Cluster randomized clinical trials in orthodontics: design, analysis and reporting issues

Cluster randomized trials (CRTs) use as the unit of randomization clusters, which are usually defined as a collection of individuals sharing some common characteristics. Common examples of clusters include entire dental practices, hospitals, schools, school classes, villages, and towns. Additionally, several measurements (repeated measurements) taken on the same individual at different time points are also considered to be clusters. In dentistry, CRTs are applicable as patients may be treated as clusters containing several individual teeth. CRTs require certain methodological procedures during sample calculation, randomization, data analysis, and reporting, which are often ignored in dental research publications. In general, due to similarity of the observations within clusters, each individual within a cluster provides less information compared with an individual in a non-clustered trial. Therefore, clustered designs require larger sample sizes compared with non-clustered randomized designs, and special statistical analyses that account for the fact that observations within clusters are correlated. It is the purpose of this article to highlight with relevant examples the important methodological characteristics of cluster randomized designs as they may be applied in orthodontics and to explain the problems that may arise if clustered observations are erroneously treated and analysed as independent (non-clustered).

Long-term clinical, microbiological, and radiographic outcomes of Brånemark™ implants installed in augmented maxillary bone for fixed full-arch rehabilitation

PURPOSE The purpose of this study was to document the long-term outcome of Brånemark implants installed in augmented maxillary bone and to identify parameters that are associated with peri-implant bone level. MATERIAL AND METHODS Patients of a periodontal practice who had been referred to a maxillofacial surgeon for iliac crest bone grafting in the atrophic maxilla were retrospectively recruited. Five months following grafting, they received 7-8 turned Brånemark implants. Following submerged healing of another 5 months, implants were uncovered and restorative procedures for fixed rehabilitation were initiated 2-3 months thereafter. The primary outcome variable was bone level defined as the distance from the implant-abutment interface to the first visible bone-to-implant contact. Secondary outcome variables included plaque index, bleeding index, probing depth, and levels of 40 species in subgingival plaque samples as identified by means of checkerboard DNA-DNA hybridization. RESULTS Nine out of 16 patients (eight females, one male; mean age 59) with 71 implants agreed to come in for evaluation after on average 9 years (SD 4; range 3-13) of function. One implant was deemed mobile at the time of inspection. Clinical conditions were acceptable with 11% of the implants showing pockets ≥ 5 mm. Periodontopathogens were encountered frequently and in high numbers. Clinical parameters and bacterial levels were highly patient dependent. The mean bone level was 2.30 mm (SD 1.53; range 0.00-6.95), with 23% of the implants demonstrating advanced resorption (bone level > 3 mm). Regression analysis showed a significant association of the patient (p < .001) and plaque index (p = .007) with bone level. CONCLUSIONS The long-term outcome of Brånemark implants installed in iliac crest-augmented maxillary bone is acceptable; however, advanced peri-implant bone loss is rather common and indicative of graft resorption. This phenomenon is patient dependent and seems also associated with oral hygiene.

Influence of rubber dam on objective and subjective parameters of stress during dental treatment of children and adolescents - a randomized controlled clinical pilot study

BACKGROUND Rubber dam is recommended for isolating the working field during adhesive dentistry procedures; however, dentists often omit rubber dam, particularly in paediatric dentistry, supposing that it would stress the patient. AIM The aim of this study was to evaluate stress parameters during a standardized dental treatment procedure performed with or without rubber dam. The treatment time was measured as a secondary outcome variable. DESIGN This study was designed as a randomized, controlled, clinical study with 72 patients (6-16 years; mean age, 11.1). During standardized fissure sealing procedures, objective parameters of stress (e.g., skin resistance, breath rate) were recorded. The operator's stress level was measured by pulse rate. Subjective pain (patients) and stress perception (operator) were evaluated by an interview. RESULTS The breath rate was significantly (P<0.05) lower and the skin resistance level was significantly higher during treatment with rubber dam compared to the control group. Subjective pain perception was significantly lower for the test group. The treatment time needed for the fissure sealing procedure was 12.4% less in the test group. CONCLUSION Isolation with rubber dam caused less stress in children and adolescents compared to relative isolation with cotton rolls if applied by an experienced dentist.

