Randomised Trial of Planned Caesarean Section Prior to Versus after 39 Weeks: Unscheduled Deliveries and Facility Logistics - A Secondary Analysis

Objectives

To compare the impact of scheduling caesarean section prior to versus after 39 completed weeks of gestation on the occurrence of unscheduled caesarean section and rescheduling of the procedure.

Methods

Secondary analysis from a multicentre randomised open-label trial including singleton pregnant women with a healthy foetus and a reliable due date. Women were allocated by computerized telephone randomisation to planned caesarean section at 38 weeks and three days or 39 weeks and three days. The outcomes were unscheduled deliveries with provided reasons, such as spontaneous labour onset or supervening complications, and any changes in the scheduled delivery date. Statistical analyses were according to intention-to-treat using Fisher’s exact test.

Results

From March 2009 to June 2011 1,274 women were included. Median difference in gestational age at delivery was six days. Compared to the 38 weeks group, the women in the 39 weeks group were more likely to have an unscheduled caesarean section (15.2% vs. 9.3%; RR 1.64, 95% CI 1.21; 2.22), to deliver between 6 pm and 8 am (10 % vs. 6%; RR 1.68, 95% CI 1.14; 2.47), or to have the procedure rescheduled (36.7% vs. 23%; RR 1.6, 95% CI 1.34;1.90).

Conclusions

Scheduling caesarean section after 39 weeks leads to a 60% increase in unscheduled caesarean sections and a 70% increase in delivery outside regular work hours as compared to scheduling of the procedure prior to 39 weeks.

Trial Registration

www.clinicaltrials.gov NCT00835003 http://www.clinicaltrials.gov/ct2/show/NCT00835003?term=NCT00835003&rank=1     

First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A,in Patients with Advanced Solid Tumors

Background

To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A).

Methods

Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety.

Results

Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity.

Conclusions

PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion.

Trial Registration

ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257     

High Uptake of Exclusive Breastfeeding and Reduced Early Post-Natal HIV Transmission

Background

Empirical data showing the clear benefits of exclusive breastfeeding (EBF) for HIV prevention are needed to encourage implementation of lactation support programs for HIV-infected women in low resource settings among whom replacement feeding is unsafe. We conducted a prospective, observational study in Lusaka, Zambia, to test the hypothesis that EBF is associated with a lower risk of postnatal HIV transmission than non-EBF.

Methods and Results

As part of a randomized trial of early weaning, 958 HIV-infected women and their infants were recruited and all were encouraged to breastfeed exclusively to 4 months. Single-dose nevirapine was provided to prevent transmission. Regular samples were collected from infants to 24 months of age and tested by PCR. Detailed measurements of actual feeding behaviors were collected to examine, in an observational analysis, associations between feeding practices and postnatal HIV transmission. Uptake of EBF was high with 84% of women reporting only EBF cumulatively to 4 months. Post-natal HIV transmission before 4 months was significantly lower (p = 0.004) among EBF (0.040 95% CI: 0.024–0.055) than non-EBF infants (0.102 95% CI: 0.047–0.157); time-dependent Relative Hazard (RH) of transmission due to non-EBF = 3.48 (95% CI: 1.71–7.08). There were no significant differences in the severity of disease between EBF and non-EBF mothers and the association remained significant (RH = 2.68 95% CI: 1.28–5.62) after adjusting for maternal CD4 count, plasma viral load, syphilis screening results and low birth weight.

Conclusions

Non-EBF more than doubles the risk of early postnatal HIV transmission. Programs to support EBF should be expanded universally in low resource settings. EBF is an affordable, feasible, acceptable, safe and sustainable practice that also reduces HIV transmission providing HIV-infected women with a means to protect their children''s lives.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00310726","term_id":"NCT00310726"}}NCT00310726     

Lactation Support and Breastfeeding Duration in Jaundiced Infants: A Randomized Controlled Trial

Objectives

Neonatal jaundice is the most common problem in full-term infants during the immediate post-natal period. We examined the effect of a lactation support intervention on breastfeeding duration in hospitalized jaundiced infants.

