A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil

Background

Praziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally.

Methodology/Principal Findings

Four trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n = 428) or 60 mg/kg (n = 428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%–98% at individual sites) with 40 mg/kg and 92.8% (88%–97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR = 0.78, 95%CI = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug-related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post-dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%).

Conclusion

A higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries.

Trial Registration

Controlled-Trials.com ISRCTN29273316 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00403611","term_id":"NCT00403611"}}NCT00403611     

Efficacy and safety of nitazoxanide, albendazole, and nitazoxanide-albendazole against Trichuris trichiura infection: a randomized controlled trial

Background

The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate.

Methodology

The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment.

Principal Findings

Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment.

Conclusions/Significance

Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis.

Trial Registration

Controlled-Trials.com ISRCTN08336605     

Controlling tungiasis in an impoverished community: an intervention study

Background

In Brazil, tungiasis is endemic in some resource-poor communities where various domestic and sylvatic animals act as reservoirs for this zoonosis. To determine the effect of control measures on the prevalence and intensity of infestation of human and animal tungiasis, a repeated cross-sectional survey with intervention was carried out.

Methodology/Principal Findings

In a traditional fishing community in Northeast Brazil, humans and reservoir animals were treated, and premise-spraying using an insecticide was done, while a second fishing community served as a control. Both communities were followed up 10 times during a 12-month period. At baseline, prevalence of tungiasis was 43% (95% confidence interval [CI]: 35%–51%) and 37% (95% CI: 31%–43%) in control and intervention villages, respectively. During the study, prevalence of tungiasis dropped to 10% (95% CI: 8%–13%; p<0.001) in the intervention village, while the prevalence remained at a high level in the control village. However, after one year, at the end of the study, in both communities the prevalence of the infestation had reached pre-intervention levels. Whereas the intensity of infestation was significantly reduced in the intervention community (p<0.001), and remained low at the end of the study (p<0.001), it did not change in the control village.

Conclusion/Significance

Our study shows that a reduction of prevalence and intensity of infestation is possible, but in impoverished communities a long-lasting reduction of disease occurrence can only be achieved by the regular treatment of infested humans, the elimination of animal reservoirs, and, likely, through environmental changes.

Trial Registration

Controlled-Trials.com ISRCTN27670575     

An international randomised placebo-controlled trial of a four-component combination pill ("polypill") in people with raised cardiovascular risk

Background

There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol (‘polypills’) to reduce cardiovascular disease. However, no reliable placebo-controlled data are available on both efficacy and tolerability.

Methods

We conducted a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated 5-year cardiovascular disease risk over 7.5%. The primary outcomes were systolic blood pressure (SBP), LDL-cholesterol and tolerability (proportion discontinued randomised therapy) at 12 weeks follow-up.

Findings

At baseline, mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23% vs 18% (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2). There was an excess of side effects known to the component medicines (58% vs 42%, p = 0.001), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment.

Conclusions

This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people. The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12607000099426     

Completeness and changes in registered data and reporting bias of randomized controlled trials in ICMJE journals after trial registration policy

Objective

We assessed the adequacy of randomized controlled trial (RCT) registration, changes to registration data and reporting completeness for articles in ICMJE journals during 2.5 years after registration requirement policy.

Methods

For a set of 149 reports of 152 RCTs with ClinicalTrials.gov registration number, published from September 2005 to April 2008, we evaluated the completeness of 9 items from WHO 20-item Minimum Data Set relevant for assessing trial quality. We also assessed changes to the registration elements at the Archive site of ClinicalTrials.gov and compared published and registry data.

Results

RCTs were mostly registered before 13 September 2005 deadline (n = 101, 66.4%); 118 (77.6%) started recruitment before and 31 (20.4%) after registration. At the time of registration, 152 RCTs had a total of 224 missing registry fields, most commonly ‘Key secondary outcomes’ (44.1% RCTs) and ‘Primary outcome’ (38.8%). More RCTs with post-registration recruitment had missing Minimum Data Set items than RCTs with pre-registration recruitment: 57/118 (48.3%) vs. 24/31 (77.4%) (χ² ₁ = 7.255, P = 0.007). Major changes in the data entries were found for 31 (25.2%) RCTs. The number of RCTs with differences between registered and published data ranged from 21 (13.8%) for Study type to 118 (77.6%) for Target sample size.

Conclusions

ICMJE journals published RCTs with proper registration but the registration data were often not adequate, underwent substantial changes in the registry over time and differed in registered and published data. Editors need to establish quality control procedures in the journals so that they continue to contribute to the increased transparency of clinical trials.     

Does a Family Meetings Intervention Prevent Depression and Anxiety in Family Caregivers of Dementia Patients? A Randomized Trial

Background

Family caregivers of dementia patients are at increased risk of developing depression or anxiety. A multi-component program designed to mobilize support of family networks demonstrated effectiveness in decreasing depressive symptoms in caregivers. However, the impact of an intervention consisting solely of family meetings on depression and anxiety has not yet been evaluated. This study examines the preventive effects of family meetings for primary caregivers of community-dwelling dementia patients.

Methods

A randomized multicenter trial was conducted among 192 primary caregivers of community dwelling dementia patients. Caregivers did not meet the diagnostic criteria for depressive or anxiety disorder at baseline. Participants were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions and four family meetings which occurred once every 2 to 3 months for a year. Outcome measures after 12 months were the incidence of a clinical depressive or anxiety disorder and change in depressive and anxiety symptoms (primary outcomes), caregiver burden and quality of life (secondary outcomes). Intention-to-treat as well as per protocol analyses were performed.

Results

A substantial number of caregivers (72/192) developed a depressive or anxiety disorder within 12 months. The intervention was not superior to usual care either in reducing the risk of disorder onset (adjusted IRR 0.98; 95% CI 0.69 to 1.38) or in reducing depressive (randomization-by-time interaction coefficient = −1.40; 95% CI −3.91 to 1.10) or anxiety symptoms (randomization-by-time interaction coefficient = −0.55; 95% CI −1.59 to 0.49). The intervention did not reduce caregiver burden or their health related quality of life.

Conclusion

This study did not demonstrate preventive effects of family meetings on the mental health of family caregivers. Further research should determine whether this intervention might be more beneficial if provided in a more concentrated dose, when applied for therapeutic purposes or targeted towards subgroups of caregivers.

Trial Registration

Controlled-Trials.com ISRCTN90163486     

Percutaneous disc decompression with nucleoplasty-volumetry of the nucleus pulposus using ultrahigh-field MRI

Purpose

To evaluate changes in nucleus pulposus volume as a potential parameter for the effects of disc decompression.

Methods

Fifty-two discs (T8 to L1) were extracted from 26 pigs and separated into thoracic (T8 to T11) and thoracolumbar discs (T12 to L1). The discs were imaged using 7.1 Tesla ultrahigh-field magnetic resonance imaging (MRI) with acquisition of axial T2-weighted turbo spin-echo sequences for determination of baseline and postinterventional nucleus pulposus volumes. Volumes were calculated using OsiriX® (http://www.osirix-viewer.com). After randomization, one group was treated with nucleoplasty, while the placebo group was treated with an identical procedure but without coblation current. The readers analyzing the MR images were blinded to the kind of procedure performed. Baseline and postinterventional volumes were compared between the nucleoplasty and placebo group.

Results

Average preinterventional nucleus volume was 0.799 (SD: 0.212) ml. Postinterventional volume reduction in the nucleoplasty group was significant at 0.052 (SD: 0.035) ml or 6.30% (p<0.0001) (thoracic discs) and 0.082 (SD: 0.042) ml or 7.25% (p = 0.0078) (thoracolumbar discs). Nucleoplasty achieved volume reductions of 0.114 (SD: 0.054) ml or 14.72% (thoracic) and 0.093 (SD: 0.081) ml or 11.61% (thoracolumbar) compared with the placebo group.

Conclusions

Nucleoplasty significantly reduces thoracic and thoracolumbar nucleus pulposus volumes in porcine discs.     

Fetal movement counting improved identification of fetal growth restriction and perinatal outcomes--a multi-centre, randomized, controlled trial

Background

Fetal movement counting is a method used by the mother to quantify her baby''s movements, and may prevent adverse pregnancy outcome by a timely evaluation of fetal health when the woman reports decreased fetal movements. We aimed to assess effects of fetal movement counting on identification of fetal pathology and pregnancy outcome.

Methodology

In a multicentre, randomized, controlled trial, 1076 pregnant women with singleton pregnancies from an unselected population were assigned to either perform fetal movement counting from gestational week 28, or to receive standard antenatal care not including fetal movement counting (controls). Women were recruited from nine Norwegian hospitals during September 2007 through November 2009. Main outcome was a compound measure of fetal pathology and adverse pregnancy outcomes. Analysis was performed by intention-to-treat.

Principal Findings

The frequency of the main outcome was equal in the groups; 63 of 433 (11.6%) in the intervention group, versus 53 of 532 (10.7%) in the control group [RR: 1.1 95% CI 0.7–1.5)]. The growth-restricted fetuses were more often identified prior to birth in the intervention group than in the control group; 20 of 23 fetuses (87.0%) versus 12 of 20 fetuses (60.0%), respectively, [RR: 1.5 (95% CI 1.0–2.1)]. In the intervention group two babies (0.4%) had Apgar scores <4 at 1 minute, versus 12 (2.3%) in the control group [RR: 0.2 (95% CI 0.04–0.7)]. The frequency of consultations for decreased fetal movement was 71 (13.1%) and 57 (10.7%) in the intervention and control groups, respectively [RR: 1.2 (95% CI 0.9–1.7)]. The frequency of interventions was similar in the groups.

Conclusions

Maternal ability to detect clinically important changes in fetal activity seemed to be improved by fetal movement counting; there was an increased identification of fetal growth restriction and improved perinatal outcome, without inducing more consultations or obstetric interventions.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00513942","term_id":"NCT00513942"}}NCT00513942     

Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Background

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods

A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings

The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion

The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical Trials Registration

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

Elderly subjects have a delayed antibody response and prolonged viraemia following yellow fever vaccination: a prospective controlled cohort study

Background

Yellow fever vaccination (YF-17D) can cause serious adverse events (SAEs). The mechanism of these SAEs is poorly understood. Older age has been identified as a risk factor. We tested the hypothesis that the humoral immune response to yellow fever vaccine develops more slowly in elderly than in younger subjects.

Method

We vaccinated young volunteers (18–28 yrs, N = 30) and elderly travelers (60–81 yrs, N = 28) with YF-17D and measured their neutralizing antibody titers and plasma YF-17D RNA copy numbers before vaccination and 3, 5, 10, 14 and 28 days after vaccination.

Results

Ten days after vaccination seroprotection was attained by 77% (23/30) of the young participants and by 50% (14/28) of the elderly participants (p = 0.03). Accordingly, the Geometric Mean Titer of younger participants was higher than the GMT of the elderly participants. At day 10 the difference was +2.9 IU/ml (95% CI 1.8–4.7, p = 0.00004) and at day 14 +1.8 IU/ml (95% CI 1.1–2.9, p = 0.02, using a mixed linear model. Viraemia was more common in the elderly (86%, 24/28) than in the younger participants (60%, 14/30) (p = 0.03) with higher YF-17D RNA copy numbers in the elderly participants.

Conclusions

We found that elderly subjects had a delayed antibody response and higher viraemia levels after yellow fever primovaccination. We postulate that with older age, a weaker immune response to yellow fever vaccine allows the attenuated virus to cause higher viraemia levels which may increase the risk of developing SAEs. This may be one piece in the puzzle of the pathophysiology of YEL-AVD.

Trial Registration

Trialregitser.nl NTR1040     

Effect of newborn resuscitation training on health worker practices in Pumwani Hospital, Kenya

Background

Birth asphyxia kills 0.7 to 1.6 million newborns a year globally with 99% of deaths in developing countries. Effective newborn resuscitation could reduce this burden of disease but the training of health-care providers in low income settings is often outdated. Our aim was to determine if a simple one day newborn resuscitation training (NRT) alters health worker resuscitation practices in a public hospital setting in Kenya.

Methods/Principal Findings

We conducted a randomised, controlled trial with health workers receiving early training with NRT (n = 28) or late training (the control group, n = 55). The training was adapted locally from the approach of the UK Resuscitation Council. The primary outcome was the proportion of appropriate initial resuscitation steps with the frequency of inappropriate practices as a secondary outcome. Data were collected on 97 and 115 resuscitation episodes over 7 weeks after early training in the intervention and control groups respectively. Trained providers demonstrated a higher proportion of adequate initial resuscitation steps compared to the control group (trained 66% vs control 27%; risk ratio 2.45, [95% CI 1.75–3.42], p<0.001, adjusted for clustering). In addition, there was a statistically significant reduction in the frequency of inappropriate and potentially harmful practices per resuscitation in the trained group (trained 0.53 vs control 0.92; mean difference 0.40, [95% CI 0.13–0.66], p = 0.004).

Conclusions/Significance

Implementation of a simple, one day newborn resuscitation training can be followed immediately by significant improvement in health workers'' practices. However, evidence of the effects on long term performance or clinical outcomes can only be established by larger cluster randomised trials.

Trial Registration

Controlled-Trials.com ISRCTN92218092     

Returning to Paid Employment after Stroke: The Psychosocial Outcomes In StrokE (POISE) Cohort Study

Objectives

To determine which early modifiable factors are associated with younger stroke survivors'' ability to return to paid work in a cohort study with 12-months of follow-up conducted in 20 stroke units in the Stroke Services NSW clinical network.

Participants

Were aged >17 and <65 years, recent (within 28 days) stroke, able to speak English sufficiently to respond to study questions, and able to provide written informed consent. Participants with language or cognitive impairment were eligible to participate if their proxy provided consent and completed assessments on the participants'' behalf. The main outcome measure was return to paid work during the 12 months following stroke.

Results

Of 441 consented participants (average age 52 years, 68% male, 83% with ischemic stroke), 218 were in paid full-time and 53 in paid part-time work immediately before their stroke, of whom 202 (75%) returned to paid part- or full-time work within 12 months. Being male, female without a prior activity restricting illness, younger, independent in activities of daily living (ADL) at 28 days after stroke, and having private health insurance was associated with return to paid work, following adjustment for other illnesses and a history of depression before stroke (C statistic 0·81). Work stress and post stroke depression showed no such independent association.

Conclusions

Given that independence in ADL is the strongest predictor of return to paid work within 12 months of stroke, these data reinforce the importance of reducing stroke-related disability and increasing independence for younger stroke survivors.

Trial Registration

Australian New Zealand Clinical Trials Registry ANZCTRN 12608000459325     

Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial

Background

Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients.

Methods

Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance.

Findings

On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections.

Interpretation

PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections.

Trial Registration

Controlled-Trials.com ISRCTN74386719     

Effectiveness of YouRAction, an intervention to promote adolescent physical activity using personal and environmental feedback: a cluster RCT

Background

In this study the one and six months effects of the computer-tailored YouRAction (targeting individual level determinants) and YouRAction+e (targeting in addition perceived environmental determinants) on compliance with the moderate-to-vigorous physical activity (MVPA) guideline and weight status are examined. In addition the use and appreciation of both interventions are studied.

Methods

A three-armed cluster randomized trial was conducted in 2009–2010 with measurements at baseline, one and six months post intervention. School classes were assigned to one of the study arms (YouRaction, YouRAction+e and Generic Information (GI) control group). MVPA was derived from self-reports at baseline, one and six months post intervention. Body Mass Index and waist circumference were measured at baseline and six months post intervention in a random sub-sample of the population. Use of the interventions was measured by webserver logs and appreciation by self-reports. Multilevel regression analyses were conducted to study the effects of the intervention against the GI control group. ANOVA''s and chi-square tests were used to describe differences in use and appreciation between study arms.

Results

There were no statistically significant intervention effects on compliance with the MVPA guideline, overweight or WC. Access to the full intervention was significantly lower for YouRAction (24.0%) and YouRAction+e (21.7%) compared to the GI (54.4%).

Conclusion

This study could not demonstrate that the YouRAction and YouRAction+e interventions were effective in promoting MVPA or improve anthropometric outcomes among adolescents, compared to generic information. Insufficient use and exposure to the intervention content may be an explanation for the lack of effects.

Trial Registration

TrialRegister.nl NTR1923     

Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: a randomized controlled trial

Background

The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People''s Republic of China.

Methodology/Principal findings

The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed.Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them.

Conclusions/Significance

Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted.

Trial Registration

www.controlled-trials.com ISRCTN47375023     

The effects of centralised and specialised intervention in the early course of severe unipolar depressive disorder: a randomised clinical trial

Background

Little is known on whether centralised and specialised combined pharmacological and psychological intervention in the early phase of severe unipolar depression improve prognosis. The aim of the present study was to assess the benefits and harms of centralised and specialised secondary care intervention in the early course of severe unipolar depression.

Methods

A randomised multicentre trial with central randomisation and blinding in relation to the primary outcome comparing a centralised and specialised outpatient intervention program with standard decentralised psychiatric treatment. The interventions were offered at discharge from first, second, or third hospitalisation due to a single depressive episode or recurrent depressive disorder. The primary outcome was time to readmission to psychiatric hospital. The data on re-hospitalisation was obtained from the Danish Psychiatric Central Register. The secondary and tertiary outcomes were severity of depressive symptoms according to the Major Depression Inventory, adherence to medical treatment, and satisfaction with treatment according to the total score on the Verona Service Satisfaction Scale-Affective Disorder (VSSS-A). These outcomes were assessed using questionnaires one year after discharge from hospital.

Results

A total of 268 patients with unipolar depression were included. There was no significant difference in the time to readmission (unadjusted hazard ratio 0.89, 95% confidence interval 0.60 to 1.32; log rank: χ² = 0.3, d.f. = 1, p = 0.6); severity of depressive symptoms (mood disorder clinic: median 21.6, quartiles 9.7–31.2 versus standard treatment: median 20.2, quartiles 10.0–29.8; p = 0.7); or the prevalence of patients in antidepressant treatment (73.9% versus 80.0%, p = 0.2). Centralised and specialised secondary care intervention resulted in significantly higher satisfaction with treatment (131 (SD 31.8) versus 107 (SD 25.6); p<0.001).

Conclusions

Centralised and specialised secondary care intervention in the early course of severe unipolar depression resulted in no significant effects on time to rehospitalisation, severity of symptoms, or use of antidepressants, but increased patient satisfaction.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00253071","term_id":"NCT00253071"}}NCT00253071     

Effectiveness of family meetings for family caregivers on delaying time to nursing home placement of dementia patients: a randomized trial

Background

Interventions relieving the burden of caregiving may postpone or prevent patient institutionalization. The objective of this study was to determine whether a family meetings intervention was superior to usual care in postponing nursing home placement of patients with dementia.

Methods

A randomized multicenter trial was conducted among 192 patients with a clinical diagnosis of dementia living at home at enrolment and their primary family caregiver. Dyads of caregivers and patients were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions with the primary caregiver and four family counseling sessions that included family members and friends. The primary outcome measure was the time until institutionalization of the patient. Intention-to-treat as well as per protocol analyses were performed. Survival analyses were carried out to evaluate the effectiveness of the intervention.

Results

During 18 months follow-up 23 of 96 relatives with dementia of caregivers in the intervention group and 18 of 96 relatives with dementia of caregivers in the usual care group were institutionalized. No significant difference between the intervention and the usual care group was found in time until institutionalization (adjusted hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.78 to 2.74). The per-protocol analysis revealed no significant effect either (adjusted HR 0.57, 95% CI 0.21 to 1.57), although the number of placements among the adherers was relatively low (9.4%). A subgroup effect was found for patients’ age, with a significantly higher risk of institutionalization for ‘younger’ patients in the intervention group compared with the usual care group (adjusted HR = 4.94, 95% CI 1.10 to 22.13).

Conclusion

This family meetings intervention for primary caregivers of patients with dementia did not postpone patient institutionalization more than usual care.

Trial Registration: Controlled-Trials.com ISRCTN90163486

     

Functional group and substructure searching as a tool in metabolomics

Background

A direct link between the names and structures of compounds and the functional groups contained within them is important, not only because biochemists frequently rely on literature that uses a free-text format to describe functional groups, but also because metabolic models depend upon the connections between enzymes and substrates being known and appropriately stored in databases.

Methodology

We have developed a database named “Biochemical Substructure Search Catalogue” (BiSSCat), which contains 489 functional groups, >200,000 compounds and >1,000,000 different computationally constructed substructures, to allow identification of chemical compounds of biological interest.

Conclusions

This database and its associated web-based search program (http://bisscat.org/) can be used to find compounds containing selected combinations of substructures and functional groups. It can be used to determine possible additional substrates for known enzymes and for putative enzymes found in genome projects. Its applications to enzyme inhibitor design are also discussed.     

Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial

Background

Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.

Methods and Findings

Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers'' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.

Conclusions

Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.

Trial registration

www.controlled-trials.com ISRCTN13968779 Please see later in the article for the Editors'' Summary     

Effect of a nutrition supplement and physical activity program on pneumonia and walking capacity in Chilean older people: a factorial cluster randomized trial

Background

Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile.

Methods and Findings

We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65–67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (∼100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrolment. Adherence was good for the nutritional supplement (∼75%), and moderate for the physical activity intervention (∼43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61–1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9–53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention.

Conclusions

Chile''s nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life.

Trial registration

Current Controlled Trials ISRCTN 48153354 Please see later in the article for the Editors'' Summary