 and 27 d, respectively; HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33). Eight-week culture-conversion rates were also similar (84.0% and 82.1% for vitamin D3 and placebo, respectively; P = 0.99). Conclusion: A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086. [ABSTRACT FROM AUTHOR]

Context Does octreotide reduce vomiting in cancer-associated bowel obstruction? Objectives To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. Methods Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine [200 mg/24 hours], dexamethasone [8 mg/24 hours], and parenteral hydration [10–20 mL/kg/24 hours]). The primary outcome was patient-reported days free of vomiting at 72 hours. Results In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours ( P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19–0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide ( P = 0.004), potentially reflecting increased colicky pain. Conclusion Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted. [ABSTRACT FROM AUTHOR]

Background: Plant sterols (PSs) lower LDL cholesterol, an established risk factor for coronary artery disease (CAD). No direct evidence is available supporting a reduced risk of CAD for foods with added PSs. Endothelial dysfunction is seen as an early indicator of atherosclerotic damage. Objectives: This study was primarily designed to investigate the effect of a low-fat spread with added PSs on brachial artery endothelial function as measured by flow-mediated dilation (FMD). Second, effects on arterial stiffness, blood pressure, serum lipids, and plasma PS concentrations were investigated. We hypothesized that PSs would not worsen FMD but would rather modestly improve FMD. Design: This study had a double-blind, randomized, placebo-controlled, parallel design. After a 4-wk run-in period, 240 hypercholesterolemic but otherwise healthy men and women consumed 20 g/d of low-fat spread without (control) or with added PSs (3 g/d) during 12 wk. Pre- and postintervention, vascular function measurements and blood sampling were performed. Results: In total, 232 participants completed the study period. For the primary endpoint FMD, 199 participants were included in the statistical analysis. PS intake did not affect FMD (+0.01 percentage points; 95% CI: —0.73, 0.75) compared with control. Measures of arterial stiffness (pulse wave velocity and augmentation index) and blood pressure were also not significantly changed compared with control. After PS intervention, LDL cholesterol significantly decreased on average by 0.26 µmol/L (95% CI: —0.40, —0.12) or 6.7% compared with control. Plasma sitosterol and campesterol concentrations significantly increased in the PS group up to on average 11.5 µmol/L and 13.9 µmol/L (expressed as geometric means), respectively. Conclusions: The intake of a low-fat spread with added PSs neither improved nor worsened FMD or other vascular function markers in hypercholesterolemic men and women. As expected, serum LDL cholesterol decreased, whereas plasma PSs increased after PS intake. This study was registered at clinicaltrials.gov as NCT01803178. Am J Clin Nutr 2015;101:733-41. [ABSTRACT FROM AUTHOR]

Background: Although iron supplementation in malaria-free areas mostly reduces infectious morbidity, it can sometimes increase morbidity from infections as a result of the dependence of pathogenic microorganisms on iron. Supplementation with n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) improved morbidity in several human studies. However, information on the combined effect of iron and n-3 LCPUFA supplementation on infectious morbidity is limited. Objective: We determined whether n-3 LCPUFAs and iron supplementation, alone or in combination, affected absenteeism and illness in iron-deficient schoolchildren with low fish intake. Design: A total of 321 South African children (aged 6-11 y) with iron deficiency (ID) were randomly divided into 4 groups to receive 1) iron plus placebo, 2) a mixture of docosahexaenoic acid and eicosa-pentaenoic acid (DHA/EPA) plus placebo, 3) iron plus DHA/EPA, or 4) placebo plus placebo as oral supplements 4 times/wk for 8.5 mo. Morbidity was recorded, and iron-status indexes were measured. The total phospholipid fatty acid composition of peripheral blood mononuclear cell membranes was analyzed in a subsample (n = 130). Results: Iron supplementation increased the number of days with illness when all symptoms were considered (B: 0.87; 95% CI: 0.71, 1.03) as well as illness that was specifically caused by respiratory symptoms (B: 1.45; 95% CI: 1.21, 1.70), whereas DHA/EPA reduced the number of days with illness at school (B: 20.96; 95% CI: - 1.33, -0.59). The increases caused by iron were reduced to the levels seen in the placebo plus placebo group when iron was provided in combination with DHA/EPA as indicated by significant iron 3 DHA/EPA interactions (both P < 0.001). Conclusion: Iron supplementation increased morbidity (mostly respiratory) in iron-deficient South African schoolchildren with low DHA/EPA intake, but when iron was given in combination with DHA/EPA, this effect was prevented. This trial was registered at clinicaltrials.gov as NCT01092377. [ABSTRACT FROM AUTHOR]

Background: Benefits of plant sterols (PS) for cholesterol lowering are compromised by large variability in efficacy across individuals. High fractional cholesterol synthesis measured by deuterium incorporation has been associated with nonresponse to PS consumption; however, prospective studies that show this association have yet to be conducted. Objective: The goal was to test whether the lathosterol-to-cholesterol ratio (L:C ratio), a surrogate marker of endogenous cholesterol synthesis, serves as an a priori predictor of cholesterol lowering in response to PS consumption. Design: Sixty-three mildly hypercholesterolemic adults who were preselected as possessing either high endogenous cholesterol synthesis [HS; n = 24; L:C = 2.03 ± 0.39 mmol/mmol (mean ± SD)] or low endogenous cholesterol synthesis (LS; n = 39; L:C = 0.99 ± 0.28 mmol/mmol) on the basis of baseline L:C consumed 2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterol sterol concentrations were measured at the end of each phase. Results: PS consumption lowered total cholesterol (TC; 20.25 ± 0.05 mmol/L; P < 0.0001) and LDL cholesterol (20.17 ± 0.04 mmol/L; P < 0.0001) overall. Specifically, LS individuals responded to PS treatment with a reduction in TC (20.40 ± 0.07 mmol/L; P < 0.0001) and LDL cholesterol (20.29 ± 0.05 mmol/L; P = 0.0002), whereas HS individuals failed to show cholesterol lowering (TC: 20.09 ± 0.09 mmol/L; P = 0.2843; LDL cholesterol: 20.05 ± 0.07 mmol/L; P = 0.4917). The odds of LS participants responding to PS consumption with cholesterol lowering better than the mean cholesterol lowering in all participants were 4.25 (95% CI: 1.242, 14.556; P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) for LDL cholesterol, which was higher than for HS participants. Conclusions: The L:C ratio predicts the extent of reduction in circulating TC and LDL cholesterol in response to PS consumption. Cholesterol synthesis assessment may thus have a use in identifying responders and nonresponders to PS therapy. This trial was registered at clinicaltrials.gov as NCT01131832. [ABSTRACT FROM AUTHOR]

Abstract: Context: Dyspnea is one of the most distressing symptoms in patients with cancer, and often worsens with breakthrough episodes on exertion. We hypothesized that fentanyl given prophylactically may alleviate breakthrough dyspnea. Objectives: To determine the feasibility of conducting a randomized trial of subcutaneous fentanyl in patients with cancer, and examine the effects of fentanyl on dyspnea, walk distance, vital signs, and adverse events. Methods: In this double-blind, randomized, controlled trial, we asked ambulatory patients with breakthrough dyspnea to perform a baseline six minute walk test (6MWT), and then assigned them to either subcutaneous fentanyl or placebo 15 minutes before a second 6MWT. We documented the change in dyspnea Numeric Rating Scale (NRS) score, walk distance, vital signs, and adverse events between the first and second 6MWT. Results: A total of 20 patients were enrolled (1:1 ratio) without attrition. Comparison between baseline and second walk showed that fentanyl was associated with significant improvements in dyspnea NRS score at the end of the 6MWT (mean [95% CI] −1.8 [−3.2, −0.4]), dyspnea NRS score at rest of 15 minutes after drug administration (−0.9 [−1.8, −0.04]), Borg Scale fatigue score at the end of the 6MWT (−1.3 [−2.4, −0.2]), 6MWT distance (+37.2m [5.8, 68.6]), and respiratory rate (−2.4 [−4.5, −0.3]). Nonstatistically significant improvements also were observed in the placebo arm, with no difference between the two study arms. No significant adverse effects were observed. Conclusion: Prophylactic fentanyl was safe and improved dyspnea, fatigue, walk distance, and respiratory rate. We also observed a large placebo effect. Our results justify larger randomized controlled trials with higher fentanyl doses (clinicaltrials.gov registration: NCT01515566). [Copyright &y& Elsevier]

Objectives: The purpose of this study was to assess the effects of qili qiangxin capsules in patients with chronic heart failure (CHF). Background: Qili qiangxin capsules are a traditional Chinese medicine that has been approved in China for the treatment of CHF, but the evidence supporting its efficacy remains unclear. Methods: A total of 512 patients with CHF were enrolled and randomly assigned to receive the placebo or qili qiangxin capsules in addition to their standard medications for the treatment of CHF. The primary endpoint was the reduction or percent change in the plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) level during 12 weeks of treatment. Results: At the 12-week follow-up, a significant reduction in the NT-proBNP level from baseline was observed in both groups, but the qili qiangxin capsule group demonstrated a significantly greater reduction than the placebo group (p = 0.002); 47.95% of patients in the qili qiangxin capsule group demonstrated reductions in NT-proBNP levels of at least 30% compared with 31.98% of patients in the placebo group (p < 0.001). Treatment with qili qiangxin capsules also demonstrated superior performance in comparison to the placebo with respect to New York Heart Association functional classification, left ventricular ejection fraction, 6-min walking distance, and quality of life. Conclusions: On a background of standard treatment, qili qiangxin capsules further reduced the levels of NT-proBNP. Together, our data suggest that qili qiangxin capsules could be used in combination therapy for CHF. [Copyright &y& Elsevier]

Objective: To compare the efficacy of leuprolide and continuous oral contraceptives in the treatment of endometriosis-associated pain.Design: Prospective, randomized, double-blind controlled trial.Setting: Academic medical centers in Rochester, New York, and Boston, Massachusetts.Patient(s): Forty-seven women with endometriosis-associated pelvic pain.Intervention(s): Forty-eight weeks of either depot leuprolide, 11.25 mg IM every 12 weeks with hormonal add-back using norethindrone acetate 5 mg orally, daily; or a generic monophasic oral contraceptive (1 mg norethindrone + 35 mg ethinyl estradiol) given daily.Main Outcome Measure(s): Biberoglu and Behrman (B&B) pain scores, numerical rating scores (NRS), Beck Depression Inventory (BDI), and Index of Sexual Satisfaction (ISS).Result(s): Based on enrollment of 47 women randomized to continuous oral contraceptives and to leuprolide, there were statistically significant declines in B&B, NRS, and BDI scores from baseline in both groups. There were no significant differences, however, in the extent of reduction in these measures between the groups.Conclusion(s): Leuprolide and continuous oral contraceptives appear to be equally effective in the treatment of endometriosis-associated pelvic pain. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) is the most common form of arthritis and the second most common cause of long-term disability among middle-aged and older adults in the United States. Methylsulfonylmethane (MSM) is a popular dietary supplement used as a single agent and in combination with other nutrients, and purported to be beneficial for arthritis. However, there is paucity of evidence to support the use of MSM.Methods: A randomized, double-blind, placebo-controlled trial was conducted. Fifty men and women, 40-76 years of age with knee OA pain were enrolled in an outpatient medical center. Intervention was MSM 3g or placebo twice a day for 12 weeks (6g/day total). Outcomes included the Western Ontario and McMaster University Osteoarthritis Index visual analogue scale (WOMAC), patient and physician global assessments (disease status, response to therapy), and SF-36 (overall health-related quality of life).Results: Compared to placebo, MSM produced significant decreases in WOMAC pain and physical function impairment (P<0.05). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM also produced improvement in performing activities of daily living when compared to placebo on the SF-36 evaluation (P<0.05).Conclusion: MSM (3g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed. [ABSTRACT FROM AUTHOR]

Data suggest that soy protein, a source of isoflavones, may have favorable effects on cardiovascular risk factors. Women (n = 205), ages 49-65 y, were randomized into this double blind, placebo-controlled trial of 43.5 mg red clover-derived isoflavones/d. A total of 177 women completed the trial. There were no differences between treatments for changes from baseline to 12 mo in total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, systolic and diastolic blood pressures, fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1) (P >/= 0.1). Interactions between treatment and menopausal status were significant for changes in triglycerides and PAI-1 (P = 0.02 and P = 0.01), and changes were significant among perimenopausal women. In the isoflavone and placebo groups, changes in triglycerides were -0.2 +/- 0.6 and 0.4 +/- 0.6 mmol/L, P = 0.02, and changes in PAI-1 were -3.06 +/- 5.88 and 4.95 +/- 6.25 IU/L, P = 0.004, respectively. Interactions between apolipoprotein E (apoE) genotype and treatment tended to be significant for changes in total and LDL cholesterol (P = 0.06 and P = 0.05), and differences between treatments were significant in E2/E3 women. In the isoflavone and placebo groups, changes in total cholesterol were -0.61 +/- 0.79 and 0.18 +/- 0.79 mmol/L, P = 0.03, and changes in LDL cholesterol were -0.84 +/- 0.79 and -0.04 +/- 0.69 mmol/L, P = 0.02, respectively. Although there were potentially beneficial changes in triglycerides and PAI-1 among perimenopausal women consuming isoflavones, this study suggests that isoflavones alone are not responsible for the well-documented effects of soy protein on blood lipids. A larger study is required to confirm the effect modification by apoE genotype. [ABSTRACT FROM AUTHOR]

Background: Torsemide has predictable absorption compared to furosemide. Thereby, torsemide results in more constant exposure to active drug. Our hypothesis was that this pharmacokinetic difference between these commonly used loop diuretics may translate into disparate antihypertensive responses in patients with chronic kidney disease (CKD).Methods: We conducted a randomized, double-blind, two-period, crossover trial to compare the pharmacodynamics of torsemide and furosemide, in 14 subjects with stage 2 or 3 CKD. We first performed an inpatient study, where after the subjects were brought into sodium balance on a 200 mEq per day diet, a single bioequivalent dose of oral loop diuretic was administered with an intervening washout period. Measurements of urinary electrolytes were made. Subjects then participated in an outpatient study, wherein they received daily therapy for 3 weeks with the loop diuretics in random order. Twenty four-hour ambulatory blood pressure monitoring was performed before and after each drug to assess the antihypertensive response.Results: In the inpatient phase, furosemide increased urinary sodium excretion from average (+/-SD) 199 +/- 49 mEq/day to 357 +/- 96 mEq/day and torsemide increased urinary sodium excretion from 213 +/- 79 mEq/day to 398 +/- 142 mEq/day. These differences between the diuretics were not significant, confirming bioequivalence. In the outpatient phase, furosemide reduced 24-hour ambulatory blood pressure from 147 +/- 17/78 +/- 11 mm Hg to 138 +/- 21/74 +/- 12 mm Hg (P = 0.021) and torsemide reduced it from 143 +/- 18/75 +/- 10 mm Hg to 133 +/- 19/71 +/- 10 mm Hg (P = 0.007). Although each diuretic was effective in reducing ambulatory blood pressure, the differences between diuretics were not statistically significant.Conclusion: Bioequivalent doses of torsemide and furosemide given in a randomized, double-blind design fail to demonstrate superiority of torsemide with respect to natriuresis or 24-hour ambulatory blood pressure control in subjects with stages 2 and 3 CKD. [ABSTRACT FROM AUTHOR]

Objective: To determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility.Design: Multicenter, double-blind, randomized, placebo-controlled trial with an internal pilot study.Setting: Nine fertility centers in the United States from December 2015 to December 2018.Patient(s): Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency.Intervention(s): Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l-carnitine, 20 mg of zinc, 1,000 μg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6.Main Outcome Measure(s): Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment.Result(s): In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median -4.0 [interquartile range-12.0, 5.7] million/mL) and placebo group (+2.4 [-9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%.Conclusion(s): Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates.Clinical Trial Registration Number: NCT02421887. [ABSTRACT FROM AUTHOR]

Context: Dexamethasone is often used to treat dyspnea in cancer patients, but evidence is lacking.Objectives: We determined the feasibility of conducting a randomized trial of dexamethasone in cancer patients and estimated the efficacy of dexamethasone in the treatment of dyspnea.Methods: In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily × four days then 4 mg twice daily × three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0-10 numeric rating scale), spirometry measures, quality of life, and toxicities.Results: A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea numeric rating scale of -1.9 (95% CI -3.3 to -0.5, P = 0.01) by Day 4 and -1.8 (95% CI -3.2 to -0.3, P = 0.02) by Day 7. In contrast, placebo was associated with a reduction of -0.7 (95% CI -2.1 to 0.6, P = 0.38) by Day 4 and -1.3 (95% CI -2.4 to -0.2, P = 0.03) by Day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities.Conclusion: A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings.Trial Registration: ClinicalTrials.govNCT01670097. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy and safety of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis. Methods A double-blind, randomized, placebo controlled study randomized 35 patients presenting sciatica pain associated with post-operative peridural lumbar fibrosis to 2 groups: IFX ( n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo n = 17), a single saline serum injection. The primary outcome was a 50% reduction in sciatica pain on visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Québec disability score, drug sparing effect and tolerance at days 10, 30, 90, and 180. Results At day 10, the placebo and IFX groups did not differ in the primary outcome (50% reduction in sciatica pain observed in 3 [17.6%] vs 5 [27.8%] patients, p = 0.69). The number of patients reaching the Patient Acceptable Symptom State for radicular pain was significantly higher in the placebo than IFX group after injection (12 [70.6%] vs 5 [27.8%], p = 0.01). The 2 groups were comparable for all other secondary outcomes. Conclusion Treatment with a single 3-mg/kg IFX injection for post-operative peridural lumbar fibrosis-associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection. [ABSTRACT FROM AUTHOR]