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     

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     

The Potential of Antimicrobials to Induce Thrombocytopenia in Critically Ill Patients: Data from a Randomized Controlled Trial

Background

Antimicrobial-induced thrombocytopenia is frequently described in the literature among critically ill patients. Several antimicrobials have been implicated, although experimental evidence to demonstrate causality is limited. We report, using a randomized trial, the potential of antimicrobials to induce thrombocytopenia.

Methods

Randomized trial allocated patients to antimicrobial treatment according to standard- of-care (SOC group) or drug-escalation in case of procalcitonin increases (high-exposure group). Patients were followed until death or day 28. Thrombocytopenia defined as absolute (platelet count ≤100x109/L) or relative (≥20% decrease in platelet count). Analyses were performed in the two randomized groups and as a merged cohort.

Results

Of the 1147 patients with platelet data available, 18% had absolute thrombocytopenia within the first 24 hours after admission to intensive care unit and additional 17% developed this complication during follow-up; 57% developed relative thrombocytopenia during follow-up. Absolute and relative thrombocytopenia day 1-4 was associated with increased mortality (HR: 1.67 [95% CI: 1.30 to 2.14]; 1.71 [95% CI: 1.30 to 2.30], P<0.0001, respectively). Patients in the high-exposure group received more antimicrobials including piperacillin/tazobactam, meropenem and ciprofloxacin compared with the SOC group, whereas cefuroxime was used more frequently in the SOC group (p<0.05). Risk of absolute and relative thrombocytopenia (RR: 0.9 [0.7-1.3], p=0.7439; 1.2 [1.0-1.4], p=0.06; respectively), as well as absolute platelet count (daily difference, high-exposure vs. SOC -1.7 [-3.8-0.5], p=0.14) was comparable between groups. In observational analyses, use of ciprofloxacin and piperacillin/tazobactam predicted risk of relative thrombocytopenia (vs. cefuroxime, RR: 2.08 [1.48-2.92]; 1.44 [1.10-1.89], respectively), however only ciprofloxacin were associated with a reduction in absolute platelet count (p=0.0005).

Conclusion

High exposure to broad-spectrum antimicrobials does not result in a reduction in thrombocytopenia in critically ill patients. However, single use of ciprofloxacin, and less so piperacillin/tazobactam, may contribute to a lower platelet count.

Trial Registration

ClinicalTrials.gov NCT00271752 http://clinicaltrials.gov/ct2/show/NCT00271752     

Multiple Sclerosis Affects Skeletal Muscle Characteristics

Background

The impact of multiple sclerosis (MS) on skeletal muscle characteristics, such as muscle fiber cross sectional area (CSA), fiber type proportion, muscle strength and whole muscle mass, remains conflicting.

Methods

In this cross sectional study, body composition and muscle strength of the quadriceps were assessed in 34 MS (EDSS: 2.5±0.19) patients and 18 matched healthy controls (HC). Hereafter a muscle biopsy (m.vastus lateralis) was taken.

Results

Compared to HC, mean muscle fiber CSA of all fibers, as well as CSA of type I, II and IIa fibers were smaller and muscle strength of the quadriceps was lower in MS patients. Whole body composition was comparable between groups. However, compared to HC, the biopsied leg tended to have a higher fat percentage (p = 0.1) and a lower lean mass (p = 0.06) in MS patients.

Conclusion

MS seems to negatively influence skeletal muscle fiber CSA, muscle strength and muscle mass of the lower limbs of mildly affected MS patients. This emphasises the need for rehabilitation programs focusing on muscle preservation of the lower limb.

Trial Registration

ClinicalTrials.gov NCT01845896     

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     

Speak Fast,Use Jargon,and Don’t Repeat Yourself: A Randomized Trial Assessing the Effectiveness of Online Videos to Supplement Emergency Department Discharge Instructions

Background

Emergency department discharge instructions are variably understood by patients, and in the setting of emergency department crowding, innovations are needed to counteract shortened interaction times with the physician. We evaluated the effect of viewing an online video of diagnosis-specific discharge instructions on patient comprehension and recall of instructions.

Methods

In this prospective, single-center, randomized controlled trial conducted between November 2011 and January 2012, we randomized emergency department patients who were discharged with one of 38 diagnoses to either view (after they left the emergency department) a vetted online video of diagnosis-specific discharge instructions, or to usual care. Patients were subsequently contacted by telephone and asked three standardized questions about their discharge instructions; one point was awarded for each correct answer. Using an intention-to-treat analysis, differences between groups were assessed using univariate testing, and with logistic regression that accounted for clustering on managing physician. A secondary outcome measure was patient satisfaction with the videos, on a 10-point scale.

