Markers Models in Survival Analysis and Applications to Issues Associated with AIDS

Jewell and Kalbfleisch (1992) consider the use of marker processes for applications related to estimation of the survival distribution of time to failure. Marker processes were assumed to be stochastic processes that, at a given point in time, provide information about the current hazard and consequently on the remaining time to failure. Particular attention was paid to calculations based on a simple additive model for the relationship between the hazard function at time t and the history of the marker process up until time t. Specific applications to the analysis of AIDS data included the use of markers as surrogate responses for onset of AIDS with censored data and as predictors of the time elapsed since infection in prevalent individuals. Here we review recent work on the use of marker data to tackle these kinds of problems with AIDS data. The Poisson marker process with an additive model, introduced in Jewell and Kalbfleisch (1992) may be a useful "test" example for comparison of various procedures.

ASSESSING THE UNRELIABILITY OF THE MEDICAL LITERATURE: A RESPONSE TO "WHY MOST PUBLISHED RESEARCH FINDINGS ARE FALSE"

A recent article in this journal (Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2: e124) argued that more than half of published research findings in the medical literature are false. In this commentary, we examine the structure of that argument, and show that it has three basic components: 1)An assumption that the prior probability of most hypotheses explored in medical research is below 50%. 2)Dichotomization of P-values at the 0.05 level and introduction of a “bias” factor (produced by significance-seeking), the combination of which severely weakens the evidence provided by every design. 3)Use of Bayes theorem to show that, in the face of weak evidence, hypotheses with low prior probabilities cannot have posterior probabilities over 50%. Thus, the claim is based on a priori assumptions that most tested hypotheses are likely to be false, and then the inferential model used makes it impossible for evidence from any study to overcome this handicap. We focus largely on step (2), explaining how the combination of dichotomization and “bias” dilutes experimental evidence, and showing how this dilution leads inevitably to the stated conclusion. We also demonstrate a fallacy in another important component of the argument –that papers in “hot” fields are more likely to produce false findings. We agree with the paper’s conclusions and recommendations that many medical research findings are less definitive than readers suspect, that P-values are widely misinterpreted, that bias of various forms is widespread, that multiple approaches are needed to prevent the literature from being systematically biased and the need for more data on the prevalence of false claims. But calculating the unreliability of the medical research literature, in whole or in part, requires more empirical evidence and different inferential models than were used. The claim that “most research findings are false for most research designs and for most fields” must be considered as yet unproven.

Survival and failure rates of orthodontic temporary anchorage devices: a systematic review

AIM: The purpose of this study was to systematically review the literature on the survival rates of palatal implants, Onplants((R)), miniplates and mini screws. MATERIAL AND METHODS: An electronic MEDLINE search supplemented by manual searching was conducted to identify randomized clinical trials, prospective and retrospective cohort studies on palatal implants, Onplants((R)), miniplates and miniscrews with a mean follow-up time of at least 12 weeks and of at least 10 units per modality having been examined clinically at a follow-up visit. Assessment of studies and data abstraction was performed independently by two reviewers. Reported failures of used devices were analyzed using random-effects Poisson regression models to obtain summary estimates and 95% confidence intervals (CI) of failure and survival proportions. RESULTS: The search up to January 2009 provided 390 titles and 71 abstracts with full-text analysis of 34 articles, yielding 27 studies that met the inclusion criteria. In meta-analysis, the failure rate for Onplants((R)) was 17.2% (95% CI: 5.9-35.8%), 10.5% for palatal implants (95% CI: 6.1-18.1%), 16.4% for miniscrews (95% CI: 13.4-20.1%) and 7.3% for miniplates (95% CI: 5.4-9.9%). Miniplates and palatal implants, representing torque-resisting temporary anchorage devices (TADs), when grouped together, showed a 1.92-fold (95% CI: 1.06-2.78) lower clinical failure rate than miniscrews. CONCLUSION: Based on the available evidence in the literature, palatal implants and miniplates showed comparable survival rates of >or=90% over a period of at least 12 weeks, and yielded superior survival than miniscrews. Palatal implants and miniplates for temporary anchorage provide reliable absolute orthodontic anchorage. If the intended orthodontic treatment would require multiple miniscrew placement to provide adequate anchorage, the reliability of such systems is questionable. For patients who are undergoing extensive orthodontic treatment, force vectors may need to be varied or the roots of the teeth to be moved may need to slide past the anchors. In this context, palatal implants or miniplates should be the TADs of choice.

The pharmacokinetic profile of fesoterodine: similarities and differences to tolterodine

BACKGROUND: Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine. DESIGN: Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis. RESULTS: The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine. CONCLUSIONS: Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.

Kaposi sarcoma-associated herpes virus and response to antiretroviral therapy: a prospective study of HIV-infected adults

BACKGROUND The possible impact of coinfection with the Kaposi sarcoma-associated herpes virus (KSHV) on the response to antiretroviral therapy (ART) is unknown. Prospective studies are rare, particularly in Africa. METHODS We enrolled a prospective cohort of HIV-infected adults initiating ART in Johannesburg, South Africa. The subjects were defined as seropositive to KSHV if they were reactive to either KSHV lytic K8.1 or latent Orf73 antigen or to both. The subjects were followed from ART initiation until 18 months of treatment. HIV viral load and CD4 counts were tested 6 monthly. Linear generalized estimating and log-binomial regression models were used to estimate the effect of KSHV infection on immunologic recovery and response and HIV viral load suppression within 18 months after ART initiation. RESULTS Three hundred eighty-five subjects initiating ART from November 2008 to March 2009 were considered to be eligible including 184 (48%) KSHV+. The KSHV+ group was similar to the KSHV- in terms of age, gender, initiating CD4 count, body mass index, tuberculosis, and hemoglobin levels. The KSHV+ group gained a similar number of cells at 6 [difference of 10 cells per cubic millimeter, 95% confidence interval (CI): -11 to 31], 12 (3 cells per cubic millimeter, 95% CI: -19 to 25), and 18 months (24 cells per cubic millimeter, 95% CI: -13 to 61) compared with that gained by the KSHV- group. Adjusted relative risk of failure to suppress viral load to <400 copies per milliliter (1.03; 95% CI: 0.90 to 1.17) were similar for KSHV+ and KSHV- by 6 months on treatment. CONCLUSIONS In a population with a high KSHV prevalence, HIV-positive adults coinfected with KSHV achieved similar immunologic and virologic responses to ART early after treatment initiation compared with those with KSHV-.

Commentary: Dedication of Additional Resources to Evaluation and Low-Income Schools is Critical to Increasing Levels of Safe Walking and Bicycling to School

A commentary on Mendoza et al.'s article entitled, "Ethnic Minority Children’s Active Commuting to School and Association with Physical Activity and Pedestrian Safety Behaviors."

Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome.

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years.

Mammalian miRNA RISC recruits CAF1 and PABP to affect PABP-dependent deadenylation.

MicroRNAs (miRNAs) inhibit mRNA expression in general by base pairing to the 3'UTR of target mRNAs and consequently inhibiting translation and/or initiating poly(A) tail deadenylation and mRNA destabilization. Here we examine the mechanism and kinetics of miRNA-mediated deadenylation in mouse Krebs-2 ascites extract. We demonstrate that miRNA-mediated mRNA deadenylation occurs subsequent to initial translational inhibition, indicating a two-step mechanism of miRNA action, which serves to consolidate repression. We show that a let-7 miRNA-loaded RNA-induced silencing complex (miRISC) interacts with the poly(A)-binding protein (PABP) and the CAF1 and CCR4 deadenylases. In addition, we demonstrate that miRNA-mediated deadenylation is dependent upon CAF1 activity and PABP, which serves as a bona fide miRNA coactivator. Importantly, we present evidence that GW182, a core component of the miRISC, directly interacts with PABP via its C-terminal region and that this interaction is required for miRNA-mediated deadenylation.

Towards a Prosperous Future for our Children and Nation

Invited Commentary on "A Multidisciplinary Team Experience with Food Insecurity and Failure to Thrive" by Drs. Kersten and Bennett.

Mechanical restoration and failure analyses of a hydrogel and scaffold composite strategy for annulus fibrosus repair

Unrepaired defects in the annulus fibrosus of intervertebral disks are associated with degeneration and persistent back pain. A clinical need exists for a disk repair strategy that can seal annular defects, be easily delivered during surgical procedures, and restore biomechanics with low risk of herniation. Multiple annulus repair strategies were developed using poly(trimethylene carbonate) scaffolds optimized for cell delivery, polyurethane membranes designed to prevent herniation, and fibrin-genipin adhesive tuned to annulus fibrosus shear properties. This three-part study evaluated repair strategies for biomechanical restoration, herniation risk and failure mode in torsion, bending and compression at physiological and hyper-physiological loads using a bovine injury model. Fibrin-genipin hydrogel restored some torsional stiffness, bending ROM and disk height loss, with negligible herniation risk and failure was observed histologically at the fibrin-genipin mid-substance following rigorous loading. Scaffold-based repairs partially restored biomechanics, but had high herniation risk even when stabilized with sutured membranes and failure was observed histologically at the interface between scaffold and fibrin-genipin adhesive. Fibrin-genipin was the simplest annulus fibrosus repair solution evaluated that involved an easily deliverable adhesive that filled irregularly-shaped annular defects and partially restored disk biomechanics with low herniation risk, suggesting further evaluation for disk repair may be warranted. Statement of significance Lower back pain is the leading cause of global disability and commonly caused by defects and failure of intervertebral disk tissues resulting in herniation and compression of adjacent nerves. Annulus fibrosus repair materials and techniques have not been successful due to the challenging mechanical and chemical microenvironment and the needs to restore biomechanical behaviors and promote healing with negligible herniation risk while being delivered during surgical procedures. This work addressed this challenging biomaterial and clinical problem using novel materials including an adhesive hydrogel, a scaffold capable of cell delivery, and a membrane to prevent herniation. Composite repair strategies were evaluated and optimized in quantitative three-part study that rigorously evaluated disk repair and provided a framework for evaluating alternate repair techniques.

Particle Accelerators and Detectors for medical Diagnostics and Therapy

This Habilitationsschrift (Habilitation thesis) is focused on my research activities on medical applications of particle physics and was written in 2013 to obtain the Venia Docendi (Habilitation) in experimental physics at the University of Bern. It is based on selected publications, which represented at that time my major scientific contributions as an experimental physicist to the field of particle accelerators and detectors applied to medical diagnostics and therapy. The thesis is structured in two parts. In Part I, Chapter 1 presents an introduction to accelerators and detectors applied to medicine, with particular focus on cancer hadrontherapy and on the production of radioactive isotopes. In Chapter 2, my publications on medical particle accelerators are introduced and put into their perspective. In particular, high frequency linear accelerators for hadrontherapy are discussed together with the new Bern cyclotron laboratory. Chapter 3 is dedicated to particle detectors with particular emphasis on three instruments I contributed to propose and develop: segmented ionization chambers for hadrontherapy, a proton radiography apparatus with nuclear emulsion films, and a beam monitor detector for ion beams based on doped silica fibres. Selected research and review papers are contained in Part II. For copyright reasons, they are only listed and not reprinted in this on-line version. They are available on the websites of the journals.

Virtual Patients in continuing medical education and residency training: a pilot project for acceptance analysis in the framework of a residency revision course in pediatrics.

AIM Virtual patients (VPs) are a one-of-a-kind e-learning resource, fostering clinical reasoning skills through clinical case examples. The combination with face-to-face teaching is important for their successful integration, which is referred to as "blended learning". So far little is known about the use of VPs in the field of continuing medical education and residency training. The pilot study presented here inquired the application of VPs in the framework of a pediatric residency revision course. METHODS Around 200 participants of a pediatric nephology lecture ('nephrotic and nephritic syndrome in children') were offered two VPs as a wrap-up session at the revision course of the German Society for Pediatrics and Adolescent Medicine (DGKJ) 2009 in Heidelberg, Germany. Using a web-based survey form, different aspects were evaluated concerning the learning experiences with VPs, the combination with the lecture, and the use of VPs for residency training in general. RESULTS N=40 evaluable survey forms were returned (approximately 21%). The return rate was impaired by a technical problem with the local Wi-Fi firewall. The participants perceived the work-up of the VPs as a worthwhile learning experience, with proper preparation for diagnosing and treating real patients with similar complaints. Case presentations, interactivity, and locally and timely independent repetitive practices were, in particular, pointed out. On being asked about the use of VPs in general for residency training, there was a distinct demand for more such offers. CONCLUSION VPs may reasonably complement existing learning activities in residency training.

Medical, psychological and socio-economic implications of chronic hand eczema: a cross-sectional study.

BACKGROUND Hand eczema (HE) is a common skin disease with major medical psychological and socio-economic implications. Onset and prognosis of HE are determined by individual as well as environmental factors. So far, most epidemiological data on HE have been reported from Scandinavian and recently German studies. OBJECTIVE To investigate the characteristics and medical care of patients with chronic HE (CHE) in Switzerland, and identify risk factors. METHODS In this cross-sectional study, data from patients with chronic HE were obtained by means of medical history, dermatological examination and patient questionnaires. Multiple logistic regression analysis was applied to identify risk factors for high severity and dermatology life quality index (DLQI). RESULTS In seven dermatology departments, 199 patients (mean age 40.4 years, 50.8% female) with CHE (mean duration 6.6 years) were enrolled. Moderate to severe HE was reported by 70.9% of patients, and was associated with age <30 or >50 years, localization of lesions and pruritus. Because of the CHE, 37.3% of patients were on sick leave over the past 12 months, 14.8% had changed or lost their job. Practically all patients applied topical therapy, 21% were treated with alitretinoin, and 21% with psoralen plus UVA light (PUVA). The effects on the health-related quality of life was moderate to large in 33.7% and 39.4% of CHE patients, respectively. Factors associated with a high impact on DLQI (mean 9.7 ± 5.8) were female sex, lesions on back of the hands and pruritus as well as mechanical skin irritation and wearing gloves. CONCLUSION In agreement with recent studies, the Swiss data demonstrate the high impact of CHE on medical well-being, patient quality of life and work ability. As it is associated with an intense use of health care services, high rate of sick leave, job loss and change, CHE may cause a high socio-economic burden.

Stiffness, Strength, and Failure Modes of Implant-Supported Monolithic Lithium Disilicate Crowns: Influence of Titanium and Zirconia Abutments

PURPOSE The objective of this study was to evaluate stiffness, strength, and failure modes of monolithic crowns produced using computer-aided design/computer-assisted manufacture, which are connected to diverse titanium and zirconia abutments on an implant system with tapered, internal connections. MATERIALS AND METHODS Twenty monolithic lithium disilicate (LS2) crowns were constructed and loaded on bone level-type implants in a universal testing machine under quasistatic conditions according to DIN ISO 14801. Comparative analysis included a 2 × 2 format: prefabricated titanium abutments using proprietary bonding bases (group A) vs nonproprietary bonding bases (group B), and customized zirconia abutments using proprietary Straumann CARES (group C) vs nonproprietary Astra Atlantis (group D) material. Stiffness and strength were assessed and calculated statistically with the Wilcoxon rank sum test. Cross-sections of each tested group were inspected microscopically. RESULTS Loaded LS2 crowns, implants, and abutment screws in all tested specimens (groups A, B, C, and D) did not show any visible fractures. For an analysis of titanium abutments (groups A and B), stiffness and strength showed equally high stability. In contrast, proprietary and nonproprietary customized zirconia abutments exhibited statistically significant differences with a mean strength of 366 N (Astra) and 541 N (CARES) (P < .05); as well as a mean stiffness of 884 N/mm (Astra) and 1,751 N/mm (CARES) (P < .05), respectively. Microscopic cross-sections revealed cracks in all zirconia abutments (groups C and D) below the implant shoulder. CONCLUSION Depending on the abutment design, prefabricated titanium abutment and proprietary customized zirconia implant-abutment connections in conjunction with monolithic LS2 crowns had the best results in this laboratory investigation.

Influence of Abutment Design on Stiffness, Strength, and Failure of Implant-Supported Monolithic Resin Nano Ceramic (RNC) Crowns

BACKGROUND Recent technical development allows the digital manufacturing of monolithic reconstructions with high-performance materials. For implant-supported crowns, the fixation requires an abutment design onto which the reconstruction can be bonded. PURPOSE The aim of this laboratory investigation was to analyze stiffness, strength, and failure modes of implant-supported, computer-assisted design and computer-aided manufacturing (CAD/CAM)-generated resin nano ceramic (RNC) crowns bonded to three different titanium abutments. MATERIALS AND METHODS Eighteen monolithic RNC crowns were produced and loaded in a universal testing machine under quasi-static condition according to DIN ISO 14801. With regard to the type of titanium abutment, three groups were defined: (1) prefabricated cementable standard; (2) CAD/CAM-constructed individualized; and (3) novel prefabricated bonding base. Stiffness and strength were measured and analyzed statistically with Wilcoxon rank sum test. Sections of the specimens were examined microscopically. RESULTS Stiffness demonstrated high stability for all specimens loaded in the physiological loading range with means and standard deviations of 1,579 ± 120 N/mm (group A), 1,733 ± 89 N/mm (group B), and 1,704 ± 162 N/mm (group C). Mean strength of the novel prefabricated bonding base (group C) was 17% lower than of the two other groups. Plastic deformations were detectable for all implant-abutment crown connections. CONCLUSIONS Monolithic implant crowns made of RNC seem to represent a feasible and stable prosthetic construction under laboratory testing conditions with strength higher than the average occlusal force, independent of the different abutment designs used in this investigation.