Study Design

We conducted a randomized controlled trial with a qualitative component involving mothers of hospitalized jaundiced breastfed infants <4 weeks of age. Mothers receiving the intervention met with an International Board-Certified Lactation Consultant in hospital and 1–3 times post discharge. Both groups received the standard care for jaundice. The primary outcome was exclusive breastfeeding at 3 months. To the exception of research assistants enrolling participants and completing qualitative interviews, all research staff, investigators and statisticians were blinded to group assignment. Qualitative interviews elicited feedback on breastfeeding experiences for both groups.

Results

99 participants were recruited, and 86 analyzed for primary outcome. There was no difference in exclusive breastfeeding at 3 months between groups (RR 0.84, 95% CI 0.56–1.24, p = 0.40) or in the secondary outcomes. 31 participants were included in the qualitative analysis. Participants in the intervention group described an increase in comfort and confidence levels with breastfeeding. Participants in the control group reported limited lactation support.

Conclusions

Our hospital-based lactation support program did not result in a higher proportion of mothers exclusively breastfeeding at 3 months compared to current hospital standard care. Qualitative feedback from the intervention group suggests that mothers’ confidence was increased, which is linked to breastfeeding duration. The decision to breastfeed is multifactorial and hospital-based lactation support may be only a small piece of the puzzle in hospitalized jaundiced infants. Further studies may be needed to fully elucidate the impact of an in-hospital lactation support program on successful breastfeeding for these infants.

Trial Registration

ClinicalTrials.gov NCT00966719 https://www.clinicaltrials.gov/ct2/show/NCT00966719?term=Lactation+Support+and+Breastfeeding+Duration+in+Jaundiced+Infants%3A+a+Randomized+Controlled+Trial&rank=1     

Genetic and Non-Genetic Determinants of Raltegravir Penetration into Cerebrospinal Fluid: A Single Arm Pharmacokinetic Study

Background

Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C→T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C→T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier.

Methods

Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose.

Results

The 4-hour CSF concentration correlated more strongly with 2-hour (r²=0.76, P=1.12x10^-11) than 4-hour (r²=0.47, P=6.89x10^-6) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC_0-4h r²=0.86, P=5.15x10^-16). There was no significant association between ABCB1 3435C→T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes.

Conclusions

Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C→T genotype but strongly correlate with plasma exposure.

Trial Registration

ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924     

Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants

Background

Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.

Methods/Findings

Standard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant''s blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.

Conclusions/Significance

Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00061321","term_id":"NCT00061321"}}NCT00061321     

Effect of Breastfeeding Promotion on Early Childhood Caries and Breastfeeding Duration among 5 Year Old Children in Eastern Uganda: A Cluster Randomized Trial

BackgroundAlthough several studies have shown short term health benefits of exclusive breastfeeding (EBF), its long term consequences have not been studied extensively in low-income contexts. This study assessed the impact of an EBF promotion initiative for 6 months on early childhood caries (ECC) and breastfeeding duration in children aged 5 years in Mbale, Eastern Uganda.MethodsParticipants were recruited from the Ugandan site of the PROMISE- EBF cluster randomised trial (ClinicalTrials.gov no: {"type":"clinical-trial","attrs":{"text":"NCT00397150","term_id":"NCT00397150"}}NCT00397150). A total of 765 pregnant women from 24 clusters were included in the ratio 1:1 to receive peer counselled promotion of EBF as the intervention or standard of care. At the 5 year follow-up, ECC was recorded under field conditions using the World Health Organization’s decayed missing filled tooth (dmft) index. Adjusted negative binomial and linear regression were used in the analysis.ResultsMean breastfeeding duration in the intervention and control groups (n=417) were 21.8 (CI 20.7–22.9) and 21.3(CI 20.7–21.9) months, respectively. The mean dmft was 1.5 (standard deviation [SD] 2.9) and 1.7 (SD 2.9) in the intervention and control groups, respectively. Corresponding prevalence estimates of ECC were 38% and 41%. Negative binomial regression analysis adjusted for cluster effects and loss-to-follow-up by inverse probability weights (IPW) showed an incidence-rate ratio (IRR) of 0.91 (95% CI 0.65–1.2). Comparing the effect of the trial arm on breastfeeding duration showed a difference in months of 0.48 (-0.72 to 1.7).ConclusionPROMISE EBF trial did not impact on early childhood caries or breastfeeding duration at 5 years of age. This study contributes to the body of evidence that promotion of exclusive breastfeeding does not raise oral health concerns. However, the high burden of caries calls for efforts to improve the oral health condition in this setting.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00397150","term_id":"NCT00397150"}}NCT00397150     

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Na?ve Patients Treated with Raltegravir,Tenofovir Disoproxil Fumarate and Emtricitabine

Background

The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood.

