Two-Arm Randomized Pilot Intervention Trial to Decrease Sitting Time and Increase Sit-To-Stand Transitions in Working and Non-Working Older Adults

Background

Excessive sitting has been linked to poor health. It is unknown whether reducing total sitting time or increasing brief sit-to-stand transitions is more beneficial. We conducted a randomized pilot study to assess whether it is feasible for working and non-working older adults to reduce these two different behavioral targets.

Methods

Thirty adults (15 workers and 15 non-workers) age 50–70 years were randomized to one of two conditions (a 2-hour reduction in daily sitting or accumulating 30 additional brief sit-to-stand transitions per day). Sitting time, standing time, sit-to-stand transitions and stepping were assessed by a thigh worn inclinometer (activPAL). Participants were assessed for 7 days at baseline and followed while the intervention was delivered (2 weeks). Mixed effects regression analyses adjusted for days within participants, device wear time, and employment status. Time by condition interactions were investigated.

Results

Recruitment, assessments, and intervention delivery were feasible. The ‘reduce sitting’ group reduced their sitting by two hours, the ‘increase sit-to-stand’ group had no change in sitting time (p < .001). The sit-to-stand transition group increased their sit-to-stand transitions, the sitting group did not (p < .001).

Conclusions

This study was the first to demonstrate the feasibility and preliminary efficacy of specific sedentary behavioral goals.

Trial Registration

clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02544867","term_id":"NCT02544867"}}NCT02544867     

Transfemoral Aortic Valve Implantation with the New Edwards Sapien 3 Valve for Treatment of Severe Aortic Stenosis—Impact of Valve Size in a Single Center Experience

Aims

The third generation Edwards Sapien 3 (Edwards Lifesciences Inc., Irvine, California) system was optimized to reduce residual aortic regurgitation and vascular complications.

Methods and Results

235 patients with severe symptomatic aortic stenosis were prospectively enrolled. Transcatheter aortic valve implantations (TAVI) were performed without general anesthesia by transfemoral approach. Patients were followed for 30 days. Patients received 23mm (N = 77), 26mm (N = 91) or 29mm (N = 67) valve based on pre-procedural 256 multislice computer tomography. Mean oversizing did not differ between the 3 valves. There was no residual moderate or severe aortic regurgitation. Rate of mild aortic regurgitation and regurgitation index did not differ between groups. There was no switch to general anesthesia or conversion to surgery. Rate of major vascular complication was 3.0% with no difference between valve and delivery sheath sizes. Within 30 days rates of all cause mortality (2.6%) and stroke (2.1%) were low.

Conclusions

In patients with severe aortic stenosis transfemoral TAVI with the Edwards Sapien 3 valve without general anesthesia was associated with a high rate of device success, no moderate or severe residual aortic regurgitation, low rates of major vascular complication, mortality and stroke within 30 days with no difference between the 3 valve sizes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02162069","term_id":"NCT02162069"}}NCT02162069     

Women's Acceptability of Misoprostol Treatment for Incomplete Abortion by Midwives and Physicians - Secondary Outcome Analysis from a Randomized Controlled Equivalence Trial at District Level in Uganda

Objective

This study aimed to assess women´s acceptability of diagnosis and treatment of incomplete abortion with misoprostol by midwives, compared with physicians.

Methods

This was an analysis of secondary outcomes from a multi-centre randomized controlled equivalence trial at district level in Uganda. Women with first trimester incomplete abortion were randomly allocated to clinical assessment and treatment with misoprostol by a physician or a midwife. The randomisation (1:1) was done in blocks of 12 and stratified for health care facility. Acceptability was measured in expectations and satisfaction at a follow up visit 14–28 days following treatment. Analysis of women’s overall acceptability was done using a generalized linear mixed-effects model with an equivalence range of -4% to 4%. The study was not masked. The trial is registered at ClinicalTrials.org, {"type":"clinical-trial","attrs":{"text":"NCT 01844024","term_id":"NCT01844024"}}NCT 01844024.

Results

From April 2013 to June 2014, 1108 women were assessed for eligibility of which 1010 were randomized (506 to midwife and 504 to physician). 953 women were successfully followed up and included in the acceptability analysis. 95% (904) of the participants found the treatment satisfactory and overall acceptability was found to be equivalent between the two study groups. Treatment failure, not feeling calm and safe following treatment, experiencing severe abdominal pain or heavy bleeding following treatment, were significantly associated with non-satisfaction. No serious adverse events were recorded.

Conclusions

Treatment of incomplete abortion with misoprostol by midwives and physician was highly, and equally, acceptable to women.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01844024","term_id":"NCT01844024"}}NCT01844024     

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol

Study Question

What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E₂) levels?

Summary Answer

The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E₂) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm.

What Is Known Already

In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1–2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol.

Study Design, Size, Duration

From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E₂ on the day of hCG administration were known were included in the analyses.

Participants/Materials, Setting, Methods

The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E₂ levels on the day of (hCG), and a combination of both, were determined.

Main Results and the Role of Chance

The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS.

Limitations, Reasons for Caution

This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins.

Wider Implications of the Findings

For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00702845","term_id":"NCT00702845"}}NCT00702845{"type":"clinical-trial","attrs":{"text":"NCT00696800","term_id":"NCT00696800"}}NCT00696800{"type":"clinical-trial","attrs":{"text":"NCT00696878","term_id":"NCT00696878"}}NCT00696878     

Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection

Background

Nitazoxanide (NTZ) plus pegylated interferon and ribavirin (Peg-IFN/RBV) improved the sustained virological response (SVR) achieved with Peg-IFN/RBV in hepatitis C virus genotype 4 (HCV-4)-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV)/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg-IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients.

Patients and Methods

This was an open-label, single arm, multicenter phase II pilot clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01529073","term_id":"NCT01529073"}}NCT01529073) enrolling HIV-infected individuals with HCV-4 chronic infection, naïve to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 μg/kg/week plus weight-adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure). A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control.

Results

Two (9.5%) of 21 patients included in the trial compared with 5 (21.7%) of 23 patients included in the historical cohort achieved SVR (SVR risk difference, -12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416). Virological failure was due to lack of response in 13 (62%) individuals recruited in the trial. Two (9.5%) patients included in the trial and two (9.5%) individuals from the historical cohort discontinued permanently due to adverse events.

Conclusions

No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg-IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01529073","term_id":"NCT01529073"}}NCT01529073     

Assessment of a Standardized Pre-Operative Telephone Checklist Designed to Avoid Late Cancellation of Ambulatory Surgery: The AMBUPROG Multicenter Randomized Controlled Trial

Objectives

To assess the impact of a standardized pre-operative telephone checklist on the rate of late cancellations of ambulatory surgery (AMBUPROG trial).

Design

Multicenter, two-arm, parallel-group, open-label randomized controlled trial.

Setting

11 university hospital ambulatory surgery units in Paris, France.

Participants

Patients scheduled for ambulatory surgery and able to be reached by telephone.

Intervention

A 7-item checklist designed to prevent late cancellation, available in five languages and two versions (for children and adults), was administered between 7 and 3 days before the planned date of surgery, by an automated phone system or a research assistant. The control group received standard management alone.

Main Outcome Measures

Rate of cancellation on the day of surgery or the day before.

Results

The study population comprised 3900 patients enrolled between November 2012 and September 2013: 1950 patients were randomized to the checklist arm and 1950 patients to the control arm. The checklist was administered to 68.8% of patients in the intervention arm, 1002 by the automated phone system and 340 by a research assistant. The rate of late cancellation did not differ significantly between the checklist and control arms (109 (5.6%) vs. 113 (5.8%), adjusted odds ratio [95% confidence interval] = 0.91 [0.65–1.29], (p = 0.57)). Checklist administration revealed that 355 patients (28.0%) had not undergone tests ordered by the surgeon or anesthetist, and that 254 patients (20.0%) still had questions concerning the fasting state.

Conclusions

A standardized pre-operative telephone checklist did not avoid late cancellations of ambulatory surgery but enabled us to identify several frequent causes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01732159","term_id":"NCT01732159"}}NCT01732159     

Chitosan Coated Textiles May Improve Atopic Dermatitis Severity by Modulating Skin Staphylococcal Profile: A Randomized Controlled Trial

Background

Atopic dermatitis (AD) patients may benefit from using textiles coated with skin microbiome–modulating compounds. Chitosan, a natural biopolymer with immunomodulatory and antimicrobial properties, has been considered potentially useful.

Objective

This randomized controlled trial assessed the clinical utility of chitosan-coated garment use in AD.

Methods

Of the 102 patients screened, 78 adult and adolescents were randomly allocated to overnight use of chitosan-coated or uncoated cotton long-sleeved pyjama tops and pants for 8 weeks. The primary outcome was change in disease severity assessed by Scoring Atopic dermatitis index (SCORAD). Other outcomes were changes in quality of life, pruritus and sleep loss, days with need for rescue medication, number of flares and controlled weeks, and adverse events. Changes in total staphylococci and Staphylococcus aureus skin counts were also assessed. Comparisons were made using analysis of variance supplemented by repeated measures analysis for the primary outcome. Interaction term between time and intervention was used to compare time trends between groups.

Results

Chitosan group improved SCORAD from baseline in 43.8%, (95%CI: 30.9 to 55.9), P = 0.01, placebo group in 16.5% (-21.6 to 54.6); P = 0.02 with no significant differences between groups; Dermatology Quality of life Index Score significantly improved in chitosan group (P = 0.02) and a significant increase of skin Coagulase negative Staphylococci (P = 0.02) was seen.

Conclusions

Chitosan coated textiles may impact on disease severity by modulating skin staphylococcal profile. Moreover, a potential effect in quality of life may be considered.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01597817","term_id":"NCT01597817"}}NCT01597817     

A Multi-Center,Randomized, Controlled,Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury

Objective

Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU).

Design, Setting, Patients

A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy.

Results

No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol’s recommended range (≤ 0.4mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol’s recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86).

Conclusion

SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01400893","term_id":"NCT01400893"}}NCT01400893 http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01400893","term_id":"NCT01400893"}}NCT01400893     

IV t-PA Influences Infarct Volume in Minor Stroke: A Pilot Study

Background

There is an ongoing debate whether stroke patients presenting with minor or moderate symptoms benefit from thrombolysis. Up until now, stroke severity on admission is typically measured with the NIHSS, and subsequently used for treatment decision.

Hypothesis

Acute MRI lesion volume assessment can aid in therapy decision for iv-tPA in minor stroke.

Methods

We analysed 164 patients with NIHSS 0–7 from a prospective stroke MRI registry, the 1000+ study (clinicaltrials.org {"type":"clinical-trial","attrs":{"text":"NCT00715533","term_id":"NCT00715533"}}NCT00715533). Patients were examined in a 3 T MRI scanner and either received (n = 62) or did not receive thrombolysis (n = 102). DWI (diffusion weighted imaging) and PI (perfusion imaging) at admission were evaluated for diffusion - perfusion mismatch. Our primary outcome parameter was final lesion volume, defined by lesion volume on day 6 FLAIR images.

Results

The association between t-PA and FLAIR lesion volume on day 6 was significantly different for patients with smaller DWI volume compared to patients with larger DWI volume (interaction between DWI and t-PA: p = 0.021). Baseline DWI lesion volume was dichotomized at the median (0.7 ml): final lesion volume at day 6 was larger in patients with large baseline DWI volumes without t-PA treatment (median difference 3, IQR −0.4–9.3 ml). Conversely, in patients with larger baseline DWI volumes final lesion volumes were smaller after t-PA treatment (median difference 0, IQR −4.1–5 ml). However, this did not translate into a significant difference in the mRS at day 90 (p = 0.577).

Conclusion

Though this study is only hypothesis generating considering the number of cases, we believe that the size of DWI lesion volume may support therapy decision in patients with minor stroke.

Trial Registration

Clinicaltrials.org {"type":"clinical-trial","attrs":{"text":"NCT00715533","term_id":"NCT00715533"}}NCT00715533     

Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects

Background

There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.

Methodology

A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; {"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306; http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306.

Principal Findings

Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed.

Conclusions and Significance

Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306 http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306.     

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized,Double-Blind Placebo-Controlled Clinical Trial

Background

HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.

Methods

Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.

Results

No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.

Conclusions

This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948     

Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines,ChAd63 ME-TRAP and MVA ME-TRAP,in Healthy Gambian and Kenyan Adults

Background

Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI).

Methodology

We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.

Results

ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC).

Conclusions

ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.

Trial Registration

Pactr.org PACTR2010020001771828 http://www.pactr.org/ Pactr.org PACTR201008000221638 http://www.pactr.org/ ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01373879","term_id":"NCT01373879"}}NCT01373879 {"type":"clinical-trial","attrs":{"text":"NCT01373879","term_id":"NCT01373879"}}NCT01373879 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01379430","term_id":"NCT01379430"}}NCT01379430 {"type":"clinical-trial","attrs":{"text":"NCT01379430","term_id":"NCT01379430"}}NCT01379430     

Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI

Background

Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.

Methods

Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5.

Results

SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype.

Conclusion

Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00808184","term_id":"NCT00808184"}}NCT00808184     

Noninvasive Mechanical Ventilation Improves Breathing-Swallowing Interaction of Ventilator Dependent Neuromuscular Patients: A Prospective Crossover Study

Background

Respiratory involvement in neuromuscular disorders may contribute to impaired breathing-swallowing interactions, swallowing disorders and malnutrition. We investigated whether the use of non-invasive ventilation (NIV) controlled by the patient could improve swallowing performances in a population of neuromuscular patients requiring daytime NIV.

Methods

Ten neuromuscular patients with severe respiratory failure requiring extensive NIV use were studied while swallowing without and with NIV (while ventilated with a modified ventilator allowing the patient to withhold ventilation as desired). Breathing-swallowing interactions were investigated by chin electromyography, cervical piezoelectric sensor, nasal flow recording and inductive plethysmography. Two water-bolus sizes (5 and 10ml) and a textured yogurt bolus were tested in a random order.

Results

NIV use significantly improved swallowing fragmentation (defined as the number of respiratory interruption of the swallowing of a single bolus) (p = 0.003) and breathing-swallowing synchronization (with a significant increase of swallows followed by an expiration) (p <0.0001). Patient exhibited piecemeal swallowing which was not influenced by NIV use (p = 0.07). NIV use also significantly reduced dyspnea during swallowing (p = 0.04) while preserving swallowing comfort, regardless of bolus type.

Conclusion

The use of patient controlled NIV improves swallowing parameters in patients with severe neuromuscular respiratory failure requiring daytime NIV, without impairing swallowing comfort.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01519388","term_id":"NCT01519388"}}NCT01519388     

The Effectiveness of Individualized Acupuncture Protocols in the Treatment of Gulf War Illness: A Pragmatic Randomized Clinical Trial

Background

Gulf War Illness is a Complex Medical Illness characterized by multiple symptoms, including fatigue, sleep and mood disturbances, cognitive dysfunction, and musculoskeletal pain affecting veterans of the first Gulf War. No standard of care treatment exists.

Methods

This pragmatic Randomized Clinical Trial tested the effects of individualized acupuncture treatments offered in extant acupuncture practices in the community; practitioners had at least 5 years of experience plus additional training provided by the study. Veterans with diagnosed symptoms of Gulf War Illness were randomized to either six months of biweekly acupuncture treatments (group 1, n = 52) or 2 months of waitlist followed by weekly acupuncture treatments (group 2, n = 52). Measurements were taken at baseline, 2, 4 and 6 months. The primary outcome is the SF-36 physical component scale score (SF-36P) and the secondary outcome is the McGill Pain scale.

Results

Of the 104 subjects who underwent randomization, 85 completed the protocol (82%). A clinically and statistically significant average improvement of 9.4 points (p = 0.03) in the SF-36P was observed for group 1 at month 6 compared to group 2, adjusting for baseline pain. The secondary outcome of McGill pain index produced similar results; at 6 months, group 1 was estimated to experience a reduction of approximately 3.6 points (p = 0.04) compared to group 2.

Conclusions

Individualized acupuncture treatment of sufficient dose appears to offer significant relief of physical disability and pain for veterans with Gulf War Illness. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program under Award No. W81XWH-09-2-0064. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01305811","term_id":"NCT01305811"}}NCT01305811     

Thymidylate Synthase Genotype-Directed Chemotherapy for Patients with Gastric and Gastroesophageal Junction Cancers

Background

Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.

Methods

In this phase II study ({"type":"clinical-trial","attrs":{"text":"NCT00515216","term_id":"NCT00515216"}}NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00515216","term_id":"NCT00515216"}}NCT00515216), patients with “good risk” TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%).

Results

The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response.

Conclusions

In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515216","term_id":"NCT00515216"}}NCT00515216     

Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

Background

Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.

Objective

To evaluate the efficacy and safety of intranasal AZD8848.

Methods

In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis ({"type":"clinical-trial","attrs":{"text":"NCT00688779","term_id":"NCT00688779"}}NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days ({"type":"clinical-trial","attrs":{"text":"NCT00770003","term_id":"NCT00770003"}}NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α₂-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.

Results

AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α₂-macroglobulin were also reduced by AZD8848.

Conclusions

Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00688779","term_id":"NCT00688779"}}NCT00688779 and {"type":"clinical-trial","attrs":{"text":"NCT00770003","term_id":"NCT00770003"}}NCT00770003 as indicated above.     

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

Aim

This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients.

Patients & Methods

A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals.

Results

The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R² = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R² = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias).

Conclusions

Results supported our rationale to incorporate individual’s genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01318057","term_id":"NCT01318057"}}NCT01318057     

High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study

Background

Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery.

Methods

This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers.

Results

The kinetics of pro- and anti-inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005).

Conclusions

This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00348920","term_id":"NCT00348920"}}NCT00348920