Patient-specific finite-element simulation of the human cornea: A clinical validation study on cataract surgery

The planning of refractive surgical interventions is a challenging task. Numerical modeling has been proposed as a solution to support surgical intervention and predict the visual acuity, but validation on patient specific intervention is missing. The purpose of this study was to validate the numerical predictions of the post-operative corneal topography induced by the incisions required for cataract surgery. The corneal topography of 13 patients was assessed preoperatively and postoperatively (1-day and 30-day follow-up) with a Pentacam tomography device. The preoperatively acquired geometric corneal topography – anterior, posterior and pachymetry data – was used to build patient-specific finite element models. For each patient, the effects of the cataract incisions were simulated numerically and the resulting corneal surfaces were compared to the clinical postoperative measurements at one day and at 30-days follow up. Results showed that the model was able to reproduce experimental measurements with an error on the surgically induced sphere of 0.38D one day postoperatively and 0.19D 30 days postoperatively. The standard deviation of the surgically induced cylinder was 0.54D at the first postoperative day and 0.38D 30 days postoperatively. The prediction errors in surface elevation and curvature were below the topography measurement device accuracy of ±5μm and ±0.25D after the 30-day follow-up. The results showed that finite element simulations of corneal biomechanics are able to predict post cataract surgery within topography measurement device accuracy. We can conclude that the numerical simulation can become a valuable tool to plan corneal incisions in cataract surgery and other ophthalmosurgical procedures in order to optimize patients' refractive outcome and visual function.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

3D Face Reconstruction from 2D Pictures: First Results of a Web-Based Computer Aided System for Aesthetic Procedures

The human face is a vital component of our identity and many people undergo medical aesthetics procedures in order to achieve an ideal or desired look. However, communication between physician and patient is fundamental to understand the patient’s wishes and to achieve the desired results. To date, most plastic surgeons rely on either “free hand” 2D drawings on picture printouts or computerized picture morphing. Alternatively, hardware dependent solutions allow facial shapes to be created and planned in 3D, but they are usually expensive or complex to handle. To offer a simple and hardware independent solution, we propose a web-based application that uses 3 standard 2D pictures to create a 3D representation of the patient’s face on which facial aesthetic procedures such as filling, skin clearing or rejuvenation, and rhinoplasty are planned in 3D. The proposed application couples a set of well-established methods together in a novel manner to optimize 3D reconstructions for clinical use. Face reconstructions performed with the application were evaluated by two plastic surgeons and also compared to ground truth data. Results showed the application can provide accurate 3D face representations to be used in clinics (within an average of 2 mm error) in less than 5 min.

First Clinical Experience With Celt ACD(®) : A Femoral Arterial Puncture Closure Device

Introduction This prospective nonrandomized study compared the safety and efficacy of a novel arterial closure device (ACD) in common femoral artery procedures to that of the FDA submitted historical manual pressure control group, who underwent either a diagnostic angiogram (DA) or a percutaneous coronary intervention (PCI) procedure. Methods and Results A total of 55 patients were enrolled in this study of the novel ACD. Of the 55 patients, 39 were enrolled in the DA group and 16 were enrolled in the PCI group. Six patients were excluded. A device was deployed in 49 patients. Time to hemostasis (TTH), time to ambulation (TTA), device function, and device-related vascular complications were measured. In the device group, the TTH for the combined DA and PCI patients was 32 seconds (0.54 ± 0.93 minutes), significantly lower when compared with 16.0 ± 12.2 minutes (P < 0.0001) for the control group. Overall major vascular complication rate did not differ significantly, device group (1/49) and the historical control group (1/217). TTA in the combined PCI and DA device group was 226.4 ± 231.9 at the German site (site ambulation policy). In the Irish site, the average TTA in the PCI group was 187 minutes (n = 8) and 85 minutes (n = 14) in the DA group. Conclusion The Celt ACD® device is safe, effective, and significantly decreases the TTH compared to manual pressure and has a low vascular complications rate. The device may be effective in early ambulation and discharge of patients postcoronary intervention procedures.

Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. PROCEDURES This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. RESULTS The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. CONCLUSIONS TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP.

Short-term clinical outcomes among patients undergoing transcatheter aortic valve implantation in Switzerland: the Swiss TAVI registry

Aims: To evaluate short-term clinical outcomes following transcatheter aortic valve implantation (TAVI) using CE-mark approved devices in Switzerland. Methods and results: The Swiss TAVI registry is a national, prospective, multicentre, monitored cohort study evaluating clinical outcomes in consecutive patients undergoing TAVI at cardiovascular centres in Switzerland. From February 2011 to March 2013, a total of 697 patients underwent TAVI for native aortic valve stenosis (98.1%), degenerative aortic bioprosthesis (1.6%) or severe aortic regurgitation (0.3%). Patients were elderly (82.4±6 years), 52% were females, and the majority highly symptomatic (73.1% NYHA III/IV). Patients with severe aortic stenosis (mean gradient 44.8±17 mmHg, aortic valve area 0.7±0.3 cm2) were either deemed inoperable or at high risk for conventional surgery (STS 8.2%±7). The transfemoral access was the most frequently used (79.1%), followed by transapical (18.1%), direct aortic (1.7%) and subclavian access (1.1%). At 30 days, rates of all-cause mortality, cerebrovascular events and myocardial infarction were 4.8%, 3.3% and 0.4%, respectively. The most frequently observed adverse events were access-related complications (11.8%), permanent pacemaker implantation (20.5%) and bleeding complications (16.6%). The Swiss TAVI registry is registered at ClinicalTrials.gov (NCT01368250). Conclusions: The Swiss TAVI registry is a national cohort study evaluating consecutive TAVI procedures in Switzerland. This first outcome report provides favourable short-term clinical outcomes in unselected TAVI patients.

4-year clinical outcomes and predictors of repeat revascularization in patients treated with new-generation drug-eluting stents: a report from the RESOLUTE All-Comers trial (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention)

OBJECTIVES The aim of the study was to investigate 4-year outcomes and predictors of repeat revascularization in patients treated with the Resolute zotarolimus-eluting stent (R-ZES) (Medtronic, Minneapolis, Minnesota) and XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Abbott Park, Illinois) in the RESOLUTE (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) All-Comers trial. BACKGROUND Data on long-term outcomes of new-generation drug-eluting stents are limited, and predictors of repeat revascularization due to restenosis and/or progression of disease are largely unknown. METHODS Patients were randomly assigned to treatment with the R-ZES (n = 1,140) or the EES (n = 1,152). We assessed pre-specified safety and efficacy outcomes at 4 years including target lesion failure and stent thrombosis. Predictors of revascularization at 4 years were identified by Cox regression analysis. RESULTS At 4 years, the rates of target lesion failure (15.2% vs. 14.6%, p = 0.68), cardiac death (5.4% vs. 4.7%, p = 0.44), and target vessel myocardial infarction (5.3% vs. 5.4%, p = 1.00), clinically-indicated target lesion revascularization (TLR) (7.0% vs. 6.5%, p = 0.62), and definite/probable stent thrombosis (2.3% vs. 1.6%, p = 0.23) were similar with the R-ZES and EES. Independent predictors of TLR were age, insulin-treated diabetes, SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score, treatment of saphenous vein grafts, ostial lesions, and in-stent restenosis. Independent predictors of any revascularization were age, diabetes, previous percutaneous coronary intervention, absence of ST-segment elevation myocardial infarction, smaller reference vessel diameter, SYNTAX score, and treatment of left anterior descending, right coronary artery, saphenous vein grafts, ostial lesions, or in-stent restenosis. CONCLUSIONS R-ZES and EES demonstrated similar safety and efficacy throughout 4 years. TLR represented less than one-half of all repeat revascularization procedures. Patient- and lesion-related factors predicting the risk of TLR and any revascularization showed considerable overlap. (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention [RESOLUTE-AC]; NCT00617084).

Clinical experience with the freedom SOLO stentless aortic valve in 277 consecutive patients.

BACKGROUND The Sorin Freedom SOLO (FS) bovine pericardial stentless valve prosthesis is designed for supraannular, subcoronary implantation. We report our experience and results with 277 consecutively implanted FS bioprostheses. METHODS 277 patients (mean age, 74.2 ± 7.3 years; 139 (50.2%) female) underwent aortic valve replacement (AVR) with the FS stentless bioprosthesis. The hemodynamic performance was investigated with transthoracic echocardiography at discharge, 6 months later, and yearly thereafter. Follow-up was 100% complete, with an average observation time of 2.6 ± 1.7 years and a total of 697.3 patient-years. RESULTS The overall 30-day mortality was 4.3%. The mortalities for isolated AVR and combined procedures were 1.9% and 7.3%, respectively. No causes of death were valve-related. Preoperative peak (74.2 ± 23.0 mm Hg) and mean (48.6 ± 16.3 mm Hg) gradients decreased to 15.6 ± 5.4 mm Hg and 8.8 ± 3.0 mm Hg postoperatively and remained unchanged for as long as 5 years. The postoperative mean effective orifice area (EOA) for valve sizes 19, 21, 23, 25, and 27 were 1.49 ± 0.32 cm(2), 1.67 ± 0.40 cm(2), 1.92 ± 0.38 cm(2), 2.01 ± 0.42 cm(2), and 2.13 ± 0.36 cm(2), respectively. Severe prosthesis-patient mismach (PPM) was completely absent, and moderate PPM occurred in 17 patients (6.1%). In isolated AVR, 0.8% of patients with preoperative sinus rhythm required a permanent pacemaker before hospital discharge. There was 100% freedom from structural valve deterioration, 99.6 % freedom from endocarditis and reoperation, and 97.3% freedom from thromboembolism at 5 years. CONCLUSIONS The FS stentless aortic valve is safe to implant, and it shows excellent hemodynamic performance and early and midterm results. Owing to the favorable EOA, the valve appears particularly attractive for patients at risk for PPM.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

