On Causal Mediation Analysis with a Survival Outcome

Suppose that having established a marginal total effect of a point exposure on a time-to-event outcome, an investigator wishes to decompose this effect into its direct and indirect pathways, also know as natural direct and indirect effects, mediated by a variable known to occur after the exposure and prior to the outcome. This paper proposes a theory of estimation of natural direct and indirect effects in two important semiparametric models for a failure time outcome. The underlying survival model for the marginal total effect and thus for the direct and indirect effects, can either be a marginal structural Cox proportional hazards model, or a marginal structural additive hazards model. The proposed theory delivers new estimators for mediation analysis in each of these models, with appealing robustness properties. Specifically, in order to guarantee ignorability with respect to the exposure and mediator variables, the approach, which is multiply robust, allows the investigator to use several flexible working models to adjust for confounding by a large number of pre-exposure variables. Multiple robustness is appealing because it only requires a subset of working models to be correct for consistency; furthermore, the analyst need not know which subset of working models is in fact correct to report valid inferences. Finally, a novel semiparametric sensitivity analysis technique is developed for each of these models, to assess the impact on inference, of a violation of the assumption of ignorability of the mediator.

On the Accelerated Failure Time Model for Current Status and Interval Censored Data

This paper introduces a novel approach to making inference about the regression parameters in the accelerated failure time (AFT) model for current status and interval censored data. The estimator is constructed by inverting a Wald type test for testing a null proportional hazards model. A numerically efficient Markov chain Monte Carlo (MCMC) based resampling method is proposed to simultaneously obtain the point estimator and a consistent estimator of its variance-covariance matrix. We illustrate our approach with interval censored data sets from two clinical studies. Extensive numerical studies are conducted to evaluate the finite sample performance of the new estimators.

GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.

Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Løken syndrome

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior-Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. METHODS: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. RESULTS: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

Immunodetection of 3-nitrotyrosine in the liver of zymosan-treated rats with a new monoclonal antibody: comparison to analysis by HPLC

Zymosan-induced peritonitis is associated with an increased production of reactive nitrogen oxides that may contribute to the often-observed failure of multiple organ systems in this model of acute inflammation. Quantitative biochemical evidence is provided for a marked 13-fold increase in protein-bound 3-nitrotyrosine (NTyr), a biomarker of reactive nitrogen oxides, in liver tissue of zymosan-treated rats. In order to investigate the localization of NTyr in this affected tissue, a monoclonal antibody, designated 39B6, was raised against 3-(4-hydroxy-3-nitrophenylacetamido) propionic acid-bovine serum albumin conjugate and its performance characterized. 39B6 was judged by competition ELISA to be approximately 2 orders of magnitude more sensitive than a commercial anti-NTyr monoclonal antibody. Binding characteristics of 39B6 were similar, but not identical, to that of a commercial affinity-purified polyclonal antibody in ELISA and immunohistochemical analyses. Western blot experiments revealed high specificity of 39B6 against NTyr and increased immunoreactivity of specific proteins from liver tissue homogenates of zymosan-treated rats. Immunohistochemical analysis of liver sections indicated a marked zymosan-induced increase in immunofluorescent staining, which was particularly intense in or adjacent to nonparenchymal cells, but not in the parenchymal cells of this tissue. Quantitative analysis of fractions enriched in these cell populations corroborated the immunofluorescent data, although the relative amounts detected in response to zymosan treatment was greatly reduced compared to whole liver tissue. These results demonstrate the high specificity of the newly developed antibody and its usefulness in Western blot and immunohistochemical analysis for NTyr, confirm the presence of NTyr by complementary methods, and suggest the possible involvement of reactive nitrogen oxides in hepatic vascular dysfunction.

Safety of Active Implantable Devices during MRI Examinations: A Finite Element Analysis of an Implantable Pump

The goal of this study was to propose a general numerical analysis methodology to evaluate the magnetic resonance imaging (MRI)-safety of active implants. Numerical models based on the finite element (FE) technique were used to estimate if the normal operation of an active device was altered during MRI imaging. An active implanted pump was chosen to illustrate the method. A set of controlled experiments were proposed and performed to validate the numerical model. The calculated induced voltages in the important electronic components of the device showed dependence with the MRI field strength. For the MRI radiofrequency fields, significant induced voltages of up to 20 V were calculated for a 0.3T field-strength MRI. For the 1.5 and 3.0T MRIs, the calculated voltages were insignificant. On the other hand, induced voltages up to 11 V were calculated in the critical electronic components for the 3.0T MRI due to the gradient fields. Values obtained in this work reflect to the worst case situation which is virtually impossible to achieve in normal scanning situations. Since the calculated voltages may be removed by appropriate protection circuits, no critical problems affecting the normal operation of the pump were identified. This study showed that the proposed methodology helps the identification of the possible incompatibilities between active implants and MR imaging, and can be used to aid the design of critical electronic systems to ensure MRI-safety

Implant Failure Predictors in the Posterior Maxilla: A Retrospective Study of 273 Consecutive Implants

Background: The goal of this study was to retrospectively analyze a cohort of 136 patients who underwent dental implant placement in the posterior maxilla at the University of Connecticut Health Center to assess and identify predictors for implant failure in the posterior maxilla. Methods: Data were retrieved from patient charts to identify subjects older than 21 years of age who received dental implant(s) in the posterior maxilla. Patients without a postoperative baseline radiograph were excluded. A recall radiograph was taken 3 to 6 months after implant placement. If there was no recall radiograph, the subject was contacted for a recall visit that included a clinical evaluation and radiographs to determine the implant status. Based on a univariate screening, variables considered potential implant failure predictors included gender, diabetes, smoking, implant length, implant diameter, membrane use, sinus-elevation technique, and surgical complications. These parameters were further assessed, and a multivariable logistic regression was performed with implant failure as a dependant variable. All tests of significance were evaluated at the 0.05 error level. Results: Two hundred seventy-three implants were placed in the posterior maxilla. Fourteen implants failed (early and late failures combined), resulting in a 94.9% overall survival rate. The survival rates for the sinus-elevation group and native bone group were 92.2% and 96.7%, respectively (P = 0.090). Based on the multivariable analysis, sinus floor-elevation procedures were not associated with increased risk for implant failure (P = 0.702). In contrast, smoking and surgical complications had a statistically significant effect on implant failure; the odds ratios for implant failure were 6.4 (P = 0.025) and 8.2 (P = 0.004), respectively. Conclusion: Sinus-elevation procedures with simultaneous or staged implant placement do not increase the risk for implant failure, whereas smoking and surgical complications markedly increase the risk for implant failure.

Measurement of dental implant stability by resonance frequency analysis and damping capacity assessment: comparison of both techniques in a clinical trial

PURPOSE: Two noninvasive methods to measure dental implant stability are damping capacity assessment (Periotest) and resonance frequency analysis (Osstell). The objective of the present study was to assess the correlation of these 2 techniques in clinical use. MATERIALS AND METHODS: Implant stability of 213 clinically stable loaded and unloaded 1-stage implants in 65 patients was measured in triplicate by means of resonance frequency analysis and Periotest. Descriptive statistics as well as Pearson's, Spearman's, and intraclass correlation coefficients were calculated with SPSS 11.0.2. RESULTS: The mean values were 57.66 +/- 8.19 implant stability quotient for the resonance frequency analysis and -5.08 +/- 2.02 for the Periotest. The correlation of both measuring techniques was -0.64 (Pearson) and -0.65 (Spearman). The single-measure intraclass correlation coefficients for the ISQ and Periotest values were 0.99 and 0.88, respectively (95% CI). No significant correlation of implant length with either resonance frequency analysis or Periotest could be found. However, a significant correlation of implant diameter with both techniques was found (P < .005). The correlation of both measuring systems is moderate to good. It seems that the Periotest is more susceptible to clinical measurement variables than the Osstell device. The intraclass correlation indicated lower measurement precision for the Periotest technique. Additionally, the Periotest values differed more from the normal (Gaussian) curve of distribution than the ISQs. Both measurement techniques show a significant correlation to the implant diameter. CONCLUSION: Resonance frequency analysis appeared to be the more precise technique.

Atrial fibrillation following device closure of patent foramen ovale

OBJECTIVES: Recurrent embolic events after device closure of patent foramen ovale (PFO) have been related to incomplete closure. Another cause could be atrial fibrillation (AF). The aim of this study was to determine the incidence of AF in stroke patients after PFO closure. METHODS: Consecutive patients with device closure of a PFO after a stroke or transient ischemic attack and control patients with stroke underwent 7-day event loop recordings 3 and 6 months after PFO closure or stroke, respectively. RESULTS: Forty patients treated by PFO device closure 96 +/- 68 days after cryptogenic ischemic stroke and 70 control patients with ischemic stroke of other etiologies (known AF excluded) were compared. AF was identified in 6 patients (15%) of the treated group and in 12 control patients (17%, p = 0.77). In multivariate analysis, the presence of an occluder device was not an independent risk factor for AF. CONCLUSIONS: The incidence of AF is high after device closure of a PFO in stroke patients and similar to that in patients with stroke of non-PFO etiology and, hence, with no device. Further studies are required to determine the risk of thromboembolism and the optimal treatment in patients developing AF after device closure of a PFO.

Psychometric properties of the MacNew heart disease health-related quality of life instrument in patients with heart failure

RATIONALE, AIMS AND OBJECTIVES: Heart failure (HF) is a severe chronic disease and impairs health-related quality of life (HRQL). While validated specific HRQL instruments are required for evaluation of treatment and rehabilitation in patients with HF, a single validated measure to document changes in HRQL for patients with different heart disease diagnoses would be invaluable. The purpose of this analysis was the psychometric analysis of the German MacNew Heart Disease Questionnaire (MacNew) in HF patients, which has previously been shown to be reliable and valid in patients with myocardial infarction, angina pectoris and arrhythmia. METHODS: We recruited 89 patients (61.7+/-11.5 years; 84.3% male) in two Austrian and one Swiss cardiology department with documented HF (effect sizes 28.9+/-10.1%). The self-administered MacNew, the Short Form-36 (SF-36) and the Hospital Anxiety and Depression Scale were completed. Internal consistency reliability (Cronbach's alpha), discriminative and evaluative validity were assessed. RESULTS: Cronbach's alpha exceeded 0.80. Each MacNew scale differentiated between patients with and without anxiety (3.9+/-1.0 vs. 5.3+/-0.8, all P<0.001), with and without depression (4.2+/-1.2 vs. 5.2+/-0.9 all P<0.03) and by the SF-36 health transition item (deteriorate=4.39, no change=4.95, improve=5.45, all P<0.02). Evaluative validity was demonstrated with effect sizes >0.70 for a subsample attending a 12-week outpatient rehabilitation programme. CONCLUSIONS: The German language version of the MacNew demonstrates consistently acceptable psychometric properties of reliability, validity and responsiveness in patients with documented HF. Together with previous documentation of reliability, validity and responsive, these findings strengthen the argument for the MacNew as a potential 'core' HRQL measure, at least in the German language.

A retrospective analysis of patients referred for implant placement to a specialty clinic: indications, surgical procedures, and early failures

Purpose: This retrospective study analyzed the pool of patients referred for treatment with dental implants over a 3-year period in a referral specialty clinic. Materials and Methods: All patients receiving dental implants between 2002 and 2004 in the Department of Oral Surgery and Stomatology, University of Bern, were included in this retrospective study. Patients were analyzed according to age, gender, indications for implant therapy, location of implants, and type and length of implants placed. A cumulative logistic regression analysis was performed to identify and analyze potential risk factors for complications or failures. Results: A total of 1,206 patients received 1,817 dental implants. The group comprised 573 men and 633 women with a mean age of 55.2 years. Almost 60% of patients were age 50 or older. The most frequent indication for implant therapy was single-tooth replacement in the maxilla (522 implants or 28.7%). A total of 726 implants (40%) were inserted in the esthetically demanding region of the anterior maxilla. For 939 implants (51.7%), additional bone-augmentation procedures were required. Of these, ridge augmentation with guided bone regeneration was performed more frequently than sinus grafting. Thirteen complications leading to early failures were recorded, resulting in an early failure rate of 0.7%. The regression analysis failed to identify statistically significant failure etiologies for the variables assessed. Conclusions: From this study it can be concluded that patients referred to a specialty clinic for implant placement were more likely to be partially edentulous and over 50 years old. Single-tooth replacement was the most frequent indication (> 50%). Similarly, additional bone augmentation was indicated in more than 50% of cases. Adhering to strict patient selection criteria and a standardized surgical protocol, an early failure rate of 0.7% was experienced in this study population

Slope stability analysis of the Pacaya Volcano, Guatemala, using limit equilibrium and finite element method

The Pacaya volcanic complex is part of the Central American volcanic arc, which is associated with the subduction of the Cocos tectonic plate under the Caribbean plate. Located 30 km south of Guatemala City, Pacaya is situated on the southern rim of the Amatitlan Caldera. It is the largest post-caldera volcano, and has been one of Central America’s most active volcanoes over the last 500 years. Between 400 and 2000 years B.P, the Pacaya volcano had experienced a huge collapse, which resulted in the formation of horseshoe-shaped scarp that is still visible. In the recent years, several smaller collapses have been associated with the activity of the volcano (in 1961 and 2010) affecting its northwestern flanks, which are likely to be induced by the local and regional stress changes. The similar orientation of dry and volcanic fissures and the distribution of new vents would likely explain the reactivation of the pre-existing stress configuration responsible for the old-collapse. This paper presents the first stability analysis of the Pacaya volcanic flank. The inputs for the geological and geotechnical models were defined based on the stratigraphical, lithological, structural data, and material properties obtained from field survey and lab tests. According to the mechanical characteristics, three lithotechnical units were defined: Lava, Lava-Breccia and Breccia-Lava. The Hoek and Brown’s failure criterion was applied for each lithotechnical unit and the rock mass friction angle, apparent cohesion, and strength and deformation characteristics were computed in a specified stress range. Further, the stability of the volcano was evaluated by two-dimensional analysis performed by Limit Equilibrium (LEM, ROCSCIENCE) and Finite Element Method (FEM, PHASE 2 7.0). The stability analysis mainly focused on the modern Pacaya volcano built inside the collapse amphitheatre of “Old Pacaya”. The volcanic instability was assessed based on the variability of safety factor using deterministic, sensitivity, and probabilistic analysis considering the gravitational instability and the effects of external forces such as magma pressure and seismicity as potential triggering mechanisms of lateral collapse. The preliminary results from the analysis provide two insights: first, the least stable sector is on the south-western flank of the volcano; second, the lowest safety factor value suggests that the edifice is stable under gravity alone, and the external triggering mechanism can represent a likely destabilizing factor.

Development of an In Situ Measurement Device for Obtaining Material Thermal Properties

This thesis presents a methodology for measuring thermal properties in situ, with a special focus on obtaining properties of layered stack-ups commonly used in armored vehicle components. The technique involves attaching a thermal source to the surface of a component, measuring the heat flux transferred between the source and the component, and measuring the surface temperature response. The material properties of the component can subsequently be determined from measurement of the transient heat flux and temperature response at the surface alone. Experiments involving multilayered specimens show that the surface temperature response to a sinusoidal heat flux forcing function is also sinusoidal. A frequency domain analysis shows that sinusoidal thermal excitation produces a gain and phase shift behavior typical of linear systems. Additionally, this analysis shows that the material properties of sub-surface layers affect the frequency response function at the surface of a particular stack-up. The methodology involves coupling a thermal simulation tool with an optimization algorithm to determine the material properties from temperature and heat flux measurement data. Use of a sinusoidal forcing function not only provides a mechanism to perform the frequency domain analysis described above, but sinusoids also have the practical benefit of reducing the need for instrumentation of the backside of the component. Heat losses can be minimized by alternately injecting and extracting heat on the front surface, as long as sufficiently high frequencies are used.