Methods

Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy.

Results

Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy.

Conclusions

ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis.

Trial Registration

Clinicaltrials.gov NCT00660972     

The Effect of Sugar-Free Versus Sugar-Sweetened Beverages on Satiety,Liking and Wanting: An 18 Month Randomized Double-Blind Trial in Children

Background

Substituting sugar-free for sugar-sweetened beverages reduces weight gain. A possible explanation is that sugar-containing and sugar-free beverages cause the same degree of satiety. However, this has not been tested in long-term trials.

Methods

We randomized 203 children aged 7-11 years to receive 250 mL per day of an artificially sweetened sugar-free beverage or a similarly looking and tasting sugar-sweetened beverage. We measured satiety on a 5-point scale by questionnaire at 0, 6, 12 and 18 months. We calculated the change in satiety from before intake to 1 minute after intake and 15 minutes after intake. We then calculated the odds ratio that satiety increased by 1 point in the sugar-group versus the sugar-free group. We also investigated how much the children liked and wanted the beverages.

Results

146 children or 72% completed the study. We found no statistically significant difference in satiety between the sugar-free and sugar-sweetened group; the adjusted odds ratio for a 1 point increase in satiety in the sugar group versus the sugar-free group was 0.77 at 1 minute (95% confidence interval, 0.46 to 1.29), and 1.44 at 15 minutes after intake (95% CI, 0.86 to 2.40). The sugar-group liked and wanted their beverage slightly more than the sugar-free group, adjusted odds ratio 1.63 (95% CI 1.05 to 2.54) and 1.65 (95% CI 1.07 to 2.55), respectively.

Conclusions

Sugar-sweetened and sugar-free beverages produced similar satiety. Therefore when children are given sugar-free instead of sugar-containing drinks they might not make up the missing calories from other sources. This may explain our previous observation that children in the sugar-free group accumulated less body fat than those in the sugar group.

Trial Registration

ClinicalTrials.gov NCT00893529 http://clinicaltrials.gov/show/NCT00893529     

Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption

BackgroundAs pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.ConclusionIn this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.

Trial Registration

ClinicalTrials.gov, Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02776748","term_id":"NCT02776748"}}NCT02776748     

Differential Effects of Early Weaning for HIV-Free Survival of Children Born to HIV-Infected Mothers by Severity of Maternal Disease

Background

We previously reported no benefit of early weaning for HIV-free survival of children born to HIV-infected mothers in intent-to-treat analyses. Since early weaning was poorly accepted, we conducted a secondary analysis to investigate whether beneficial effects may have been hidden.

Methods

958 HIV-infected women in Lusaka, Zambia, were randomized to abrupt weaning at 4 months (intervention) or to continued breastfeeding (control). Children were followed to 24 months with regular HIV PCR tests and examinations to determine HIV infection or death. Detailed behavioral data were collected on when all breastfeeding ended. Most participants were recruited before antiretroviral treatment (ART) became available. We compared outcomes among mother-child pairs who weaned earlier or later than intended by study design adjusting for potential confounders.

Results

Of infants alive, uninfected and still breastfeeding at 4 months in the intervention group, 16.1% who weaned as instructed acquired HIV or died by 24 months compared to 16.0% who did not comply (p = 0.98). Children of women with less severe disease during pregnancy (not eligible for ART) had worse outcomes if their mothers weaned as instructed (RH = 2.60 95% CI: 1.06–6.36) compared to those who continued breastfeeding. Conversely, children of mothers with more severe disease (eligible for ART but did not receive it) who weaned early had better outcomes (p-value interaction = 0.002). In the control group, weaning before 15 months was associated with 3.94-fold (95% CI: 1.65–9.39) increase in HIV infection or death among infants of mothers with less severe disease.

Conclusion

Incomplete adherence did not mask a benefit of early weaning. On the contrary, for women with less severe disease, early weaning was harmful and continued breastfeeding resulted in better outcomes. For women with more advanced disease, ART should be given during pregnancy for maternal health and to reduce transmission, including through breastfeeding.

