Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials

Background

The safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV) were evaluated in children and adults.

Methods/Principal Findings

Two randomized, double-blind, placebo-controlled studies were completed in children (2–17 y) and adults (18–49 y). Subjects were assigned 4∶1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1–8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65) and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60) were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5%) pediatric vaccine recipients and 1 (1.5%) placebo recipient (rate difference, 0%; 95% CI: –6.4%, 3.1%). No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo) were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: –9.6%, 13.8%) and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%). Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: –5.6%, 12.6%) and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: –0.8%, 16.3%) after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo) occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred.

Conclusions/Significance

In subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00946101","term_id":"NCT00946101"}}NCT00946101, {"type":"clinical-trial","attrs":{"text":"NCT00945893","term_id":"NCT00945893"}}NCT00945893     

Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience

Purpose

We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer.

Experimental Design

Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models.

Results

In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12–0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79–1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67–1.15, P = 0.340).

Conclusions

Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00460317","term_id":"NCT00460317"}}NCT00460317, {"type":"clinical-trial","attrs":{"text":"NCT00369070","term_id":"NCT00369070"}}NCT00369070     

A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs

Background

Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection.

Methods and Findings

A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether–lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120–4786 and 7–40 respectively; p<0.01).

Conclusions

This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials.

Trial Registration:

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01055002","term_id":"NCT01055002"}}NCT01055002     

Serum 25(OH)D Is a 2-Year Predictor of All-Cause Mortality, Cardiac Death and Sudden Cardiac Death in Chest Pain Patients from Northern Argentina

Background

Several studies have shown an association between vitamin D deficiency and cardiovascular risk. Vitamin D status is assessed by determination of 25-hydroxyvitamin D [25(OH)D] in serum.

Methods

We assessed the prognostic utility of 25(OH)D in 982 chest-pain patients with suspected acute coronary syndrome (ACS) from Salta, Northern Argentina. 2-year follow-up data including all-cause mortality, cardiac death and sudden cardiac death were analyzed in quartiles of 25(OH)D, applying univariate and multivariate analysis.

Results

There were statistically significant changes in seasonal 25(OH)D levels. At follow-up, 119 patients had died. The mean 25(OH)D levels were significantly lower among patients dying than in long-term survivors, both in the total population and in patients with a troponin T (TnT) release (n = 388). When comparing 25(OH)D in the highest quartile to the lowest quartile in a multivariable Cox regression model for all-cause mortality, the hazard ratio (HR) for cardiac death and sudden cardiac death in the total population was 0.37 (95% CI, 0.19–0.73), p = 0.004, 0.23 (95% CI, 0.08–0.67), p = 0.007, and 0.32 (95% CI, 0.11–0.94), p = 0.038, respectively. In patients with TnT release, the respective HR was 0.24 (95% CI, 0.10–0.54), p = 0.001, 0.18 (95% CI, 0.05–0.60), p = 0.006 and 0.25 (95% CI, 0.07–0.89), p = 0.033. 25(OH)D had no prognostic value in patients with no TnT release.

Conclusion

Vitamin D was shown to be a useful biomarker for prediction of mortality when obtained at admission in chest pain patients with suspected ACS.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01377402","term_id":"NCT01377402"}}NCT01377402     

Ethnic Differences in Cardiometabolic Risk Profile at Age 5-6 Years: The ABCD Study

Background

To examine ethnic differences in cardiometabolic risk profile in early age, and explore whether such differences can be explained by differences in body mass index (BMI) or waist circumference (WC).

Method

Anthropometric measurements, blood pressure and (in a subsample) fasting blood were collected during a health check of 2,509 children aged 5–6 years. Four ethnic groups were distinguished: Dutch (n = 2,008; blood n = 1,300), African descent (n = 199; blood n = 105), Turkish (n = 108; blood n = 57) and Moroccan (n = 194; blood n = 94). Ethnic differences in diastolic and systolic blood pressure (DBP/SBP), fasting glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were determined and the explanatory role of BMI and WC was examined with regression analysis.

Results

After adjustment for confounders, African descent children showed higher DBP (β2.22 mmHg; 95%CI:1.09–3.36) and HDL levels (β:0.09 mmol/l; 95%CI:0.03–0.16) compared to Dutch children (reference group). Turkish children showed higher SBP (β:1.89 mmHg; 95%CI:0.25–3.54), DBP (β:2.62 mmHg; 95%CI:1.11–4.13), glucose (β:0.12 mmol/L; 95%CI:0.00–0.25) and triglyceride levels (β:0.13 mmol/L; 95%CI:0.02–0.25). Higher BMI values were found in all non–Dutch groups (differences ranged from 0.53–1.03 kg/m²) and higher WC in Turkish (β:1.68 cm; 95%CI:0.99–2.38) and Moroccan (β:1.65 cm; 95%CI:1.11–2.19) children. BMI and WC partly explained the higher SBP/DBP and triglyceride levels in Turkish children.

Conclusion

Ethnic differences in cardiometabolic profile exist early in life and are partly explained by differences in BMI and WC. African children showed favourable HDL levels and Turkish children the most unfavourable overall profile, whereas their Moroccan peers have less increased cardiometabolic risk in spite of their high BMI and WC.     

Internet-based cognitive behavior therapy vs. cognitive behavioral group therapy for social anxiety disorder: a randomized controlled non-inferiority trial

Background and Aims

Cognitive behavioral group therapy (CBGT) is an effective, well-established, but not widely available treatment for social anxiety disorder (SAD). Internet-based cognitive behavior therapy (ICBT) has the potential to increase availability and facilitate dissemination of therapeutic services for SAD. However, ICBT for SAD has not been directly compared with in-person treatments such as CBGT and few studies investigating ICBT have been conducted in clinical settings. Our aim was to investigate if ICBT is at least as effective as CBGT for SAD when treatments are delivered in a psychiatric setting.

Methods

We conducted a randomized controlled non-inferiority trial with allocation to ICBT (n = 64) or CBGT (n = 62) with blinded assessment immediately following treatment and six months post-treatment. Participants were 126 individuals with SAD who received CBGT or ICBT for a duration of 15 weeks. The Liebowitz Social Anxiety Scale (LSAS) was the main outcome measure. The following non-inferiority margin was set: following treatment, the lower bound of the 95 % confidence interval (CI) of the mean difference between groups should be less than 10 LSAS-points.

Results

Both groups made large improvements. At follow-up, 41 (64%) participants in the ICBT group were classified as responders (95% CI, 52%–76%). In the CBGT group, 28 participants (45%) responded to the treatment (95% CI, 33%–58%). At post-treatment and follow-up respectively, the 95 % CI of the LSAS mean difference was 0.68–17.66 (Cohen’s d between group = 0.41) and −2.51–15.69 (Cohen’s d between group = 0.36) favoring ICBT, which was well within the non-inferiority margin. Mixed effects models analyses showed no significant interaction effect for LSAS, indicating similar improvement across treatments (F = 1.58; df = 2, 219; p = .21).

Conclusions

ICBT delivered in a psychiatric setting can be as effective as CBGT in the treatment of SAD and could be used to increase availability to CBT.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00564967","term_id":"NCT00564967"}}NCT00564967     

Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study

Background

Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control.

Methodology/Principal Findings

One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA_1c (HbA_1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA_1c after one year of treatment. At enrolment, mean (standard deviation) HbA_1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA_1c, 0.13% (−0.19; 0.44), p = 0.422; Total daily insulin dose, −5.7 U/day (−8.6; −2.9), p<0.001; body weight, −1.74 kg (−3.32; −0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated.

Conclusions/Significance

In patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00118937","term_id":"NCT00118937"}}NCT00118937     

Characterization of a large group of individuals with huntington disease and their relatives enrolled in the COHORT study

Background

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.

Methods

We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington''s Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.

Results

As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of “high normal” repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.

Conclusion

Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00313495","term_id":"NCT00313495"}}NCT00313495     

Towards a rational screening strategy for albuminuria: results from the unreferred renal insufficiency trial

Background

There remains debate about the screening strategies for albuminuria. This study evaluated whether a screening strategy in an apparently healthy population based on basic clinical and biochemical parameters could be more effective than a strategy where screening for albuminuria is performed unselectively.

