Objectives: Indigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines. Design: A randomized, double-blind, placebo-controlled trial of Sutherlandia leaf powder in healthy adults. Setting: Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa. Participants: 25 adults who provided informed consent and had no known significant diseases or allergic conditions nor clinically abnormal laboratory blood profiles during screening. Intervention: 12 participants randomized to a treatment arm consumed 400 mg capsules of Sutherlandia leaf powder twice daily (800 mg/d). 13 individuals randomized to the control arm consumed a placebo capsule. Each participant received 180 capsules for the trial duration of 3 mo. Outcome Measures: The primary endpoint was frequency of adverse events; secondary endpoints were changes in physical, vital, blood, and biomarker indices. Results: There were no significant differences in general adverse events or physical, vital, blood, and biomarker indices between the treatment and placebo groups (p > 0.05). However, participants consuming Sutherlandia reported improved appetite compared to those in the placebo group (p = 0.01). Although the treatment group exhibited a lower respiration rate (p < 0.04) and higher platelet count (p = 0.03), MCH (p = 0.01), MCHC (p = 0.02), total protein (p = 0.03), and albumin (p = 0.03), than the placebo group, these differences remained within the normal physiological range, and were not clinically relevant. The Sutherlandia biomarker canavanine was undetectable in participant plasma. Conclusion: Consumption of 800 mg/d Sutherlandia leaf powder capsules for 3 mo was tolerated by healthy adults.
Endpoints are outcome measures used to address the objectives of a clinical trial. The primary endpoint is the most important outcome and is used to assess the primary objective of a trial (e.g., the variable used to compare the effect difference of two treatment groups). A fundamental principle in the design of randomized trials involves setting out in advance the endpoints that will be assessed in the trial [1], as failure to prespecify endpoints can introduce bias into a trial and creates opportunities for manipulation. However, sometimes new information may come to light that could merit changes to endpoints during the course of a trial. This new information might include, for example, results from other trials or identification of better biomarkers or surrogate outcome measures. Such changes can allow incorporation of up-to-date knowledge into the trial design. However, changes to endpoints can also compromise the scientific integrity of a trial. Here I discuss some of the issues and decision-making processes that should be considered when evaluating whether to make changes to endpoints, and discuss the documentation and reporting of clinical trials that have revised endpoints.
OBJECTIVES:To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1-infected pregnant women.DESIGN:Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis.SETTING:27 hospitals in Thailand.PARTICIPANTS:1,436 HIV-infected pregnant women in PHPT-1.INTERVENTION:Zidovudine prophylaxis initiation at 28 or 35 wk gestation.OUTCOME MEASURES:Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load.RESULTS:Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] -0.4 [-0.5 to -0.3], -423 [-703 to -142], -485 [-757 to -213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts.CONCLUSION:Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV.
OBJECTIVE: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.DESIGN:Randomized, double-blind, placebo-controlled, 2 x 2 factorial design.SETTING:Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States.PARTICIPANTS:62 abdominally obese adults aged 40-75 with impaired glucose tolerance.INTERVENTIONS:GH (8 microg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk.OUTCOME MEASURES: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.RESULTS:BASELINE: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 +/- 7.4 cm(2) in GH group, mean difference from placebo: -28.1 cm(2) (95% CI -49.9 to -6.3 cm(2); 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 cm(2) (95% CI -56.5 cm(2) to -6.3 cm(2); 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.CONCLUSIONS: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.
Currently more than 20 antiretrovirals are commercially available for treatment of HIV infection [1]. Using them in combination therapy, we are able to treat HIV-infected patients with highly potent regimens and suppress the virus below detectable levels. Correct adherence to these regimens is important to ensure that the viral load will remain undetectable and that the disease does not progress. Moreover, even if adherence is not perfect and the virus becomes resistant to a first-line regimen, there are other treatment options to suppress the virus again to undetectable levels. Given the choice of several different potent antiretroviral regimens, doctors and patients will tend to prefer those regimens that are easy to take and that have limited short-term and long-term side effects. One potential side effect of antiretroviral treatment that has received very little scientific attention so far is sexual dysfunction. Sexual dysfunction is defined as difficulty during any stage of the sexual act, including desire, arousal, orgasm, and resolution, that prevents the individual or couple from enjoying sexual activity [2], and, according to DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria, causing ‘‘marked level of distress or interpersonal difficulty’’ [3]. Sexual dysfunction disorders are generally classified into four categories: sexual desire disorders, sexual arousal disorders, orgasm disorders, and sexual pain disorders [2,3]. Most data relating to the association between antiretroviral therapy and sexual dysfunction are based on cross-sectional studies or case series, and have emerged from industrialised countries [4–12]. Some studies have suggested that antiretrovirals, in particular certain protease inhibitors, may cause sexual problems or dysfunction [4–10]; however, other studies have not confirmed this observation [11,12]. Furthermore, sexual dysfunctions in people infected with HIV may be caused by many different factors. Both organic and psychological factors have been identified, including coping with HIV, pre-existing sexual dysfunctions, sex hormone abnormalities, neuropathy from HIV itself (or related treatment for HIVcaused illnesses), and other iatrogenic causes [13]. Sexual dysfunctions are conceptualised as one component of sexual health, which is an essential element of overall healthrelated quality of life (HRQOL). While it may include a variety of diverse issues, comprehensive definitions such as the World Health Organization’s (WHO) working definition define sexual health as a state of physical, emotional, mental, and social well-being, and not merely the absence of disease, dysfunction, or infirmity. Sexual health encompasses the possibility of having pleasurable and safe sexual experiences [14]. The essence of such lengthy definitions has been summarised in one single statement as ‘‘the enjoyment of sexual activity of one’s choice, without causing or suffering physTable 1. Overview of the Most Commonly Used Questionnaires in Clinical HIV Trials
Objectives: 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). Design: A randomized, placebo-controlled, double-blind clinical trial. Setting: Radboud University Nijmegen Medical Centre, The Netherlands. Participants: 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. Intervention: Acclydine or placebo for 14 wk. Outcome measures: 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. Results: 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). Conclusion: 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.
The Abacavir Trial in Context HIV-associated dementia (HAD) and milder forms of cognitive impairment produce a spectrum of disability that ranges from complete inability to care for oneself to reduced work efficiency and quality of life. HAD is believed to arise from a confluence of adverse effects on neuronal function resulting both from HIV itself and from disturbances in cellular signalling, particularly in the immune system, that further damage neurons. More than two decades after the recognition of HAD as a clinical entity, guidelines for antiretroviral drug treatment in people with HAD and cognitive impairment have yet to be established. The study reported in PLoS Clinical Trials by Brew et al. [1] was designed to help develop such guidelines by testing whether adding a single ‘‘neuroactive’’ antiretroviral, abacavir, to an existing regimen would benefit brain function in patients with dementia. Abacavir is a potent inhibitor of HIV reverse transcriptase that interferes with the viral lifecycle and shows reasonably good penetration into central nervous system (CNS) tissues. The trial was historically important because it was done at a pivotal time in the development of antiretroviral therapy, as potent combination drug regimens including protease inhibitors emerged into widespread use in the United States, Europe, and Australia. The rationale for the study was simple and transparent. It was anticipated that this ‘‘CNS active’’ agent would suppress a potential reservoir of HIV in the central nervous system, where other drugs, especially protease inhibitors, might not be effective. At the time this study was designed, a number of important scientific observations about HAD and its treatment had been made. Zidovudine, the earliest available nucleoside reverse transcriptase inhibitor, seemed to improve the motor functions of people with HAD when given in higher doses than normally used for treatment of systemic HIV disease [2]. Additionally, observational data showed that dementia prevalence in the West dropped after zidovudine became available, suggesting that zidovudine prevented HAD [3,4]. Even so, the burden of mild cognitive impairment in HIV remained substantial [5–7].
OBJECTIVE: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).DESIGN:Paired randomised controlled trial.PARTICIPANTS:Clinicians and systematic reviewers.INTERVENTIONS: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.OUTCOME MEASURES: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.RESULTS: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%).CONCLUSIONS: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.
OBJECTIVES:To assess the efficacy of an acute multidisciplinary group intervention on self-perceived recovery following minor traffic-related musculoskeletal injuries.DESIGN:Open, randomized controlled trial.SETTING:A large inner-city hospital.PARTICIPANTS:127 patients (> or = 15 y) with traffic-related acute minor musculoskeletal injuries and predicted to be at risk for delayed recovery were randomized into an intervention group (n = 65) or a control group (n = 62).INTERVENTION:Four 1 1/2-h sessions in open groups with the aim of providing information about injuries in general, calling attention to the importance of self-care and promoting physical activity. In addition, both groups received standard medical care by regular staff.OUTCOME MEASURES:The main outcome measure was self-reported recovery at 12 mo. Secondary outcome measures were ratings of functional health status (SF-36, SMFA), pain and mental distress on visual analog scales, and self-reported duration of sick leave.RESULTS:At 12 mo, there was a 21.9 percentage point difference: 52.4% of the patients in the intervention group and 30.5% in the control group reported self-perceived recovery (95% confidence interval for the difference 5%-38%; p = 0.03). There were no statistically significant differences between the groups regarding the secondary outcome measures.CONCLUSION:A simple group intervention may accelerate the self-perceived recovery in selected patients. As we did not find evidence of improvements in the secondary outcome measures, the clinical significance of the treatment benefit remains to be defined.
Objectives: To assess the safety and immunogenicity of two vaccines, MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites. Design: A Phase 1 open-label, dose-escalating study. Setting: Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005. Participants: Sixty healthy malaria-naïve volunteers 18–48 y of age. Interventions: The C-terminal 42-kDa region of merozoite surface protein 1 (MSP142) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 μg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y. Outcome Measures: The safety of MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP142, MSP119, and MSP133 recombinant proteins and recognition of FVO and 3D7 parasites. Results: Anti-MSP142 antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP142-FVO/Alhydrogel or MSP142-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP142-FVO and MSP142-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP142, although low-level antibodies to the N-terminal 33-kDa domain of MSP142 were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed. Conclusions: The MSP142/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine.
There is a consensus among paediatricians that outcome of children presenting with life-threatening infections, irrespective of the infecting pathogen, can be improved by timely recognition and prompt intervention to correct disordered physiology using simple approaches to resuscitation [1–3]. These approaches include the provision of oxygen and the correction of fluid, electrolyte, and glucose deficits [4,5]. Indeed, studies have shown that most of the recent gains in survival of children with severe infections have come through the application of this approach by non-specialists during the initial hours of management [6,7]. Correction of hypotension and volume depletion through fluid administration is a fundamental component of resuscitation in most critically ill children [8,9], but its role in severe malaria remains uncertain and thus represents one of the most important theoretical gaps in our understanding of supportive treatments in this condition. Many children with severe malaria have signs of cardiovascular compromise or compensated shock on presentation to hospital and a smaller proportion are hypotensive [10]. One of the major unresolved aspects of management is whether volume expansion should be undertaken in children displaying signs of compensated shock, as is recommended in other paediatric disorders. Intravascular volume depletion (hypovolaemic shock) results in impaired cardiovascular function and inadequate tissue and organ perfusion, and would usually be corrected rapidly. Simple dehydration, predominantly affecting the intracellular compartment, can be safely corrected gradually. The choice of the optimum fluid for resuscitation is also unclear. Colloidal solutions, although more costly, are less likely to precipitate cerebral and pulmonary oedema due to their oncotic properties. Recognising the importance of adequate fluid management to the outcome of the critically ill child, the group at Kilifi has conducted a staged series of studies over the last 15 years to address each of these questions. In a collaboration that included specialists in paediatric intensive care, neurology, and clinical trials, the group demonstrated the importance, prognostic implications [11], and clinical correlates of metabolic acidosis in children with severe malaria [12] and provided clear evidence of intravascular hypovolaemia by using standard methods for studying critical illness [13]. We have undertaken two randomised trials to assess the safety of and response to volume expansion, and to determine whether colloid replacement offers any advantage over crystalloid replacement [13,14]. We hypothesised that administration of colloids such as human albumin solution with volume expansion would help to retain fluid in the intravascular compartment and may also improve endothelial function. In each of these trials we observed that albumin administration was associated with a lower mortality than saline. Although this data suggested the need for a large clinical trial of albumin, in view of the cost of albumin we thought that cheaper synthetic colloids should be assessed before embarking on a phase III trial. The intention in the small phase II trial, recently published in PLoS Clinical Trials [15], was to provide sufficient physiological data on succinylated gelatin to inform the design of the next phase, rather than to establish statistical superiority of one colloid over the other. For this purpose the trial was most instructive. Again we observed the same benefits of albumin: only one child who received albumin died, out of a group of participants that included children treated as emergencies who were subsequently found to be ineligible for the trial. The results for Gelofusine, however, were not encouraging. The combined findings that death, severe allergic reaction, and acute neurological events were more common in the Gelofusine group suggested that albumin, rather than a cheaper substitute, should be taken forward into the next phase. This was supported by the analysis of the combined data from three trials, including 238 children receiving volume expansion. While this small phase II study was not powered to prove that Gelofusine was superior to saline or albumin, the results suggest that Gelofusine is unlikely to offer any advantage over the cheaper saline solution. Given the continued controversy over the use of resuscitation fluids in the management of severe malaria, we suggest that this can only be resolved through a definitive clinical trial. Woodrow and Planche [16] have chosen a different interpretation. The evidence presented from two studies conducted in Gabon, one which assessed volume depletion in only 12 survivors [17] and the other larger study conducted in less critically unwell children [18], supports a position of equipoise—the basis which usually prompts the need for a definitive clinical trial.
Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. Setting: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. Participants: 126 healthy adults 21–45 years of age. Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. Outcome Measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.
OBJECTIVES:To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation.DESIGN:This was a Phase II randomized, partially double blinded, 2x2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk.SETTING:The Weill-Cornell General Clinical Research Center.PARTICIPANTS:Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4+ T cells/microl.INTERVENTIONS:An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12-24 wk.OUTCOME MEASURES:Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log10 HIV RNA copies/ml ([HIV]) from weeks 21-25, and (3) proportion of individuals eligible for trial Step III.RESULTS:44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log10 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17).CONCLUSIONS:Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy.
we identified a functional chromogen gene C from wild rice, providing a new insight of anthocyanin biosynthesis pathway in indica and japonica. Accumulation of anthocyanin is a desirable trait to be selected in rice domestication, but the molecular mechanism of anthocyanin biosynthesis in rice remains largely unknown. In this study, a novel allele of chromogen gene C, OrC1, from Oryza rufipongon was cloned and identified as a determinant regulator of anthocyanin biosynthesis. Although OrC1 functions in purple apiculus, leaf sheath and stigma in indica background, it only promotes purple apiculus in japonica. Transcriptome analysis revealed that OrC1 regulates flavonoid biosynthesis pathway and activates a few bHLH and WD40 genes of ternary MYB-bHLH-WD40 complex in indica. Differentially expressed genes and metabolites were found in the indica and japonica backgrounds, indicating that OrC1 activated the anthocyanin biosynthetic genes OsCHI, OsF3H and OsANS and produced six metabolites independently. Artificial selection and domestication of C1 gene in rice occurred on the coding region in the two subspecies independently. Our results reveal the regulatory system and domestication of C1, provide new insights into MYB transcript factor involved in anthocyanin biosynthesis, and show the potential of engineering anthocyanin biosynthesis in rice.
To assess the safety and immunogenicity of two vaccines, MSP1(42)-FVO/Alhydrogel and MSP1(42)-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites.A Phase 1 open-label, dose-escalating study.Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005.Sixty healthy malaria-naïve volunteers 18-48 y of age.The C-terminal 42-kDa region of merozoite surface protein 1 (MSP1(42)) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 microg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y.The safety of MSP1(42)-FVO/Alhydrogel and MSP1(42)-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP1(42), MSP1(19), and MSP1(33) recombinant proteins and recognition of FVO and 3D7 parasites.Anti-MSP1(42) antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP1(42)-FVO/Alhydrogel or MSP1(42)-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP1(42)-FVO and MSP1(42)-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP1(42), although low-level antibodies to the N-terminal 33-kDa domain of MSP1(42) were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed.The MSP1(42)/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine.