Results

Among 133 patients enrolled, mean age was 46.1 (s.d.D. 21.5) and 55% were female. Patients in the video group had 19% higher mean scores (2.5, s.d. 0.7) than patients in the control group (2.1, s.d. 0.8) (p=0.002). After adjustment for patient age, sex, first language, triage acuity score, and clustering, the odds of achieving a fully correct score (3 out of 3) were 3.5 (95% CI, 1.7 to 7.2) times higher in the video group, compared to the control group. Among those who viewed the videos, median rating of the videos was 10 (IQR 8 to 10).

Conclusions

In this single-center trial, patients who viewed an online video of their discharge instructions scored higher on their understanding of key concepts around their diagnosis and subsequent care. Those who viewed the videos found them to be a helpful addition to standard care.

Trial Registration

ClinicalTrials.gov NCT01361932 http://clinicaltrials.gov/ct2/show/NCT01361932?term=nct01361932&rank=1     

Formalin-Inactivated EV71 Vaccine Candidate Induced Cross-Neutralizing Antibody against Subgenotypes B1, B4, B5 and C4A in Adult Volunteers

Background

Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac) at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.

Methods

Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.

Results

The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had <8 pre-vaccination neutralization titers (Nt) against the B4 vaccine strain. After the first EV71vac immunization, 95% of vaccinees have >4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants) against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8) against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.

Conclusion

EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.

Trial Registration

ClinicalTrials.gov __NCT01268787     

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/     

Comparison of Immunogenicity and Safety of Four Doses and Four Double Doses vs. Standard Doses of Hepatitis B Vaccination in HIV-Infected Adults: A Randomized,Controlled Trial

Background

HBV vaccination is recommended in HIV-infected adults with CD4+ cell count >200/mm³ although the efficacy is only 33.3% -65%. We conducted a randomized, controlled trial to evaluate the efficacy and safety of three regimens of HBV vaccination at Chiang Mai University Hospital, Thailand.

Methods

From February 4, 2011 to May 4, 2012, 132 HIV-infected adults with CD4+ cell counts >200 cells/mm³, undetectable plasma HIV-1 RNA, and negative for all HBV markers were randomly assigned to receive one of three recombinant vaccine (Hepavax-Gene^® Berna, Korea) regimens: 20 μg IM at months 0, 1, and 6 (Standard doses group, n=44), 20 μg IM at months 0, 1, 2, 6 (four doses group, n=44), or 40 μg IM at months 0, 1, 2, and 6 (four double doses group, n=44). The primary outcomes were to compare the immunogenicity and safety between the four-doses groups with the Standard doses group.

Results

At months 7 and 12, the percentages of responders (anti-HBs ≥10 mIU/mL) were 88.6% and 70.4% in the Standard doses group, 93.2% and 86.4% in the four doses group, (P=0.713 and 0.119), and 95.4% and 88.6% in the four double doses group, (P=0.434 and 0.062), respectively. Factors associated with a high titer level (anti-HBs ≥100 mIU/mL) were vaccination schedule and younger age. The most common adverse event was pain at the injection site (42.4%); this was significantly more frequent in the four double doses group compared to the Standard doses group. No serious adverse events were observed.

Conclusions

In Northern Thailand, the standard three-doses HBV vaccination in HIV-infected adults with CD4+ cell counts >200 cells/mm³ and undetectable plasma HIV-1 RNA is highly effective. Although regimens of four injections of either standard or double doses could not significantly increase the response rate, these regimens may induce higher levels of antibody to the virus.Trial registration information: ClinicalTrials.gov; NCT1289106; http://clinicaltrials.gov/ct2/show/NCT01289106     

A Randomized,Single-Ascending-Dose,Ivermectin-Controlled,Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

Background

Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin''s safety and efficacy. Effects on the parasite were also assessed.

Methodology/Principal Findings

Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).

Conclusions/Significance

The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.

Trial Registration

ClinicalTrails.gov NCT00300768     

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     

Pharmacodynamic Consequences of Administration of VLA-4 Antagonist CDP323 to Multiple Sclerosis Subjects: A Randomized,Double-Blind Phase 1/2 Study

Background

Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).

Objective

Investigate the effect of CDP323, an oral α₄-integrin inhibitor, on lymphocyte biomarkers in RMS.

Methods

Seventy-one RMS subjects aged 18–65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.

Results

Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α₄-integrin on VCAM-1–binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.