Methodology/Principal Findings

The Unreferred Renal Insufficiency (URI) Study is a cross-sectional study on the prevalence of metabolic risk factors in Belgian workers, volunteering to be screened during a routine yearly occupational check-up. Subjects (n = 295) with treated hypertension, known diabetes, treated dyslipidaemia, cardiovascular and renal disease were excluded. Among 1,191 apparently healthy subjects, 23% had unknown hypertension, 13% had impaired glucose tolerance, 15.4% had normoalbuminuria, 4.2% had microalbuminuria and 0.4% had macroalbuminuria. Subjects with resting heart rate ≥85 bpm, plasma glucose ≥5.6 mmol/L and blood pressure ≥140/90 mmHg were associated with albuminuria of any degree. A strategy where only subjects with at least one of these risk factors (n = 431) were screened for albuminuria, would identify all subjects with macroalbuminuria (5/5), 64% of those with microalbuminuria (32/50), and less than half of those with normoalbuminuria (81/183). An alternative strategy whereby subjects were first screened for presence of albuminuria, and additional cardiovascular risk factors were only measured in subjects positive for albuminuria (n = 238), would identify only 27% (118/431) of the subjects with additional and potentially modifiable cardiovascular risk factors. On the other hand, half of the subjects in this study with albuminuria (120/238, of which 102 had normoalbuminuria), had no additional cardiovascular risk factor at all.

Conclusions

Screening an apparently healthy population directly for albuminuria will result in a high percentage of false positives, mostly measured in the normal range. Screening for microalbuminuria and macroalbuminuria based on presence of additional, potentially modifiable risk factors appears to be more beneficial. Trial registration 2006 {"type":"clinical-trial","attrs":{"text":"NCT00365911","term_id":"NCT00365911"}}NCT00365911     

Cocoa, hazelnuts, sterols and soluble fiber cream reduces lipids and inflammation biomarkers in hypertensive patients: a randomized controlled trial

Background

Cocoa, mixed with other food ingredients, intake can have beneficial effects on cardiovascular disease (CVD) biomarkers. We compared the effects of 4 cocoa cream products on some of these biomarkers.

Methods and Findings

In this multi-centered, randomized, controlled, double-blind, parallel trial, volunteers (n = 113; age range: 43–65 years) who were pre-hypertensive, stage-1 hypertensive and hypercholesterolemic received one of 4 cocoa cream products (13 g/unit; 1 g cocoa/unit, 6 units/d; 465 Kcal/d) added to a low saturated fat diet for 4 weeks. The groups were: A) (n = 28), cocoa cream considered as control; B) (n = 28), cocoa+hazelnut cream (30 g/d hazelnuts); C) (n = 30), cocoa+hazelnuts+phytosterols (2 g/d); and D) (n = 27), cocoa+hazelnuts+phytosterols+soluble fiber (20 g/d) the patented “LMN product”. Primary outcome measures were BP, LDL-c, apolipoprotein B-100 (Apo B), ApoB/ApoA ratio, oxidized LDL (oxLDL) and high-sensitive C-reactive protein (hsCRP) determined at baseline and post-cocoa cream product intake. Statistical analysis used was ANCOVA or mixed models (in case of repeated measurements), with baseline observation included as a covariate. After 4 weeks, compared to product A, product C reduced LDL-c by 11.2%, Apo B by 8.1% and ApoB/ApoA ratio by 7.8% (P = 0.01). LMN decreased LDL-c by 9.2%, Apo B-100 by 8.5%, ApoB/ApoA ratio by 10.5%, hsCRP by 33.4% and oxLDL by 5.9% (P = 0.01). Surprisingly, even “control” product A reduced systolic BP (−7.89 mmHg; 95%CI: −11.45 to −4.3) and diastolic BP (−5.54 mmHg; 95%CI: −7.79 to −3.29). The BP reductions were similar with the other 3 products. Limitations of the study are that the trial period was relatively short and that a better “BP control” product would have been preferable.

Conclusion

The creams (particularly the LMN) have anti-inflammatory and antioxidant effects in addition to lowering LDL-c, Apo B and ApoB/ApoA ratio. Thus, the soluble fiber effects amplified with sterols (as contained in the cocoa creams) provide new dietary therapeutic perspectives.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00511420","term_id":"NCT00511420"}}NCT00511420     

Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace: a randomized controlled trial

Background

Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT).

Methods

We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study.

Results

The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, −0.21 to 0.52, and p = 0.50, ES = 0.02, −0.34 to 0.39, respectively).

Conclusion

Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00885014","term_id":"NCT00885014"}}NCT00885014     

Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: cohort study

Objective

Turnover of the extracellular matrix in all solid organs is governed mainly by a balance between the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). An altered extracellular matrix metabolism has been implicated in a variety of diseases. We investigated relations of serum levels of MMP-9 and TIMP-1 to mortality risk from an etiological perspective.

Design

The prospective Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, followed from 1991–1995 for up to 18.1 years. A random population-based sample of 1,082 71-year-old men, no loss to follow-up. Endpoints were all-cause (n = 628), cardiovascular (n = 230), non-cardiovascular (n = 398) and cancer mortality (n = 178), and fatal or non-fatal myocardial infarction (n = 138) or stroke (n = 163).

Results

Serum MMP-9 and TIMP-1 levels were associated with risk of all-cause mortality (Cox proportional hazard ratio [HR] per standard deviation 1.10, 95% confidence interval [CI] 1.03–1.19; and 1.11, 1.02–1.20; respectively). TIMP-1 levels were mainly related to risks of cardiovascular mortality and stroke (HR per standard deviation 1.22, 95% CI 1.09–1.37; and 1.18, 1.04–1.35; respectively). All relations except those of TIMP-1 to stroke risk were attenuated by adjustment for cardiovascular disease risk factors. Relations in a subsample without cardiovascular disease or cancer were similar to those in the total sample.

Conclusion

In this community-based cohort of elderly men, serum MMP-9 and TIMP-1 levels were related to mortality risk. An altered extracellular matrix metabolism may be involved in several detrimental pathways, and circulating MMP-9 or TIMP-1 levels may be relevant markers thereof.     

Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults

Background

Cannabis dependence is a significant public health problem. Because there are no approved medications for this condition, treatment must rely on behavioral approaches empirically complemented by such lifestyle change as exercise.

Aims

To examine the effects of moderate aerobic exercise on cannabis craving and use in cannabis dependent adults under normal living conditions.

Design

Participants attended 10 supervised 30-min treadmill exercise sessions standardized using heart rate (HR) monitoring (60–70% HR reserve) over 2 weeks. Exercise sessions were conducted by exercise physiologists under medical oversight.

Participants

Sedentary or minimally active non-treatment seeking cannabis-dependent adults (n = 12, age 25±3 years, 8 females) met criteria for primary cannabis dependence using the Substance Abuse module of the Structured Clinical Interview for DSM-IV (SCID).

Measurements

Self-reported drug use was assessed for 1-week before, during, and 2-weeks after the study. Participants viewed visual cannabis cues before and after exercise in conjunction with assessment of subjective cannabis craving using the Marijuana Craving Questionnaire (MCQ-SF).

Findings

Daily cannabis use within the run-in period was 5.9 joints per day (SD = 3.1, range 1.8–10.9). Average cannabis use levels within the exercise (2.8 joints, SD = 1.6, range 0.9–5.4) and follow-up (4.1 joints, SD = 2.5, range 1.1–9.5) periods were lower than during the run-in period (both P<.005). Average MCQ factor scores for the pre- and post-exercise craving assessments were reduced for compulsivity (P  = .006), emotionality (P  = .002), expectancy (P  = .002), and purposefulness (P  = .002).

Conclusions

The findings of this pilot study warrant larger, adequately powered controlled trials to test the efficacy of prescribed moderate aerobic exercise as a component of cannabis dependence treatment. The neurobiological mechanisms that account for these beneficial effects on cannabis use may lead to understanding of the physical and emotional underpinnings of cannabis dependence and recovery from this disorder.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00838448","term_id":"NCT00838448"}}NCT00838448]     

Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation

Background

Studies suggest that micronutrients may modify the risk or delay progression of prostate cancer; however, the molecular mechanisms involved are poorly understood. We examined the effects of lycopene and fish oil on prostate gene expression in a double-blind placebo-controlled randomized clinical trial.

Methods

Eighty-four men with low risk prostate cancer were stratified based on self-reported dietary consumption of fish and tomatoes and then randomly assigned to a 3-month intervention of lycopene (n = 29) or fish oil (n = 27) supplementation or placebo (n = 28). Gene expression in morphologically normal prostate tissue was studied at baseline and at 3 months via cDNA microarray analysis. Differential gene expression and pathway analyses were performed to identify genes and pathways modulated by these micronutrients.

Results

Global gene expression analysis revealed no significant individual genes that were associated with high intake of fish or tomato at baseline or after 3 months of supplementation with lycopene or fish oil. However, exploratory pathway analyses of rank-ordered genes (based on p-values not corrected for multiple comparisons) revealed the modulation of androgen and estrogen metabolism in men who routinely consumed more fish (p = 0.029) and tomato (p = 0.008) compared to men who ate less. In addition, modulation of arachidonic acid metabolism (p = 0.01) was observed after 3 months of fish oil supplementation compared with the placebo group; and modulation of nuclear factor (erythroid derived-2) factor 2 or Nrf2-mediated oxidative stress response for either supplement versus placebo (fish oil: p = 0.01, lycopene: p = 0.001).