Correction: A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: The UK-Vanguard study. PLoS Clin Trials 2(5): e23.
The pedicled nasoseptal flap has been a key element in advancing the endoscopic transnasal approach (ETA) for the treatment of skull base lesions from the anterior cranial fossa to the occipitocervical junction. To preserve vascular supply, an anatomical knowledge of the location of the posterior septal artery (PSA) is essential. The objective of this work is to establish the relationship between PSA and the superior edge of the choana to define a safety margin during the opening of the sphenoidal rostrum preserving PSA. One hundred and eighty angiotomographies of the brain were assessed. The sphenopalatine artery (SPA) was evaluated in the pterygopalatine fossa and PSA at its entrance into the nasal cavity and on the sphenoidal rostrum. PSA was found in all 3 tomographic planes (axial, coronal and sagittal) in 100 patients (200 PSAs). Thirty-five were male and 65 were females. Average age was 62 years with a range of 19–90 years. Total average distance between PSA and the superior edge of the choana was 8.5 mm with a range of 2.5–18 (12.45 90th percentile). Although the distance between the choanal edge and PSA is 8.5 mm on average, due to its variability, a distance of at least 12.45 mm for the opening of the sphenoidal sinus in the ETA approach should be considered as a safety margin.
This review is a brief summary of the history of the development of the Prothrombinase complex paradigm and its incorporation into the “extrinsic pathway”. It summarizes my laboratory’s research from 1968 to 2012 and identifies many of the key players in these efforts.
Introduction Endpoints are outcome measures used to address the objectives of a clinical trial. The primary endpoint is the most important outcome and is used to assess the primary objective of a trial (e.g., the variable used to compare the effect difference of two treatment groups). A fundamental principle in the design of randomized trials involves setting out in advance the endpoints that will be assessed in the trial [1], as failure to prespecify endpoints can introduce bias into a trial and creates opportunities for manipulation. However, sometimes new information may come to light that could merit changes to endpoints during the course of a trial. This new information might include, for example, results from other trials or identification of better biomarkers or surrogate outcome measures. Such changes can allow incorporation of up-to-date knowledge into the trial design. However, changes to endpoints can also compromise the scientific integrity of a trial. Here I discuss some of the issues and decisionmaking processes that should be considered when evaluating whether to make changes to endpoints, and discuss the documentation and reporting of clinical trials that have revised endpoints.
Objectives: To evaluate the short-term symptomatic efficacy of rofecoxib and diclofenac versus placebo in acute episodes of shoulder pain. Design: Randomized controlled trial of 7 days. Setting: Rheumatologists and/or general practitioners totaling 47. Participants: Acute shoulder pain. Interventions: Rofecoxib 50 mg once daily, diclofenac 50 mg three times daily, and placebo. Outcome measures: Pain, functional impairment, patient's global assessment of his/her disease activity, and local steroid injection requirement for persistent pain. The primary variable was the Kaplan-Meier estimates of the percentage of patients at day 7 fulfilling the definition of success (improvement in pain intensity and a low pain level sustained to the end of the 7 days of the study; log-rank test). Results: There was no difference in the baseline characteristics between the three groups (rofecoxib n = 88, placebo n = 94, and diclofenac n = 89). At day 7, the Kaplan-Meier estimates of successful patients was higher in the treatment groups than in the placebo (54%, 56%, and 38% in the diclofenac, rofecoxib, and placebo groups respectively, p = 0.0070 and p = 0.0239 for placebo versus rofecoxib and diclofenac, respectively). During the 7 days of the study, there was a statistically significant difference between placebo and both active arms (rofecoxib and diclofenac) in all the evaluated outcome measures A local steroid injection had to be performed in 33 (35%) and 19 (22%) patients in the placebo and rofecoxib group respectively. Number needed to treat to avoid such rescue therapy was 7 patients (95% confidence interval 5–15). Conclusion: This study highlights the methodological aspects of clinical trials, e.g., eligibility criteria and outcome measures, in acute painful conditions. The data also establish that diclofenac and rofecoxib are effective therapies for the management of acute painful shoulder and that they reduce the requirement for local steroid injection.