Trial Registration

Clinical trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00310726","term_id":"NCT00310726"}}NCT00310726     

Effect of Alpha Linolenic Acid Supplementation on Serum Prostate Specific Antigen (PSA): Results from the Alpha Omega Trial

Background

Alpha linolenic acid (ALA) is the major omega-3 fatty acid in the diet. Evidence on health effects of ALA is not conclusive, but some observational studies found an increased risk of prostate cancer with higher intake of ALA. We examined the effect of ALA supplementation on serum concentrations of prostate-specific antigen (PSA), a biomarker for prostate cancer.

Methods

The Alpha Omega Trial (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452) was a double-blind, placebo-controlled trial of ALA and the fish fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) on the recurrence of cardiovascular disease, using a 2×2 factorial design. Blood was collected at the start and the end of the intervention period. The present analysis included 1622 patients with a history of a myocardial infarction, aged 60–80 years with an initial PSA concentration <4 ng/mL. They received either 2 g per day of ALA or placebo in margarine spreads for 40 months. T-tests and logistic regression were used to assess the effects of ALA supplementation on changes in serum PSA (both continuously and as a dichotomous outcome, cut-off point: >4 ng/mL).

Findings

Mean serum PSA increased by 0.42 ng/mL on placebo (n = 815) and by 0.52 ng/mL on ALA (n = 807), a difference of 0.10 (95% confidence interval: −0.02 to 0.22) ng/mL (P = 0·12). The odds ratio for PSA rising above 4 ng/mL on ALA versus placebo was 1.15 (95% CI: 0.84–1.58).

Interpretation

An additional amount of 2 g of ALA per day increased PSA by 0.10 ng/mL, but the confidence interval ranged from −0.02 to 0.22 ng/mL and included no effect. Therefore, more studies are needed to establish whether or not ALA intake has a clinically significant effect on PSA or prostate cancer.

Trial registration information

ClinicalTrials.gov; Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452. URL: http://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452.     

Measurement of Cardiac Index by Transpulmonary Thermodilution Using an Implanted Central Venous Access Port: A Prospective Study in Patients Scheduled for Oncologic High-Risk Surgery

Background

Transpulmonary thermodilution allows the measurement of cardiac index for high risk surgical patients. Oncologic patients often have a central venous access (port-a-catheter) for chronic treatment. The validity of the measurement by a port-a-catheter of the absolute cardiac index and the detection of changes in cardiac index induced by fluid challenge are unknown.

Methods

We conducted a monocentric prospective study. 27 patients were enrolled. 250 ml colloid volume expansions for fluid challenge were performed during ovarian cytoreductive surgery. The volume expansion-induced changes in cardiac index measured by transpulmonary thermodilution by a central venous access (CIcvc) and by a port-a-catheter (CIport) were recorded.

Results

23 patients were analyzed with 123 pairs of measurements. Using a Bland and Altman for repeated measurements, the bias (lower and upper limits of agreement) between CIport and CIcvc was 0.14 (−0.59 to 0.88) L/min/m². The percentage error was 22%. The concordance between the changes in CIport and CIcvc observed during volume expansion was 92% with an r = 0.7 (with exclusion zone). No complications (included sepsis) were observed during the follow up period.

Conclusions

The transpulmonary thermodilution by a port-a-catheter is reliable for absolute values estimation of cardiac index and for measurement of the variation after fluid challenge.

Trial Registration

clinicaltrials.gov NCT02063009     

A Phase 1b Randomized,Controlled, Double-Blinded Dosage-Escalation Trial to Evaluate the Safety,Reactogenicity and Immunogenicity of an Adenovirus Type 35 Based Circumsporozoite Malaria Vaccine in Burkinabe Healthy Adults 18 to 45 Years of Age

Background

Ad35.CS.01 is a pre-erythrocytic malaria candidate vaccine. It is a codon optimized nucleotide sequence representing the P. falciparum circumsporozoite (CS) surface antigen inserted in a replication deficient Adenovirus 35 backbone. A Phase 1a trial has been conducted in the USA in naïve adults and showed that the vaccine was safe. The aim of this study is to assess the safety and immunogenicity of ascending dosages in sub Saharan Africa.