A novel multidimensional geriatric screening tool in the ED: evaluation of feasibility and clinical relevance

PURPOSES Geriatric problems frequently go undetected in older patients in emergency departments (EDs), thus increasing their risk of adverse outcomes. We evaluated a novel emergency geriatric screening (EGS) tool designed to detect geriatric problems. BASIC PROCEDURES The EGS tool consisted of short validated instruments used to screen 4 domains (cognition, falls, mobility, and activities of daily living). Emergency geriatric screening was introduced for ED patients 75 years or older throughout a 4-month period. We analyzed the prevalence of abnormal EGS and whether EGS increased the number of EGS-related diagnoses in the ED during the screening, as compared with a preceding control period. MAIN FINDINGS Emergency geriatric screening was performed on 338 (42.5%) of 795 patients presenting during screening. Emergency geriatric screening was unfeasible in 175 patients (22.0%) because of life-threatening conditions and was not performed in 282 (35.5%) for logistical reasons. Emergency geriatric screening took less than 5 minutes to perform in most (85.8%) cases. Among screened patients, 285 (84.3%) had at least 1 abnormal EGS finding. In 270 of these patients, at least 1 abnormal EGS finding did not result in a diagnosis in the ED and was reported for further workup to subsequent care. During screening, 142 patients (42.0%) had at least 1 diagnosis listed within the 4 EGS domains, significantly more than the 29.3% in the control period (odds ratio 1.75; 95% confidence interval, 1.34-2.29; P<.001). Emergency geriatric screening predicted nursing home admission after the in-hospital stay (odds ratio for ≥3 vs <3 abnormal domains 12.13; 95% confidence interval, 2.79-52.72; P=.001). PRINCIPAL CONCLUSIONS The novel EGS is feasible, identifies previously undetected geriatric problems, and predicts determinants of subsequent care.

Ethical procedures and patient consent differ in Europe.

BACKGROUND Research ethics approvals, procedures and requirements for institutional research ethics committees vary considerably by country and by type of organisation. OBJECTIVE To evaluate the requirements and procedures of research ethics committees, details of patient information and informed consent based on a multicentre European trial. DESIGN Survey of European hospitals participating in the prospective observational study on chronic postsurgical pain (euCPSP) using electronic questionnaires. SETTING Twenty-four hospitals in 11 European countries. PARTICIPANTS From the 24 hospitals, 23 local investigators responded; 23 answers were analysed. OUTCOME MEASURES Comparison of research ethics procedures and committee requirements from the perspective of clinical researchers. Comparison of the institutions' procedures regarding patient information and consent. Description of further details such as costs and the duration of the approval process. RESULTS The approval process lasted from less than 2 weeks up to more than 2 months with financial fees varying between 0 and 575 &OV0556;. In 20 hospitals, a patient information sheet of variable length (half page up to two pages) was provided. Requirements for patients' informed consent differed. Written informed consent was mandatory at 12, oral at 10 and no form of consent at one hospital. Details such as enough time for consideration, possibility for withdrawal and risks/benefits of participation were provided in 25 to 30% of the institutions. CONCLUSION There is a considerable variation in the administrative requirements for approval procedures by research ethics committees in Europe. This results in variation of the extent of information and consent procedures for the patients involved. TRIAL REGISTRATION euCPSP in Clinicaltrials.gov identifier: NCT01467102; PAIN-OUT in Clinicaltrials.gov identifier: NCT02083835.

Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice.