Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications.

OBJECTIVE To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: protocol for a randomized, controlled, multicenter study comparing the Solitaire revascularization device with IV tPA with IV tPA alone in acute ischemic stroke.

RATIONALE Early reperfusion in patients experiencing acute ischemic stroke is critical, especially for patients with large vessel occlusion who have poor prognosis without revascularization. Solitaire™ stent retriever devices have been shown to immediately restore vascular perfusion safely, rapidly, and effectively in acute ischemic stroke patients with large vessel occlusions. AIM The aim of the study was to demonstrate that, among patients with large vessel, anterior circulation occlusion who have received intravenous tissue plasminogen activator, treatment with Solitaire revascularization devices reduces degree of disability 3 months post stroke. DESIGN The study is a global multicenter, two-arm, prospective, randomized, open, blinded end-point trial comparing functional outcomes in acute ischemic stroke patients who are treated with either intravenous tissue plasminogen activator alone or intravenous tissue plasminogen activator in combination with the Solitaire device. Up to 833 patients will be enrolled. PROCEDURES Patients who have received intravenous tissue plasminogen activator are randomized to either continue with intravenous tissue plasminogen activator alone or additionally proceed to neurothrombectomy using the Solitaire device within six-hours of symptom onset. STUDY OUTCOMES The primary end-point is 90-day global disability, assessed with the modified Rankin Scale (mRS). Secondary outcomes include mortality at 90 days, functional independence (mRS ≤ 2) at 90 days, change in National Institutes of Health Stroke Scale at 27 h, reperfusion at 27 h, and thrombolysis in cerebral infarction 2b/3 flow at the end of the procedure. ANALYSIS Statistical analysis will be conducted using simultaneous success criteria on the overall distribution of modified Rankin Scale (Rankin shift) and proportions of subjects achieving functional independence (mRS 0-2).

A complete-pelvis segmentation framework for image-free total hip arthroplasty (THA): methodology and clinical study

Background Complete-pelvis segmentation in antero-posterior pelvic radiographs is required to create a patient-specific three-dimensional pelvis model for surgical planning and postoperative assessment in image-free navigation of total hip arthroplasty. Methods A fast and robust framework for accurately segmenting the complete pelvis is presented, consisting of two consecutive modules. In the first module, a three-stage method was developed to delineate the left hemipelvis based on statistical appearance and shape models. To handle complex pelvic structures, anatomy-specific information processing techniques were employed. As the input to the second module, the delineated left hemi-pelvis was then reflected about an estimated symmetry line of the radiograph to initialize the right hemi-pelvis segmentation. The right hemi-pelvis was segmented by the same three-stage method, Results Two experiments conducted on respectively 143 and 40 AP radiographs demonstrated a mean segmentation accuracy of 1.61±0.68 mm. A clinical study to investigate the postoperative assessment of acetabular cup orientations based on the proposed framework revealed an average accuracy of 1.2°±0.9° and 1.6°±1.4° for anteversion and inclination, respectively. Delineation of each radiograph costs less than one minute. Conclusions Despite further validation needed, the preliminary results implied the underlying clinical applicability of the proposed framework for image-free THA.

Beyond statistical learning? Continuous sequence repetition matters in implicit sequence learning

Typically, statistical learning is investigated by testing the acquisition of specific items or forming general rules. As implicit sequence learning also involves the extraction of regularities from the environment, it can also be considered as an instance of statistical learning. In the present study, a Serial Reaction Time Task was used to test whether the continuous versus interleaved repetition of a sequence affects implicit learning despite the equal exposure to the sequences. The results revealed a sequence learning advantage for the continuous repetition condition compared to the interleaved condition. This suggests that by repetition, additional sequence information was extracted although the exposure to the sequences was identical as in the interleaved condition. The results are discussed in terms of similarities and potential differences between typical statistical learning paradigms and sequence learning.

Peri-implant soft tissue colour around titanium and zirconia abutments: a prospective randomized controlled clinical study

OBJECTIVES To objectively determine the difference in colour between the peri-implant soft tissue at titanium and zirconia abutments. MATERIALS AND METHODS Eleven patients, each with two contralaterally inserted osteointegrated dental implants, were included in this study. The implants were restored either with titanium abutments and porcelain-fused-to-metal crowns, or with zirconia abutments and ceramic crowns. Prior and after crown cementation, multi-spectral images of the peri-implant soft tissues and the gingiva of the neighbouring teeth were taken with a colorimeter. The colour parameters L*, a*, b*, c* and the colour differences ΔE were calculated. Descriptive statistics, including non-parametric tests and correlation coefficients, were used for statistical analyses of the data. RESULTS Compared to the gingiva of the neighbouring teeth, the peri-implant soft tissue around titanium and zirconia (test group), showed distinguishable ΔE both before and after crown cementation. Colour differences around titanium were statistically significant different (P = 0.01) only at 1 mm prior to crown cementation compared to zirconia. Compared to the gingiva of the neighbouring teeth, statistically significant (P < 0.01) differences were found for all colour parameter, either before or after crown cementation for both abutments; more significant differences were registered for titanium abutments. Tissue thickness correlated positively with c*-values for titanium at 1 mm and 2 mm from the gingival margin. CONCLUSIONS Within their limits, the present data indicate that: (i) The peri-implant soft tissue around titanium and zirconia showed colour differences when compared to the soft tissue around natural teeth, and (ii) the peri-implant soft tissue around zirconia demonstrated a better colour match to the soft tissue at natural teeth than titanium.

Diagnostic endoscopy of the navicular bursa using a needle endoscope by direct or transthecal approach: A comparative cadaver study

OBJECTIVES: To compare the practicability, visualization of structures, and iatrogenic damage of direct and transthecal approaches to the navicular bursa for diagnostic needle endoscopy. STUDY DESIGN: Descriptive study. SAMPLE POPULATION: Equine cadaver forelimbs (n = 30). METHODS: Direct and transthecal approaches for insertion of a needle endoscope into the navicular bursa were performed. Video recordings of endoscopic procedures were assessed to determine all structures visualized within the navicular bursa. Number of attempts to gain access to the navicular bursa and total time for insertion and examination were recorded. Distribution and severity of iatrogenic lesions were assessed and scored after dissection. RESULTS: There were no statistical differences for number of attempts or time needed for insertion and examination between direct and transthecal approaches. The direct approach offered significantly increased visibility of the ipsilateral abaxial and proximal margins of the navicular bone, and ipsilateral collateral sesamoidean ligament. Iatrogenic lesions were superficial and focal, regardless of approach taken, or whether a blunt or sharp trocar tip was used. CONCLUSIONS: The direct approach provided significantly better visualization of the ipsilateral structures within the navicular bursa compared to the transthecal approach. Needle endoscopy offers a reliable technique to evaluate the navicular bursa and may complement or replace other diagnostic modalities in horses with lameness localized to the navicular region.

Sustained impact of a short small group course with systematic feedback in addition to regular clinical clerkship activities on musculoskeletal examination skills-a controlled study.

BACKGROUND The discrepancy between the extensive impact of musculoskeletal complaints and the common deficiencies in musculoskeletal examination skills lead to increased emphasis on structured teaching and assessment. However, studies of single interventions are scarce and little is known about the time-dependent effect of assisted learning in addition to a standard curriculum. We therefore evaluated the immediate and long-term impact of a small group course on musculoskeletal examination skills. METHODS All 48 Year 4 medical students of a 6 year curriculum, attending their 8 week clerkship of internal medicine at one University department in Berne, participated in this controlled study. Twenty-seven students were assigned to the intervention of a 6×1 h practical course (4-7 students, interactive hands-on examination of real patients; systematic, detailed feedback to each student by teacher, peers and patients). Twenty-one students took part in the regular clerkship activities only and served as controls. In all students clinical skills (CS, 9 items) were assessed in an Objective Structured Clinical Examination (OSCE) station, including specific musculoskeletal examination skills (MSES, 7 items) and interpersonal skills (IPS, 2 items). Two raters assessed the skills on a 4-point Likert scale at the beginning (T0), the end (T1) and 4-12 months after (T2) the clerkship. Statistical analyses included Friedman test, Wilcoxon rank sum test and Mann-Whitney U test. RESULTS At T0 there were no significant differences between the intervention and control group. At T1 and T2 the control group showed no significant changes of CS, MSES and IPS compared to T0. In contrast, the intervention group significantly improved CS, MSES and IPS at T1 (p < 0.001). This enhancement was sustained for CS and MSES (p < 0.05), but not for IPS at T2. CONCLUSIONS Year 4 medical students were incapable of improving their musculoskeletal examination skills during regular clinical clerkship activities. However, an additional small group, interactive clinical skills course with feedback from various sources, improved these essential examination skills immediately after the teaching and several months later. We conclude that supplementary specific teaching activities are needed. Even a single, short-lasting targeted module can have a long lasting effect and is worth the additional effort.

First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases

BACKGROUND This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients. METHODS Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings. RESULTS No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement. CONCLUSION The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.

Metal Artifact Reduction in Pelvic Computed Tomography With Hip Prostheses: Comparison of Virtual Monoenergetic Extrapolations From Dual-Energy Computed Tomography and an Iterative Metal Artifact Reduction Algorithm in a Phantom Study.

OBJECTIVE The aim of this study was to directly compare metal artifact reduction (MAR) of virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (CT) with iterative MAR (iMAR) from single energy in pelvic CT with hip prostheses. MATERIALS AND METHODS A human pelvis phantom with unilateral or bilateral metal inserts of different material (steel and titanium) was scanned with third-generation dual-source CT using single (120 kVp) and dual-energy (100/150 kVp) at similar radiation dose (CT dose index, 7.15 mGy). Three image series for each phantom configuration were reconstructed: uncorrected, VME, and iMAR. Two independent, blinded radiologists assessed image quality quantitatively (noise and attenuation) and subjectively (5-point Likert scale). Intraclass correlation coefficients (ICCs) and Cohen κ were calculated to evaluate interreader agreements. Repeated measures analysis of variance and Friedman test were used to compare quantitative and qualitative image quality. Post hoc testing was performed using a corrected (Bonferroni) P < 0.017. RESULTS Agreements between readers were high for noise (all, ICC ≥ 0.975) and attenuation (all, ICC ≥ 0.986); agreements for qualitative assessment were good to perfect (all, κ ≥ 0.678). Compared with uncorrected images, VME showed significant noise reduction in the phantom with titanium only (P < 0.017), and iMAR showed significantly lower noise in all regions and phantom configurations (all, P < 0.017). In all phantom configurations, deviations of attenuation were smallest in images reconstructed with iMAR. For VME, there was a tendency toward higher subjective image quality in phantoms with titanium compared with uncorrected images, however, without reaching statistical significance (P > 0.017). Subjective image quality was rated significantly higher for images reconstructed with iMAR than for uncorrected images in all phantom configurations (all, P < 0.017). CONCLUSIONS Iterative MAR showed better MAR capabilities than VME in settings with bilateral hip prosthesis or unilateral steel prosthesis. In settings with unilateral hip prosthesis made of titanium, VME and iMAR performed similarly well.

Assessment of the nonoperated root after apical surgery of the other root in mandibular molars: a 5-year follow-up study

INTRODUCTION If a surgical approach is chosen to treat a multirooted tooth affected by persistent periapical pathosis, usually only the affected roots are operated on. The present study assessed the periapical status of the nonoperated root 5 years after apical surgery of the other root in mandibular molars. METHODS Patients treated with apical surgery of mandibular molars with a follow-up of 5 years were selected. Patient-related and clinical parameters (sex, age, smoking, symptoms, and signs of infection) before surgery were recorded. Preoperative intraoral periapical radiographs and radiographs 5 years after surgery were examined. The following data were collected: tooth, operated root, type and quality of the coronal restoration, marginal bone level, length and homogeneity of the root canal filling, presence of a post/screw, periapical index (PAI) of each root, and radiographic healing of the operated root. The presence of apical pathosis of the nonoperated root was analyzed statistically in relation to the recorded variables. RESULTS Thirty-seven patients fulfilled the inclusion criteria. Signs of periapical pathosis in the nonoperated root 5 years after surgery (PAI ≥ 3) could be observed in only 3 cases (8.1%). Therefore, statistical analysis in relation to the variables was not possible. The PAI of the nonoperated root before surgery had a weak correlation with signs of apical pathosis 5 years after surgery. CONCLUSIONS Nonoperated roots rarely developed signs of new apical pathosis 5 years after apical surgery of the other root in mandibular molars. It appears reasonable to resect and fill only roots with a radiographically evident periapical lesion.

Statistical testing against baseline was common in dental research

OBJECTIVES To assess the presence of within-group comparisons with baseline in a subset of leading dental journals and to explore possible associations with a range of study characteristics including journal and study design. STUDY DESIGN AND SETTING Thirty consecutive issues of five leading dental journals were electronically searched. The conduct and reporting of statistical analysis in respect of comparisons against baseline or otherwise along with the manner of interpretation of the results were assessed. Descriptive statistics were obtained, and chi-square test and Fisher's exact were undertaken to test the association between trial characteristics and overall study interpretation. RESULTS A total of 184 studies were included with the highest proportion published in Journal of Endodontics (n = 84, 46%) and most involving a single center (n = 157, 85%). Overall, 43 studies (23%) presented interpretation of their outcomes based solely on comparisons against baseline. Inappropriate use of baseline testing was found to be less likely in interventional studies (P < 0.001). CONCLUSION Use of comparisons with baseline appears to be common among both observational and interventional research studies in dentistry. Enhanced conduct and reporting of statistical tests are required to ensure that inferences from research studies are appropriate and informative.

Cerebral Gaseous Microemboli are Detectable During Continuous Venovenous Hemodialysis in Critically Ill Patients: An Observational Pilot Study

BACKGROUND Continuous venovenous hemodialysis (CVVHD) may generate microemboli that cross the pulmonary circulation and reach the brain. The aim of the present study was to quantify (load per time interval) and qualify (gaseous vs. solid) cerebral microemboli (CME), detected as high-intensity transient signals, using transcranial Doppler ultrasound. MATERIALS AND METHODS Twenty intensive care unit (ICU group) patients requiring CVVHD were examined. CME were recorded in both middle cerebral arteries for 30 minutes during CVVHD and a CVVHD-free interval. Twenty additional patients, hospitalized for orthopedic surgery, served as a non-ICU control group. Statistical analyses were performed using the Mann-Whitney U test or the Wilcoxon matched-pairs signed-rank test, followed by Bonferroni corrections for multiple comparisons. RESULTS In the non-ICU group, 48 (14.5-169.5) (median [range]) gaseous CME were detected. In the ICU group, the 67.5 (14.5-588.5) gaseous CME detected during the CVVHD-free interval increased 5-fold to 344.5 (59-1019) during CVVHD (P<0.001). The number of solid CME was low in all groups (non-ICU group: 2 [0-5.5]; ICU group CVVHD-free interval: 1.5 [0-14.25]; ICU group during CVVHD: 7 [3-27.75]). CONCLUSIONS This observational pilot study shows that CVVHD was associated with a higher gaseous but not solid CME burden in critically ill patients. Although the differentiation between gaseous and solid CME remains challenging, our finding may support the hypothesis of microbubble generation in the CVVHD circuit and its transpulmonary translocation toward the intracranial circulation. Importantly, the impact of gaseous and solid CME generated during CVVHD on brain integrity of critically ill patients currently remains unknown and is highly debated.

Adjustment Disorders Are Uniquely Suited for eHealth Interventions: Concept and Case Study

Background: Adjustment disorders (also known as mental distress in response to a stressor) are among the most frequently diagnosed mental disorders in psychiatry and clinical psychology worldwide. They are also commonly diagnosed in clients engaging in deliberate self-harm and in those consulting general practitioners. However, their reputation in research-oriented mental health remains weak since they are largely underresearched. This may change when the International Statistical Classification of Diseases-11 (ICD-11) by the World Health Organization is introduced, including a new conceptualization of adjustment disorders as a stress-response disorder with positively defined core symptoms. Objective: This paper provides an overview of evidence-based interventions for adjustment disorders. Methods: We reviewed the new ICD-11 concept of adjustment disorder and discuss the the rationale and case study of an unguided self-help protocol for burglary victims with adjustment disorder, and its possible implementation as an eHealth intervention. Results: Overall, the treatment with the self-help manual reduced symptoms of adjustment disorder, namely preoccupation and failure to adapt, as well as symptoms of depression, anxiety, and stress. Conclusions: E-mental health options are considered uniquely suited for offering early intervention after the experiences of stressful life events that potentially trigger adjustment disorders.

