Maxillary sinus grafting with Bio-Oss or Straumann Bone Ceramic: histomorphometric results from a randomized controlled multicenter clinical trial

INTRODUCTION: This investigation was designed to compare the histomorphometric results from sinus floor augmentation with anorganic bovine bone (ABB) and a new biphasic calcium phosphate, Straumann Bone Ceramic (BCP). MATERIALS AND METHODS: Forty-eight maxillary sinuses were treated in 37 patients. Residual bone width was > or =6 mm and height was > or =3 mm and <8 mm. Lateral sinus augmentation was used, with grafting using either ABB (control group; 23 sinuses) or BCP (test group; 25 sinuses); sites were randomly assigned to the control or test groups. After 180-240 days of healing, implant sites were created and biopsies taken for histological and histomorphometric analyses. The parameters assessed were (1) area fraction of new bone, soft tissue, and graft substitute material in the grafted region; (2) area fraction of bone and soft tissue components in the residual alveolar ridge compartment; and (3) the percentage of surface contact between the graft substitute material and new bone. RESULTS: Measurable biopsies were available from 56% of the test and 81.8% of the control sites. Histology showed close contact between new bone and graft particles for both groups, with no significant differences in the amount of mineralized bone (21.6+/-10.0% for BCP vs. 19.8+/-7.9% for ABB; P=0.53) in the biopsy treatment compartment of test and control site. The bone-to-graft contact was found to be significantly greater for ABB (48.2+/-12.9% vs. 34.0+/-14.0% for BCP). Significantly less remaining percentage of graft substitute material was found in the BCP group (26.6+/-5.2% vs. 37.7+/-8.5% for ABB; P=0.001), with more soft tissue components (46.4+/-7.7% vs. 40.4+/-7.3% for ABB; P=0.07). However, the amount of soft tissue components for both groups was found not to be greater than in the residual alveolar ridge. DISCUSSION: Both ABB and BCP produced similar amounts of newly formed bone, with similar histologic appearance, indicating that both materials are suitable for sinus augmentation for the placement of dental implants. The potential clinical relevance of more soft tissue components and different resorption characteristics of BCP requires further investigation.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER http://www.clinicaltrials.gov; Identifier: NCT02165774.

Organizational perspectives on the management and evaluation of large -scale multicenter controlled clinical trials: An exploratory study of participation in the beta -blocker heart attack trial

A review of literature related to appointment-keeping served as the basis for the development of an organizational paradigm for the study of appointment-keeping in the Beta-blocker Heart Attack Trial (BHAT). Features of the organizational environment, demographic characteristics of BHAT enrollees, organizational structure and processes and previous organizational performance variables were measured so as to provide exploratory information relating to the appointment-keeping behavior of 3,837 participants enrolled at thirty-two Clinical Centers. Results suggest that the social context of individual behavior is an important consideration for the understanding of patient compliance. In particular, the degree to which previous organizational performance--as measured by obtaining recruitment goals--and the ability to utilize resources had particularly strong bivariate associations with appointment-keeping. Implications for future theory development, research and practical implications were provided as was a suggestion for the development of multidisciplinary research efforts conducted within the context of Centers for the study and application of adherence behaviors. ^

Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

BACKGROUND The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. METHODS The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. DISCUSSION This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients. TRIAL REGISTRATION NCT01689077.

St. John’s wort and Kava in treating major depressive disorder with comorbid anxiety : a randomised double-blind placebo-controlled pilot trial

Objective - We report the first randomised controlled trial (RCT) using a combination of St. John’s wort (SJW) and Kava for the treatment of major depressive disorder (MDD) with comorbid anxiety. Methods - Twenty-eight adults with MDD and co-occurring anxiety were recruited for a double-blind RCT. After a placebo run-in of 2 weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of 4 weeks. The primary analyses used intention-to-treat and completer analyses. Results - On both intention-to-treat ( p¼0.047) and completer analyses ( p¼0.003), SJW and Kava gave a significantly greater reduction in self-reported depression on the Beck Depression Inventory (BDI-II) over placebo in the first controlled phase. However, in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life. Conclusion - There was some evidence of antidepressant effects using SJW and Kava in a small sample with comorbid anxiety. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava.

Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis

Background Chaperonin 10 (Cpn10) is a mitochondrial molecule involved in protein folding. The aim of this study was to determine the safety profile of Cpn10 in patients with multiple sclerosis (MS). Methods A total of 50 patients with relapse-remitting or secondary progressive MS were intravenously administered 5 mg or 10 mg of Cpn10 weekly for 12 weeks in a double-blind, randomized, placebo controlled, phase II trial. Clinical reviews, including Expanded Disability Status Scale and magnetic resonance imaging (MRI) with Gadolinium, were undertaken every 4 weeks. Stimulation of patient peripheral blood mononuclear cells with lipopolysaccharide ex vivo was used to measure the in vivo activity of Cpn10. Results No significant differences in the frequency of adverse events were seen between treatment and placebo arms. Leukocytes from both groups of Cpn10-treated patients produced significantly lower levels of critical proinflammatory cytokines. A trend toward improvement in new Gadolinium enhancing lesions on MRI was observed, but this difference was not statistically significant. No differences in clinical outcome measures were seen. Conclusions Cpn10 is safe and well tolerated when administered to patients with MS for 3 months, however, a further extended phase II study primarily focused on efficacy is warranted.

Breathe easier online : evaluation of a randomized controlled pilot trial of an internet-based intervention to improve well-being in children and adolescents with a chronic respiratory condition

Background Chronic respiratory illnesses are the most common group of childhood chronic health conditions and are overrepresented in socially isolated groups. Objective To conduct a randomized controlled pilot trial to evaluate the efficacy of Breathe Easier Online (BEO), an Internet-based problem-solving program with minimal facilitator involvement to improve psychosocial well-being in children and adolescents with a chronic respiratory condition. Methods We randomly assigned 42 socially isolated children and adolescents (18 males), aged between 10 and 17 years to either a BEO (final n = 19) or a wait-list control (final n = 20) condition. In total, 3 participants (2 from BEO and 1 from control) did not complete the intervention. Psychosocial well-being was operationalized through self-reported scores on depression symptoms and social problem solving. Secondary outcome measures included self-reported attitudes toward their illness and spirometry results. Paper-and-pencil questionnaires were completed at the hospital when participants attended a briefing session at baseline (time 1) and in their homes after the intervention for the BEO group or a matched 9-week time period for the wait-list group (time 2). Results The two groups were comparable at baseline across all demographic measures (all F < 1). For the primary outcome measures, there were no significant group differences on depression (P = .17) or social problem solving (P = .61). However, following the online intervention, those in the BEO group reported significantly lower depression (P = .04), less impulsive/careless problem solving (P = .01), and an improvement in positive attitude toward their illness (P = .04) compared with baseline. The wait-list group did not show these differences. Children in the BEO group and their parents rated the online modules very favorably. Conclusions Although there were no significant group differences on primary outcome measures, our pilot data provide tentative support for the feasibility (acceptability and user satisfaction) and initial efficacy of an Internet-based intervention for improving well-being in children and adolescents with a chronic respiratory condition. Trial registration Australian New Zealand Clinical Trials Registry number: ACTRN12610000214033;

Facilitating lifestyle changes to manage menopausal symptoms in women with breast cancer: A randomized controlled pilot trial of The Pink Women’s Wellness Program

OBJECTIVE Women diagnosed as having breast cancer may experience difficulties with posttreatment effects such as menopausal symptoms. The aims of this pilot study were to (1) evaluate the impact of a multimodal lifestyle program on reducing menopausal symptoms in women with breast cancer and (2) examine the impact of the program on health-related quality of life (HRQoL) and adherence to lifestyle recommendations. METHODS Overall, 55 women aged 45 to 60 years with one moderate to severe menopausal symptom and a history of breast cancer were randomized into an intervention group (n = 26) or a control group (n = 29). Women in the intervention group received a lifestyle intervention (The Pink Women’s Wellness Program) that included clinical consultations and a tailored health education program. Measurements of menopausal symptoms (Greene Climacteric Scale), HRQoL (SF-12 and Functional Assessment of Cancer Therapy—Breast), and modifiable lifestyle factors (food intake, physical activity, smoking and alcohol use, and sleep disturbance) were taken at baseline and 12 weeks. RESULTS Women in the intervention group reported clinically significant reductions in many menopausal symptoms, specifically somatic symptoms (d = 0.52), vasomotor symptoms (d = 0.55), sexual dysfunction (d = .65), and overall menopausal symptoms (d = 0.54), at 12 weeks compared with the control group (d = 0.03, d = 0.24, d = 0.18, and d = 0.05, respectively). Women in the intervention group reported improvements in Functional Assessment of Cancer Therapy—Breast subscale scores, physical well-being and functional well-being, and Functional Assessment of Cancer Therapy—General total scores (intervention group: d = 0.54, d = 0.50, and d = 0.48, respectively; control group: d = 0.22, d = 0.11, and d = 0.05, respectively). CONCLUSIONS The Pink Women’s Wellness Program is effective in decreasing menopausal symptoms, thus improving HRQoL. This being a pilot study, further research is recommended to investigate the benefits of combining nonpharmacological interventions for women with breast cancer to reduce their treatment-related menopausal symptoms.

Randomized clinical trial of the timing it right stroke family support program: Research protocol

Background Family caregivers provide invaluable support to stroke survivors during their recovery, rehabilitation, and community re-integration. Unfortunately, it is not standard clinical practice to prepare and support caregivers in this role and, as a result, many experience stress and poor health that can compromise stroke survivor recovery and threaten the sustainability of keeping the stroke survivor at home. We developed the Timing it Right Stroke Family Support Program (TIRSFSP) to guide the timing of delivering specific types of education and support to meet caregivers' evolving needs. The objective of this multi-site randomized controlled trial is to determine if delivering the TIRSFSP across the stroke care continuum improves caregivers' sense of being supported and emotional well-being. Methods/design Our multi-site single-blinded randomized controlled trial will recruit 300 family caregivers of stroke survivors from urban and rural acute care hospitals. After completing a baseline assessment, participants will be randomly allocated to one of three groups: 1) TIRSFSP guided by a stroke support person (health care professional with stroke care experience), delivered in-person during acute care and by telephone for approximately the first six to 12 months post-stroke; 2) caregiver self-directed TIRSFSP with an initial introduction to the program by a stroke support person, or; 3) standard care receiving the educational resource "Let's Talk about Stroke" prepared by the Heart and Stroke Foundation. Participants will complete three follow-up quantitative assessments 3, 6, and 12-months post-stroke. These include assessments of depression, social support, psychological well-being, stroke knowledge, mastery (sense of control over life), caregiving assistance provided, caregiving impact on everyday life, and indicators of stroke severity and disability. Qualitative methods will also be used to obtain information about caregivers' experiences with the education and support received and the impact on caregivers' perception of being supported and emotional well-being. Discussion This research will determine if the TIRSFSP benefits family caregivers by improving their perception of being supported and emotional well-being. If proven effective, it could be recommended as a model of stroke family education and support that meets the Canadian Stroke Best Practice Guideline recommendation for providing timely education and support to families through transitions.

Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations

Background: Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods: Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 mu g budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64 (R), Aldo-Union, Spain and Rhinocort 64 (R), AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90% CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results: All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUC(t) (2.6 +/- 1.5 vs 2.2 +/- 0.7), AUCi (2.9 +/- 1.5 vs 2.4 +/- 0.7), t(max) (0.4 +/- 0.1 vs 0.4 +/- 0.2), C(max)/AUC(i) (0.3 +/- 0.1 vs 0.3 +/- 0.0), and MRT (5.0 +/- 1.4 vs 4.5 +/- 0.6), but not in the case of C(max) (0.9 +/- 0.3 vs 0.7 +/- 0.2) and t(1/2) (3.7 +/- 1.8 vs 2.9 +/- 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion: The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market.

A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir.

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.

A randomized controlled trial of tea tree oil (5%) body wash versus standard body wash to prevent colonization with methicillin-resistant Staphylococcus aureus (MRSA) in critically ill adults: research protocol

Background
Over the past ten years MRSA has become endemic in hospitals and is associated with increased healthcare costs. Critically ill patients are most at risk, in part because of the number of invasive therapies that they require in the intensive care unit (ICU). Washing with 5% tea tree oil (TTO) has been shown to be effective in removing MRSA on the skin. However, to date, no trials have evaluated the potential of TTO body wash to prevent MRSA colonization or infection. In addition, detecting MRSA by usual culture methods is slow. A faster method using a PCR assay has been developed in the laboratory, but requires evaluation in a large number of patients.

Methods/Design
This study protocol describes the design of a multicentre, phase II/III prospective open-label randomized controlled clinical trial to evaluate whether a concentration of 5% TTO is effective in preventing MRSA colonization in comparison with a standard body wash (Johnsons Baby Softwash) in the ICU. In addition we will evaluate the cost-effectiveness of TTO body wash and assess the effectiveness of the PCR assay in detecting MRSA in critically ill patients. On admission to intensive care, swabs from the nose and groin will be taken to screen for MRSA as per current practice. Patients will be randomly assigned to be washed with the standard body wash or TTO body wash. On discharge from the unit, swabs will be taken again to identify whether there is a difference in MRSA colonization between the two groups.

Discussion
If TTO body wash is found to be effective, widespread implementation of such a simple colonization prevention tool has the potential to impact on patient outcomes, healthcare resource use and patient confidence both nationally and internationally.

Trial Registration
[ISRCTN65190967]

A randomized clinical trial of hydroxymethylglutaryl-Coenzyme A reductase inhibition for Acute Lung Injury (The HARP study)

Rationale: There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI.

Objectives: To test whether simvastatin improves physiological and biological outcomes in ALI.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein.

Measurements and Main Results: Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group.

Conclusions: Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation.