PLoS Clinical Trials

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EISSN : 15555887
Current Publisher: Public Library of Science (PLoS) (10.1371)
Total articles ≅ 64
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Charles Kooperberg, Mary Cushman, Judith Hsia, Jennifer G Robinson, Aaron K Aragaki, John K Lynch, Alison E Baird, Karen C Johnson, Lewis H Kuller, Shirley A. A Beresford, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020028

The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT). The hormone trials were randomized, double-blind, and placebo controlled. The Women's Health Initiative trials were conducted at 40 clinical centers in the United States. The trials enrolled 27,347 postmenopausal women, aged 50–79 y. We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03). Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance. Background: The Women's Health Initiative hormone trials originally set out to evaluate whether postmenopausal hormone therapy (HT, estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced the risk of heart attacks and strokes, as compared to placebo. The trials were stopped early, and the investigators found that both estrogen alone, as well as estrogen plus progestin increased the risk of stroke amongst women participating in the trials. As part of a secondary analysis of data from these trials, the investigators aimed to explore possible associations between various biological markers (such as variants in particular genes, and levels of particular lipids, proteins, and other markers in blood), and the risk of a woman experiencing a stroke in the trials. Specifically, they wanted to evaluate whether there was any evidence for particular markers being associated with the risk of a stroke; and then whether that risk was modified by whether a woman took HT in the trials. What the trial...
Ingrid M Bakker, Berend Terluin, Harm Van Marwijk, Daniëlle A. W. M Van Der Windt, Frank Rijmen, Willem Van Mechelen, Wim A. B Stalman
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020026

Mental health problems often affect functioning to such an extent that they result in sick leave. The worldwide reported prevalence of mental health problems in the working population is 10%–18%. In developed countries, mental health problems are one of the main grounds for receiving disability benefits. In up to 90% of cases the cause is stress-related, and health-care utilisation is mainly restricted to primary care. The aim of this study was to assess the effectiveness of our Minimal Intervention for Stress-related mental disorders with Sick leave (MISS) in primary care, which is intended to reduce sick leave and prevent chronicity of symptoms. Cluster-randomised controlled educational trial. Primary health-care practices in the Amsterdam area, The Netherlands. A total of 433 patients (MISS n = 227, usual care [UC] n = 206) with sick leave and self-reported elevated level of distress. Forty-six primary care physicians were randomised to either receive training in the MISS or to provide UC. Eligible patients were screened by mail. The primary outcome measure was duration of sick leave until lasting full return to work. The secondary outcomes were levels of self-reported distress, depression, anxiety, and somatisation. No superior effect of the MISS was found on duration of sick leave (hazard ratio 1.06, 95% confidence interval 0.87–1.29) nor on severity of self-reported symptoms. We found no evidence that the MISS is more effective than UC in our study sample of distressed patients. Continuing research should focus on the potential beneficial effects of the MISS; we need to investigate which elements of the intervention might be useful and which elements should be adjusted to make the MISS effective. Background: People who take sick leave from work as a result of mental health problems very often report that the cause is stress-related. Although stress-related sick leave imposes a significant burden on individuals and economies, few evidence-based therapies exist to prevent sick leave in people who are experiencing stress-related mental health problems. The researchers carrying out this study wanted to evaluate the effectiveness of an intervention for stress-related mental health disorders amongst people who had been on sick leave for less than three months. The intervention involved short training sessions for primary health-care practitioners, during which the practitioners were taught how to diagnose stress-related problems; how to provide information to patients and encourage their recovery and active return to work; and how to give advice and monitor patients' recovery. The researchers carried out a cluster-randomized trial evaluating this training program, in which 46 primary care practitioners were assigned by chance to receive either the training program or to practice usual care. Over the course of the trial, 433 patients with elevated levels of distress and sick leave were included in the study, 227 of whom were treated by...
Leigh Peterson, Ug Taylor, Ronald Roddy, Ghiorghis Belai, Pamela Phillips, Kavita Nanda, Robert Grant, Edith Essie Kekawo Clarke, Anderson Sama Doh, Renee Ridzon, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020027

The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women. This was a phase 2, randomized, double-blind, placebo-controlled trial. The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria. We enrolled 936 HIV-negative women at high risk of HIV infection into this study. Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo. The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2. Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved. Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study. Background: The World Health Organization has estimated that in 2006 around 4.3 million people were newly infected with HIV. Infection rates seem to be increasing in some countries, and there is an urgent need to find safe and effective ways of preventing HIV from being transmitted from one person to another. Many strategies for the prevention of HIV transmission between adults, such as use of condoms or changes to behavior, are not completely reliable, and women, in particular, may not always be able to negotiate condom use. Additional strategies for reducing the risk of HIV transmission are needed. One of these strategies is called “pre-exposure prophylaxis.” This strategy involves individuals who are at high risk of becoming infected with HIV taking antiviral drugs to prevent HIV infection. One particular drug, tenofovir disoproxil fumarate, is currently approved as a treatment for HIV infection, and is also being investigated as a strong candidate for pre-exposure prophylaxis. The research presented here reports on results of a trial carried out at three...
Gerard K. H The, Gijs Bleijenberg, Jos W. M Van Der Meer
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020019

It is unclear whether insulin-like growth factor (IGF) function is involved in the pathophysiology of chronic fatigue syndrome (CFS). Unpublished data and reports in patient organization newsletters suggest that Acclydine, a food supplement, could be effective in the treatment of CFS by increasing biologically active IGF1 levels. Here we aimed to measure the IGF1 and IGF binding protein (IGFBP) 3 status of CFS patients compared to age- and gender-matched neighborhood controls, and to assess the effect of Acclydine on fatigue severity, functional impairment, and biologically active IGF1 level (IGFBP3/IGF1 ratio). A randomized, placebo-controlled, double-blind clinical trial. Radboud University Nijmegen Medical Centre, The Netherlands. Fifty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention criteria for CFS. IGF status of 22 CFS patients was compared to that of 22 healthy age- and gender-matched neighborhood control individuals. Acclydine or placebo for 14 wk. Outcomes were fatigue severity (Checklist Individual Strength, subscale fatigue severity [CIS-fatigue]), functional impairment (Sickness Impact Profile-8 [SIP-8]), and biologically active IGF1 serum concentrations. Analyses were on an intention-to-treat basis. There was no difference in IGF status in 22 CFS patients compared to healthy age- and gender-matched control individuals. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (95% CI −4.4 to +6.5, p = 0.70), SIP-8 +59.1 (95% CI −201.7 to +319.8, p = 0.65), and IGFBP3/IGF1 ratio −0.5 (95% CI −2.8 to +1.7, p = 0.63). We found no differences in IGF1 status in CFS patients compared to healthy matched neighborhood controls. In addition, the results of this clinical trial do not demonstrate any benefit of Acclydine over placebo in the treatment of CFS. Background: Chronic fatigue syndrome is a complicated and poorly understood illness. People with the condition experience tiredness that carries on for a long period of time and does not get better with rest. Other symptoms include sleeping problems, muscle and joint pains, concentration difficulties, and headaches. The causes of chronic fatigue syndrome are not known. There is evidence for the effectiveness of certain behavioral interventions, such as exercise therapy and cognitive behavioral therapy, in improving certain symptoms. However, some doctors are concerned that a food supplement called Acclydine, derived from a plant called Solanum dulcamara, is being used and promoted as a treatment for chronic fatigue syndrome when there is little evidence about the efficacy or safety of this supplement. The researchers here carried out a randomized trial in The Netherlands, recruiting adult patients who met the internationally accepted criteria for chronic fatigue syndrome. The participants were allocated by chance to receive either 14 weeks of treatment...
Moses R. Kamya, Adoke Yeka, Hasifa Bukirwa, Myers Lugemwa, John B Rwakimari, Sarah G Staedke, Ambrose O Talisuna, Bryan Greenhouse, François H. Nosten, Philip J Rosenthal, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020020

To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. Randomized single-blinded clinical trial. Apac, Uganda, an area of very high malaria transmission intensity. Children aged 6 mo to 10 y with uncomplicated falciparum malaria. Treatment of malaria with AL or DP, each following standard 3-d dosing regimens. Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%–26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%–19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%–12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%–16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs. DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity. Background: The burden of death and disease caused by malaria is very high, particularly amongst young children in sub-Saharan Africa. Many African countries have adopted combinations of drugs for first-line malaria treatment that include a compound based on the plant-derived molecule artemisinin. In Uganda, the artemisinin-based compound therapy (ACT) adopted as first-line therapy is artemether-lumefantrine (AL). However, there are limitations to the use of this drug; dosing is not convenient and it needs to be given with fatty food. There are also concerns that even though AL and other ACTs successfully treat the initial infection, there is a risk of malaria recurring soon after therapy, particularly in areas where mosquito attack rates are high. Therefore, the researchers here wanted to compare AL treatment with another ACT, dihydroartemisinin-piperaquine (DP), for treatment of uncomplicated malaria in children who live in an area of Uganda where malaria is transmitted at a very high rate. What the trial shows: 421 children aged between...
Robert L. Davis, Jeffrey Wright, Francie Chalmers, Linda Levenson, Julie C Brown, Paula Lozano, Dimitri A Christakis
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020025

Having shown previously that an electronic prescription writer and decision support system improved pediatric prescribing behavior for otitis media in an academic clinic setting, we assessed whether point-of-care delivery of evidence could demonstrate similar effects for a wide range of other common pediatric conditions. Cluster randomized controlled trial. A teaching clinic/clinical practice site and a primary care pediatric clinic serving a rural and semi-urban patient mix. A total of 36 providers at the teaching clinic/practice site and eight providers at the private primary pediatric clinic. An evidence-based message system that presented real-time evidence to providers based on prescribing practices for acute otitis media, allergic rhinitis, sinusitis, constipation, pharyngitis, croup, urticaria, and bronchiolitis. The proportion of prescriptions dispensed in accordance with evidence. The proportion of prescriptions dispensed in accordance with evidence improved four percentage points, from 38% at baseline to 42% following the intervention. The control group improved by one percentage point, from 39% at baseline to 40% at trial's conclusion. The adjusted difference between the intervention and control groups was 8% (95% confidence interval 1%, 15%). Intervention effectiveness did not decrease with time. For common pediatric outpatient conditions, a point-of-care evidence-based prescription writer and decision support system was associated with significant improvements in prescribing practices. Background: Computerized systems for managing health-care information, such as medical records and prescriptions, have the potential to improve medical care. These improvements could come about as a result of embedding software within a medical record system that alerts clinicians to evidence that is relevant to the care they are providing. For example, such a system might deliver a pop-up reminder that informs a clinician about a potential prescribing error, or that the prescription ordered is not supported by recent evidence. Systematic reviews of randomized controlled trials evaluating the benefits of such systems have shown that computerized feedback and reminder systems can improve clinician behavior. However, much of this evidence comes from academic clinics caring for adults, and there is not very much evidence available on children or from community-based, nonacademic clinical practices. The researchers here wanted to evaluate whether a computerized system providing clinical decision support at the time of electronic prescribing could improve prescribing in pediatric primary care. In order to test this, the researchers carried out a cluster randomized trial. This means that individual health-care providers were randomized to receive evidence-based prompts via the computerized system or not, depending on which arm of the trial they were randomized to, but outcome data for the trial were collected at the level of the individual patient's...
Simona Bo, Giovannino Ciccone, Marilena Durazzo, Roberto Gambino, Paola Massarenti, Ileana Baldi, Antonela Lezo, Elisa Tiozzo, Daniela Pauletto, Maurizio Cassader, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020017

Few in vitro studies have examined the participation of resistin, a recently discovered adipokine, in oxidative processes. We investigated whether in vivo treatment with the antioxidant vitamin C might affect resistin serum levels. Randomized prospective open trial. San Giovanni Battista Hospital, Turin, Italy. Eighty healthy individuals. Administration of 2 g of ascorbic acid orally for 2 wk (n = 40; experimental group) or no supplementation (n = 40; control group). The primary end point was the between-group difference in the before–after change in resistin serum level after vitamin C supplementation. Secondary endpoints were the within- and between-group changes in glucose, insulin, lipid parameters, C-reactive protein fasting values, and markers of oxidative stress. In the experimental group, vitamin C supplementation was significantly associated with both resistin concentration reduction (from 4.3 ± 1.5 to 2.9 ± 0.8 ng/ml; 95% confidence interval [CI] −1.87, −1.03) and ascorbic acid level increase (from 9.4 ± 2.9 to 19.0 ± 5.2 mg/l; 95% CI 7.9, 11.2). In the control group, resistin levels did not change significantly (from 4.2 ± 1.0 to 4.3 ± 0.9 ng/ml; 95% CI −0.07, 0.37). The between-group differences were highly significant (p < 0.001). Vitamin C supplementation was also associated with a statistically significant reduction in nitrotyrosine level and incremental increase in reduced glutathione. In a linear regression model, within-individual changes in vitamin C concentrations were inversely correlated with changes in resistin levels in both groups (each unit increase of vitamin C corresponded to a decrease of about 0.10 units of resistin levels (95% CI 0.13, 0.08; p < 0.001). This is to our knowledge the first randomized trial in humans that has demonstrated that short-term vitamin C supplementation could significantly reduce resistin levels, independent of changes in inflammatory or metabolic variables. Future investigations of resistin participation in oxidative processes are warranted. Background: Resistin is a hormone that is produced by fat cells. Much of the work on resistin has been done in mice, and as a result of this research the hormone was thought to explain the link between obesity and development of diabetes. In obese mice, higher levels of resistin are seen, and this hormone seems to interfere with the normal role of insulin in reducing blood sugar levels. However, the exact biochemical pathways in mice and humans seem to be very different, and it is not obvious whether resistin plays the same role in the development of diabetes in humans as it does in mice. At the same time, some researchers have suggested links between resistin and oxidative stress, which is thought to be involved in the development of certain diseases, particularly cardiovascular disease. The researchers here wanted to more fully explore these links by finding out whether an antioxidant, vitamin C, affected levels of resistin in blood....
Hamdee Attallah, Anne L Friedlander, Matilde Nino-Murcia, Andrew R. Hoffman
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020021

Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time. Randomized, double-blind, placebo-controlled, 2 × 2 factorial design. Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States. 62 abdominally obese adults aged 40–75 with impaired glucose tolerance. GH (8 μg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk. Baseline and after 40 wk of treatment, VAT content was quantified by CT scan, glucose tolerance was assessed using a 75-g oral glucose tolerance test, and insulin sensitivity was measured using steady-state plasma glucose levels obtained during insulin suppression test. Baseline: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 ± 7.4 cm2 in GH group, mean difference from placebo: −28.1 cm2 (95% CI −49.9 to −6.3 cm2; p = 0.02). Insulin resistance declined 52 ± 11.8 mg/dl with PIO, mean difference from placebo of −58.8 mg/dl (95% CI −99.7 to −18.0 mg/dl; p = 0.01). VAT and SSPG declined with GH and PIO combined, mean differences from placebo of −31.4 cm2 (95% CI −56.5 cm2 to −6.3 cm2; p = 0.02) and −55.3 mg/dl (95% CI −103.9 to −6.7 mg/dl; p = 0.02), respectively. Fasting plasma glucose increased transiently in GH group. No significant changes in BMI were observed. Addition of PIO to GH attenuated the short-term diabetogenic effect of GH; the drug combination reduced VAT and insulin resistance over time. GH plus PIO may have added benefit on body composition and insulin sensitivity in the metabolic syndrome. Background: People who are overweight are at higher risk of developing type 2 diabetes, particularly if they have impaired glucose tolerance (IGT). When an individual has IGT, their cells are not able to respond properly to insulin in the blood, which means that blood sugar levels can remain high, and fat cells do not take up fatty acids from blood at the rate they should. The term prediabetes is often used to refer to these linked characteristics. However, if such individuals are able to lose weight they can reduce their chances of becoming diabetic in the future. In particular, loss of a particular type of fat, the visceral fat (packed in around the internal organs, as opposed to fat immediately under the skin), is thought to be beneficial for people at risk of developing type 2 diabetes. Some researchers have suggested that giving human growth hormone (GH) to people who are overweight might help reduce their levels of visceral fat. At the same time, drugs known as thiazolidinediones are currently used, in combination with other drugs, diet, and exercise, as a treatment for type 2 diabetes. The researchers carrying out this study...
Lola Fourcade, Isabelle Boutron, David Moher, Lucie Ronceray, Gabriel Baron, Philippe Ravaud
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020022

The aim of this study was to develop and evaluate a pedagogical tool to enhance the understanding of a checklist that evaluates reports of nonpharmacological trials (CLEAR NPT). Paired randomised controlled trial. Clinicians and systematic reviewers. We developed an Internet-based computer learning system (ICLS). This pedagogical tool used many examples from published randomised controlled trials to demonstrate the main coding difficulties encountered when using this checklist. Randomised participants received either a specific Web-based training with the ICLS (intervention group) or no specific training. The primary outcome was the rate of correct answers compared to a criterion standard for coding a report of randomised controlled trials with the CLEAR NPT. Between April and June 2006, 78 participants were randomly assigned to receive training with the ICLS (39) or no training (39). Participants trained by the ICLS did not differ from the control group in performance on the CLEAR NPT. The mean paired difference and corresponding 95% confidence interval was 0.5 (−5.1 to 6.1). The rate of correct answers did not differ between the two groups regardless of the CLEAR NPT item. Combining both groups, the rate of correct answers was high or items related to allocation sequence (79.5%), description of the intervention (82.0%), blinding of patients (79.5%), and follow-up schedule (83.3%). The rate of correct answers was low for items related to allocation concealment (46.1%), co-interventions (30.3%), blinding of outcome assessors (53.8%), specific measures to avoid ascertainment bias (28.6%), and intention-to-treat analysis (60.2%). Although we showed no difference in effect between the intervention and control groups, our results highlight the gap in knowledge and urgency for education on important aspects of trial conduct. Background: A key part of the practice of evidence-based medicine (essentially, the appropriate use of current best evidence in determining care of individual patients) involves appraising the quality of individual research papers. This process helps an individual to understand what has been done in a clinical research study, and to decipher the strengths, limitations, and importance of the work. Several tools already exist to help clinicians and researchers to assess the quality of particular types of study, including randomised controlled trials. One of these tools is called CLEAR NPT, which consists of a checklist that helps individuals to evaluate reports of nonpharmacological trials (i.e., trials not evaluating drugs but other types of intervention, such as surgery). The researchers who developed CLEAR NPT also produced an Internet-based computer learning system to help researchers use CLEAR NPT correctly. They wanted to evaluate to what extent this learning system helped people use CLEAR NPT and, therefore, carried out a randomised trial comparing the learning system to no specific training. A total of 78 health...
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