Pelvic Fractures in Children Results from the German Pelvic Trauma Registry: A Cohort Study.

As pelvic fractures in children and adolescents are very rare, the surgical management is not well delineated nor are the postoperative complications. The aim of this study using the prospective data from German Pelvic Trauma Registry study was to evaluate the various treatment approaches compared to adults and delineated the differences in postoperative complications after pelvic injuries.Using the prospective pelvic trauma registry established by the German Society of Traumatology and the German Section of the Arbeitsgemeinschaft für Osteosynthesefragen (AO), International in 1991, patients with pelvic fractures over a 12-year time frame submitted by any 1 of the 23 member level I trauma centers were reviewed.We identified a total of 13,525 patients including pelvic fractures in 13,317 adults and 208 children aged ≤14 years and compared these 2 groups. The 2 groups' Injury Severitiy Score (ISS) did not differ statistically. Lethality in the pediatric group was 6.3%, not statistically different from the adults' 4.6%. In all, 18.3% of the pediatric pelvic fractures were treated surgically as compared to 22.7% in the adult group. No child suffered any thrombosis/embolism, acute respiratory distress syndrome (ARDS), multiorgan failure (MOF), or neurologic deficit, nor was any septic MOF detected. The differences between adults and children were statistically significant in that the children suffered less frequently from thrombosis/embolism (P = 0.041) and ARDS and MOF (P = 0.006).This prospective multicenter study addressing patients with pelvic fractures reveals that the risk for a thrombosis/embolism, ARDS, and MOF is significant lower in pediatric patients than in adults. No statistical differences could be found in the ratios of operative therapy of the pelvic fractures in children compared to adults.

STUDY OF THE EFFECTS OF TOTAL MODULATION TRANSFER FUNCTION CHANGES ON OBSERVER PERFORMANCE USING CLINICAL MAMMOGRAMS

The main goal of this study was to relate physical changes in image quality measured by Modulation Transfer Function (MTF) to diagnostic accuracy.^ One Hundred and Fifty Kodak Min-R screen/film combination conventional craniocaudal mammograms obtained with the Pfizer Microfocus Mammographic system were selected from the files of the Department of Radiology, at M.D. Anderson Hospital and Tumor Institute.^ The mammograms included 88 cases with a variety of benign diagnosis and 62 cases with a variety of malignant biopsy diagnosis. The average age of the patient population was 55 years old. 70 cases presented calcifications with 30 cases having calcifications smaller than 0.5mm. 46 cases presented irregular bordered masses larger than 1 cm. 30 cases presented smooth bordered masses with 20 larger than 1 cm.^ Four separated copies of the original images were made each having a different change in the MTF using a defocusing technique whereby copies of the original were obtained by light exposure through different thicknesses (spacing) of transparent film base.^ The mammograms were randomized, and evaluated by three experienced mammographers for the degree of visibility of various anatomical breast structures and pathological lesions (masses and calicifications), subjective image quality, and mammographic interpretation.^ 3,000 separate evaluations were anayzed by several statistical techniques including Receiver Operating Characteristic curve analysis, McNemar test for differences between proportions and the Landis et al. method of agreement weighted kappa for ordinal categorical data.^ Results from the statistical analysis show: (1) There were no statistical significant differences in the diagnostic accuracy of the observers when diagnosing from mammograms with the same MTF. (2) There were no statistically significant differences in diagnostic accuracy for each observer when diagnosing from mammograms with the different MTF's used in the study. (3) There statistical significant differences in detail visibility between the copies and the originals. Detail visibility was better in the originals. (4) Feature interpretations were not significantly different between the originals and the copies. (5) Perception of image quality did not affect image interpretation.^ Continuation and improvement of this research ca be accomplished by: using a case population more sensitive to MTF changes, i.e., asymptomatic women with minimum breast cancer, more observers (including less experienced radiologists and experienced technologists) must collaborate in the study, and using a minimum of 200 benign and 200 malignant cases.^