Conclusions

CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.

Trial Registration

ClinicalTrials.gov NCT00726648.     

SLCO1B1 and SLC19A1 Gene Variants and Irinotecan-Induced Rapid Response and Survival: A Prospective Multicenter Pharmacogenetics Study of Metastatic Colorectal Cancer

Background

Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.

Materials and Methods

Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing

Results

Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher''s exact test p=0.002). Their significances were all maintained even after multiple testing (all p _c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.

Conclusions

Polymorphisms of solute carriers’ may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.

Trial Registry

ClinicalTrials.gov NCT01282658 http://www.clinicaltrials.gov/ct2/show/NCT01282658     

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     

Feasibility of Progressive Strength Training Implemented in the Acute Ward after Hip Fracture Surgery

Importance

Patients with a hip fracture lose more than 50% knee-extension strength in the fractured limb within one week of surgery. Hence, immediate progressive strength training following hip fracture surgery may be rational, but the feasibility unknown.

Objective

To examine the feasibility of in-hospital progressive strength training implemented in the acute ward following hip fracture surgery, based on pre-specified criteria for feasibility.

Design, Setting and Patients

A prospective cohort study conducted in an acute orthopedic hip fracture unit at a university hospital. A consecutive sample of 36 patients, 18 with a cervical and 18 with a trochanteric hip fracture (27 women and 9 men, mean (SD) age of 79.4 (8.3) years) were included between June and December 2012.

Intervention

A daily (on weekdays) program of progressive knee-extension strength training for the fractured limb, using ankle weight cuffs in 3 sets of 10 repetition maximum loadings.

Main outcomes and Measures

The primary outcome was the change in training load (kg) during the knee-extension strength training. The secondary outcomes were changes in hip fracture-related pain and maximal isometric knee-extension strength.

Results

The strength training was commenced at a mean of 2.4 (0.7) days after surgery. The training loads (kilograms lifted) increased from 1.6 (0.8) to 4.3 (1.7) kg over 4.3 (2.2) training sessions (P<.001). The maximal isometric knee-extension strength of the fractured limb increased from 0.37 (0.2) to 0.61 (0.3) Nm/kg (P<.001), while the average strength deficit in the fractured limb decreased from 50% to 32% (% non-fractured, P<.001). Only 3 of 212 sessions were not performed because of severe hip fracture-related pain.

Conclusion and Relevance

Progressive knee-extension strength training of the fractured limb commenced in the acute ward seems feasible, and may reduce strength asymmetry between limbs without hip pain interfering. The clinical efficacy needs confirmation in a randomized controlled design.

Trial Registration

ClinicalTrials.gov ID: NCT01616030     

A Randomized Cross-Over Trial of the Postprandial Effects of Three Different Diets in Patients with Type 2 Diabetes

Background

In the clinic setting both fasting levels of glucose and the area under the curve (AUC) of glucose, by determination of HbA1c levels, are used for risk assessments, in type 2 diabetes (NIDDM). However little is known about postprandial levels, and hence AUC, regarding other traditional risk factors such as insulin and blood-lipids and how this is affected by different diets.

Objective

To study postprandial effects of three diets, during a single day, in NIDDM.

Methods

A low-fat diet (45–56 energy-% from carbohydrates), and a low-carbohydrate diet (16–24 energy-% from carbohydrates) was compared with a Mediterranean-style diet (black coffee for breakfast and the same total-caloric intake as the other two diets for lunch with red wine, 32–35 energy−% from carbohydrates) in a randomized cross-over design. Total-caloric intake/test-day at the clinic from food was 1025–1080 kCal in men and 905–984 kCal in women. The test meals were consumed at a diabetes ward under supervision.

Results

Twenty-one participants were recruited and 19 completed the studies. The low-carbohydrate diet induced lower insulin and glucose excursions compared with the low-fat diet (p<0.0005 for both AUC). The insulin-response following the single Mediterranean-style lunch-meal was more pronounced than during the low-fat diet lunch (insulin increase-ratio of the low-fat diet: 4.35±2.2, of Mediterranean-style diet: 8.12±5.2, p = 0.001) while postprandial glucose levels were similar. The increase-ratio of insulin correlated with the elevation of the incretin glucose-dependent insulinotropic-polypeptide following the Mediterranean-style diet lunch (Spearman, r = 0.64, p = 0.003).

Conclusions

The large Mediterranean-style lunch-meal induced similar postprandial glucose-elevations as the low-fat meal despite almost double amount of calories due to a pronounced insulin-increase. This suggests that accumulation of caloric intake from breakfast and lunch to a single large Mediterranean style lunch-meal in NIDDM might be advantageous from a metabolic perspective.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01522157","term_id":"NCT01522157"}}NCT01522157 {"type":"clinical-trial","attrs":{"text":"NCT01522157","term_id":"NCT01522157"}}NCT01522157     

Restoration of CMV-Specific-CD4 T Cells with ART Occurs Early and Is Greater in Those with More Advanced Immunodeficiency

Objectives

Restoration of Cytomegalovirus-specific-CD4 T cell (CMV-Sp-CD4) responses partly accounts for the reduction of CMV-disease with antiretroviral-therapy (ART), but CMV-Sp-CD4 may also drive immune activation and immunosenescence. This study characterized the dynamics of CMV-Sp-CD4 after ART initiation and explored associations with CD4 T cell recovery as well as frequency of naïve CD4 T cells at week 96.

Methods

Fifty HIV-infected, ART-naïve Thai adults with CD4 T cell count ≤350cells/µL and starting ART were evaluated over 96 weeks (ClinicalTrials.gov identifier NCT01296373). CMV-Sp-CD4 was detected by co-expression of CD25/CD134 by flow cytometry after CMV-antigen stimulation.

Results

All subjects were CMV sero-positive, 4 had quantifiable CMV-DNA (range 2.3-3.9 log₁₀ copies/mL) at baseline but none had clinically apparent CMV-disease. Baseline CMV-Sp-CD4 response was positive in 40 subjects. Those with CD4 T cell count <100cells/µL were less likely to have positive baseline CMV-Sp-CD4 response (P=0.003). Positive baseline CMV-Sp-CD4 response was associated with reduced odds of quantifiable CMV-DNA (P=0.022). Mean CD4 T cell increase at week 96 was 213 cells/µL. This was associated positively with baseline HIV-VL (P=0.001) and negatively with age (P=0.003). The frequency of CMV-Sp-CD4 increased at week 4 (P=0.008), then declined. Those with lower baseline CMV-Sp-CD4 (P=0.009) or CDC category C (P<0.001) had greater increases in CMV-Sp-CD4 at week 4. At week 96, CD4 T cell count was positively (P<0.001) and the frequency of CMV-Sp-CD4 was negatively (P=0.001) associated with the percentage of naïve CD4 T cells.

Conclusions

Increases in CMV-Sp-CD4 with ART occurred early and were greater in those with more advanced immunodeficiency. The frequency of CMV-Sp-CD4 was associated with reduced naïve CD4 T cells, a marker associated with immunosenescence.     

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.     

No Evidence of Harms of Probiotic Lactobacillus rhamnosus GG ATCC 53103 in Healthy Elderly—A Phase I Open Label Study to Assess Safety,Tolerability and Cytokine Responses

Background

Although Lactobacillus rhamnosus GG ATCC 53103 (LGG) has been consumed by 2 to 5 million people daily since the mid 1990s, there are few clinical trials describing potential harms of LGG, particularly in the elderly.

Objectives

The primary objective of this open label clinical trial is to assess the safety and tolerability of 1×10¹⁰ colony forming units (CFU) of LGG administered orally twice daily to elderly volunteers for 28 days. The secondary objectives were to evaluate the effects of LGG on the gastrointestinal microbiome, host immune response and plasma cytokines.

Methods

Fifteen elderly volunteers, aged 66–80 years received LGG capsules containing 1×10¹⁰ CFU, twice daily for 28 days and were followed through day 56. Volunteers completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits in the Clinical Research Center at baseline, day 28 and day 56 to determine whether adverse events had occurred. Assessments included prompted and open-ended questions.

Results

There were no serious adverse events. The 15 volunteers had a total of 47 events (range 1–7 per volunteer), 39 (83%) of which were rated as mild and 40% of which were considered related to consuming LGG. Thirty-one (70%) of the events were expected, prompted symptoms while 16 were unexpected events. The most common adverse events were gastrointestinal (bloating, gas, and nausea), 27 rated as mild and 3 rated as moderate. In the exploratory analysis, the pro-inflammatory cytokine interleukin 8 decreased during LGG consumption, returning towards baseline one month after discontinuing LGG (p = 0.038) while there was no difference in other pro- or anti-inflammatory plasma cytokines.

Conclusions

Lactobacillus rhamnosus GG ATCC 53103 is safe and well tolerated in healthy adults aged 65 years and older.

Trial Registration

ClinicalTrials.gov NCT 01274598