Methods

A double blind, randomized, controlled, dose escalation, phase Ib trial was conducted in a rural area of Balonghin, the Saponé health district (Burkina Faso). Forty-eight healthy adults aged 18-45 years were randomized into 4 cohorts of 12 to receive three vaccine doses (day 0, 28 and 84) of 10⁹, 10¹⁰, 5X10¹⁰, 10¹¹ vp of Ad35.CS.01 or normal saline by intra muscular injection. Subjects were monitored carefully during the 14 days following each vaccination for non serious adverse events. Severe and serious adverse events were collected throughout the participant study duration (12 months from the first vaccination). Humoral and cellular immune responses were measured on study days 0, 28, 56, 84, 112 and 140.

Results

Of the forty-eight subjects enrolled, forty-four (91.7%) received all three scheduled vaccine doses. Local reactions, all of mild severity, occurred in thirteen (27.1%) subjects. Severe (grade 3) laboratory abnormalities occurred in five (10.4%) subjects. One serious adverse event was reported and attributed to infection judged unrelated to vaccine. The vaccine induced both antibody titers and CD8 T cells producing IFNγ and TNFα with specificity to CS while eliciting modest neutralizing antibody responses against Ad35.

Conclusion

Study vaccine Ad35.CS.01 at four different dose levels was well-tolerated and modestly immunogenic in this population. These results suggest that Ad35.CS.01 should be further investigated for preliminary efficacy in human challenge models and as part of heterologous prime-boost vaccination strategies.

Trial Registration

ClinicalTrials.gov NCT01018459 http://clinicaltrials.gov/ct2/show/NCT01018459     

Effectiveness of Educational Poster on Knowledge of Emergency Management of Dental Trauma - Part 2: Cluster Randomised Controlled Trial for Secondary School Students

Objective

To investigate the effectiveness of educational poster on improving secondary school students'' knowledge of emergency management of dental trauma.

Methods

A cluster randomised controlled trial was conducted. 16 schools with total 671 secondary students who can read Chinese or English were randomised into intervention (poster, 8 schools, 364 students) and control groups (8 schools, 305 students) at the school level. Baseline knowledge of dental trauma was obtained by a questionnaire. Poster containing information of dental trauma management was displayed in a classroom for 2 weeks in each school in the intervention group whereas in the control group there was no display of such posters. Students of both groups completed the same questionnarie after 2 weeks.

Results

Two-week display of posters improved the knowledge score by 1.25 (p-value = 0.0407) on average.

Conclusion

Educational poster on dental trauma management significantly improved the level of knowledge of secondary school students in Hong Kong.

Trial Registration

HKClinicalTrial.com HKCTR-1343 ClinicalTrials.gov NCT01809457     

Adductor Canal Block for Postoperative Pain Treatment after Revision Knee Arthroplasty: A Blinded,Randomized, Placebo-Controlled Study

Background

Revision knee arthroplasty is assumed to be even more painful than primary knee arthroplasty and predominantly performed in chronic pain patients, which challenges postoperative pain treatment. We hypothesized that the adductor canal block, effective for pain relief after primary total knee arthroplasty, may reduce pain during knee flexion (primary endpoint: at 4 h) compared with placebo after revision total knee arthroplasty. Secondary endpoints were pain at rest, morphine consumption and morphine-related side effects.

Methods

We included patients scheduled for revision knee arthroplasty in general anesthesia into this blinded, placebo-controlled, randomized trial. Patients were allocated to an adductor canal block via a catheter with either ropivacaine or placebo; bolus of 0.75% ropivacaine/saline, followed by infusion of 0.2% ropivacaine/saline. Clinicaltrials.gov ID: NCT01191593.

Results

We enrolled 36 patients, of which 30 were analyzed. Mean pain scores during knee flexion at 4 h (primary endpoint) were: 52±22 versus 71±25 mm (mean difference 19, 95% CI: 1 to 37, P = 0.04), ropivacaine and placebo group respectively. When calculated as area under the curve (1–8 h/7 h) pain scores were 55±21 versus 69±21 mm during knee flexion (P = 0.11) and 39±18 versus 45±23 mm at rest (P = 0.43), ropivacaine and placebo group respectively. Groups were similar regarding morphine consumption and morphine-related side effects (P>0.05).

Conclusions

The only statistically significant difference found between groups was in the primary endpoint: pain during knee flexion at 4 h. However, due to a larger than anticipated dropout rate and heterogeneous study population, the study was underpowered.

Trial Registration

Clinicaltrials.gov NCT01191593     

IgA and Neutralizing Antibodies to Influenza A Virus in Human Milk: A Randomized Trial of Antenatal Influenza Immunization

Background

Antenatal immunization of mothers with influenza vaccine increases serum antibodies and reduces the rates of influenza illness in mothers and their infants. We report the effect of antenatal immunization on the levels of specific anti-influenza IgA levels in human breast milk. (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00142389","term_id":"NCT00142389"}}NCT00142389; http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00142389","term_id":"NCT00142389"}}NCT00142389).

Methods and Findings

The Mother''s Gift study was a prospective, blinded, randomized controlled trial that assigned 340 pregnant Bangladeshi mothers to receive either trivalent inactivated influenza vaccine, or 23-valent pneumococcal polysaccharide vaccine during the third trimester. We evaluated breast milk at birth, 6 weeks, 6 months, and 12 months, and serum at 10 weeks and 12 months. Milk and serum specimens from 57 subjects were assayed for specific IgA antibody to influenza A/New Caledonia (H1N1) using an enzyme-linked immunosorbent assay (ELISA) and a virus neutralization assay, and for total IgA using ELISA. Influenza-specific IgA levels in breast milk were significantly higher in influenza vaccinees than in pneumococcal controls for at least 6 months postpartum (p = 0.04). Geometric mean concentrations ranged from 8.0 to 91.1 ELISA units/ml in vaccinees, versus 2.3 to 13.7 ELISA units/mL in controls. Virus neutralization titers in milk were 1.2 to 3 fold greater in vaccinees, and correlated with influenza-specific IgA levels (r = 0.86). Greater exclusivity of breastfeeding in the first 6 months of life significantly decreased the expected number of respiratory illness with fever episodes in infants of influenza-vaccinated mothers (p = 0.0042) but not in infants of pneumococcal-vaccinated mothers (p = 0.4154).

Conclusions

The sustained high levels of actively produced anti-influenza IgA in breast milk and the decreased infant episodes of respiratory illness with fever suggest that breastfeeding may provide local mucosal protection for the infant for at least 6 months. Studies are needed to determine the cellular and immunologic mechanisms of breast milk-mediated protection after antepartum immunization.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00142389","term_id":"NCT00142389"}}NCT00142389     

Severe Painful Vaso-Occlusive Crises and Mortality in a Contemporary Adult Sickle Cell Anemia Cohort Study

Background

Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort.

Methods

Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation.

Results

Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality.

Conclusions

Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies.

Trial Registration

ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov/     

A Multicenter,Randomized Clinical Trial Comparing the Three-Weekly Docetaxel Regimen plus Prednisone versus Mitoxantone plus Prednisone for Chinese Patients with Metastatic Castration Refractory Prostate Cancer

Purpose

To explore the feasibility and efficacy of docetaxel plus prednisone for Chinese population with metastatic castration refractory prostate cancer (mCRPC).

Patients and methods

A total of 228 patients recruited from 15 centers were randomized to receive 10 cycles of D3P arm (docetaxel: 75 mg/m², intravenous infusion, every three weeks; Prednisone 10mg orally given daily) or M3P arm (mitoxantrone: 12 mg/m², intravenous infusion, every three weeks; Prednisone 10mg orally given daily). Primary end point was overall survival, and secondary end points were events progression-free survival (PFS), response rate, response duration. Quality of life (QoL) was also assessed in both treatment groups.

Results

The median overall survival was 21.88 months in D3P arm and 13.67 months in M3P arm (P = 0.0011, hazard ratio = 0.63, 95% confidence interval, 0.46–0.86). Subgroup analysis was consistent with the results of overall analysis. Events progression-free survival (pain, PSA, tumor and disease) were significantly improved in D3P arm compared with M3P arm. PSA response rate was 35.11% for patients treated by D3P arm and 19.39% for M3P arm (P = 0.0155). Pain response rate was higher in D3P arm (61.11%, P = 0.0011) than in M3P (23.08%) arm. No statistical differences were found between D3P arm and M3P arm for QoL, tumor response rate and response duration of PSA and pain. The tolerability and overall safety of D3P arm were generally comparable to that of M3P arm.

Conclusions

Compared with M3P arm, D3P arm significantly prolonged overall survival for the Chinese patients with mCRPC and improved the response rate for PSA and pain.

Trial Registration

clinicaltrials.gov NCT00436839