Conclusions

We did not detect significant individual genes associated with dietary intake and supplementation of lycopene and fish oil. However, exploratory analyses revealed candidate in vivo pathways that may be modulated by these micronutrients.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00402285","term_id":"NCT00402285"}}NCT00402285     

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study

Background

A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.

Methods

This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.

Findings

42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).

Conclusion

Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease

Background

Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.

Methods

We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.

Results

36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).

Conclusions

Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00126672","term_id":"NCT00126672"}}NCT00126672     

Effect of seven-valent pneumococcal conjugate vaccine on Staphylococcus aureus colonisation in a randomised controlled trial

Background

Heptavalent pneumococcal conjugate vaccine (PCV7) shifts nasopharyngeal colonisation with vaccine serotype pneumococci towards nonvaccine serotypes. Because of the reported negative association of vaccine serotype pneumococci and Staphylococcus aureus in the nasopharynx, we explored the effect of PCV7 on nasopharyngeal colonisation with S. aureus in children and parents.

Methodology/Principal Findings

This study was part of a randomised controlled trial on the effect of PCV7 on pneumococcal carriage, enrolling healthy newborns who were randomly assigned (1∶1∶1) to receive PCV7 (1) at 2 and 4 months of age (2) at 2, 4 and 11 months or (3) no PCV7 (controls). Nasopharyngeal colonisation of S. aureus was a planned secondary outcome. Nasopharyngeal swabs were obtained from all children over a 2-year period with 6-months interval and from one parent at the child''s age of 12 and 24 months and cultured for Streptococcus pneumoniae and S. aureus. Between July 2005 and February 2006, 1005 children were enrolled and received either 2-doses of PCV7 (n = 336), 2+1-doses (336) or no dose (n = 333) before PCV7 implementation in the Dutch national immunization program. S. aureus colonisation had doubled in children in the 2+1-dose group at 12 months of age compared with unvaccinated controls (10.1% versus 5.0%; p = 0.019). A negative association for co-colonisation of S. pneumoniae and S. aureus was observed for both vaccine serotype (adjusted odds ratio (aOR) 0.53, 95% confidence interval (CI) 0.38–0.74) and nonvaccine serotype pneumococci (aOR 0.67, 95% CI 0.52–0.88).

Conclusions/Significance

PCV7 induces a temporary increase in S. aureus colonisation in children around 12 months of age after a 2+1-dose PCV7 schedule. The potential clinical consequences are unknown and monitoring is warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00189020","term_id":"NCT00189020"}}NCT00189020     

Randomized controlled trial of fish oil and montelukast and their combination on airway inflammation and hyperpnea-induced bronchoconstriction

Background

Both fish oil and montelukast have been shown to reduce the severity of exercise-induced bronchoconstriction (EIB). The purpose of this study was to compare the effects of fish oil and montelukast, alone and in combination, on airway inflammation and bronchoconstriction induced by eucapnic voluntary hyperpnea (EVH) in asthmatics.

Methods

In this model of EIB, twenty asthmatic subjects with documented hyperpnea-induced bronchoconstriction (HIB) entered a randomized double-blind trial. All subjects entered on their usual diet (pre-treatment, n = 20) and then were randomly assigned to receive either one active 10 mg montelukast tablet and 10 placebo fish oil capsules (n = 10) or one placebo montelukast tablet and 10 active fish oil capsules totaling 3.2 g EPA and 2.0 g DHA (n = 10) taken daily for 3-wk. Thereafter, all subjects (combination treatment; n = 20) underwent another 3-wk treatment period consisting of a 10 mg active montelukast tablet or 10 active fish oil capsules taken daily.

Results

While HIB was significantly inhibited (p<0.05) by montelukast, fish oil and combination treatment compared to pre-treatment, there was no significant difference (p>0.017) between treatment groups; percent fall in forced expiratory volume in 1-sec was −18.4±2.1%, −9.3±2.8%, −11.6±2.8% and −10.8±1.7% on usual diet (pre-treatment), fish oil, montelukast and combination treatment respectively. All three treatments were associated with a significant reduction (p<0.05) in F_ENO, exhaled breathe condensate pH and cysteinyl-leukotrienes, while the fish oil and combination treatment significantly reduced (p<0.05) urinary 9α, 11β-prostaglandin F₂ after EVH compared to the usual diet; however, there was no significant difference (p>0.017) in these biomarkers between treatments.

Conclusion

While fish oil and montelukast are both effective in attenuating airway inflammation and HIB, combining fish oil with montelukast did not confer a greater protective effect than either intervention alone. Fish oil supplementation should be considered as an alternative treatment for EIB.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00676468","term_id":"NCT00676468"}}NCT00676468     

BCG Vaccination: A Role for Vitamin D?

Background

BCG vaccination is administered in infancy in most countries with the aim of providing protection against tuberculosis. There is increasing interest in the role of vitamin D in immunity to tuberculosis. This study objective was to determine if there was an association between circulating 25(OH)D concentrations and BCG vaccination status and cytokine responses following BCG vaccination in infants.

Methods

Blood samples were collected from UK infants who were vaccinated with BCG at 3 (n = 47) and 12 (n = 37) months post BCG vaccination. These two time-points are denoted as time-point 1 and time-point 2. Two blood samples were also collected from age-matched unvaccinated infants (n = 32 and 28 respectively), as a control group. Plasma vitamin D concentrations (25(OH)D) were measured by radio-immunoassay. The cytokine IFNγ was measured in supernatants from diluted whole blood stimulated with M.tuberculosis (M.tb) PPD for 6 days.

Results

58% of infants had some level of hypovitaminosis (25(OH)D <30ng/ml) at time-point 1, and this increased to 97% 9 months later. BCG vaccinated infants were almost 6 times (CI: 1.8–18.6) more likely to have sufficient vitamin D concentrations than unvaccinated infants at time-point 1, and the association remained strong after controlling for season of blood collection, ethnic group and sex. Among vaccinees, there was also a strong inverse association between IFNγ response to M.tb PPD and vitamin D concentration, with infants with higher vitamin D concentrations having lower IFNγ responses.

Conclusions

Vitamin D may play an immuno-regulatory role following BCG vaccination. The increased vitamin D concentrations in BCG vaccinated infants could have important implications: vitamin D may play a role in immunity induced by BCG vaccination and may contribute to non-specific effects observed following BCG vaccination.     

The spectrum of central nervous system infections in an adult referral hospital in hanoi, Vietnam

Objectives

To determine prospectively the causative pathogens of central nervous system (CNS) infections in patients admitted to a tertiary referral hospital in Hanoi, Vietnam.

Methods

From May 2007 to December 2008, cerebrospinal fluid (CSF) samples from 352 adults with suspected meningitis or encephalitis underwent routine testing, staining (Gram, Ziehl-Nielsen, India ink), bacterial culture and polymerase chain reaction targeting Neisseria meningitidis, Streptococcus pneumoniae, S. suis, Haemophilus influenzae type b, Herpes simplex virus (HSV), Varicella Zoster virus (VZV), enterovirus, and 16S ribosomal RNA. Blood cultures and clinically indicated radiology were also performed. Patients were classified as having confirmed or suspected bacterial (BM), tuberculous (TBM), cryptococcal (CRM), eosinophilic (EOM) meningitis, aseptic encephalitis/meningitis (AEM), neurocysticercosis and others.

Results

352 (male: 66%) patients were recruited: median age 34 years (range 13–85). 95/352 (27.3%) diagnoses were laboratory confirmed and one by cranial radiology: BM (n = 62), TBM (n = 9), AEM (n = 19), CRM (n = 5), and neurocysticercosis (n = 1, cranial radiology). S. suis predominated as the cause of BM [48/62 (77.4%)]; Listeria monocytogenese (n = 1), S. pasteurianus (n = 1) and N. meningitidis (n = 2) were infrequent. AEM viruses were: HSV (n = 12), VZV (n = 5) and enterovirus (n = 2). 5 patients had EOM. Of 262/352 (74.4%) patients with full clinical data, 209 (79.8%) were hospital referrals and 186 (71%) had been on antimicrobials. 21 (8%) patients died: TBM (15.2%), AEM (10%), and BM (2.8%).

Conclusions

Most infections lacked microbiological confirmation. S. suis was the most common cause of BM in this setting. Improved diagnostics are needed for meningoencephalitic syndromes to inform treatment and prevention strategies.