Freely accessible software for recruitment prediction and recruitment monitoring of clinical trials: A systematic review.

Background: The successful completion of clinical trials ultimately depends on realistic recruitment predictions. Statistical methods for recruitment prediction implemented in a free-of-charge open-source software could be routinely used by researchers worldwide to design clinical trials. However, the availability of such software implementations is currently unclear. Methods: Two independent reviewers conducted a systematic review following PRISMA guidelines. Eligible articles included English publications focused on statistical methods for recruitment prediction and monitoring that referred to software implementations. The list of articles retrieved from well-established data bases was enriched by backtracking of references provided by eligible articles. The current software availability and open-source status were tabulated. Results: We found 21 eligible articles, 7 of which (33 %) provide freely accessible software. Ultimately, only one article provides a link to an easy-to-comprehend, well-documented, and currently directly applicable free-of-charge open-source software. The lack of availability is mainly caused by blocked access and outdated links. Conclusions: While several software implementations exist for recruitment prediction, only a small fraction is freely accessible. These results highlight the need for future efforts to achieve free access to well-documented software implementations supporting researchers in routinely using statistical methods to arrive at realistic recruitment predictions in clinical trials.

Teaching: confidence, prediction and tolerance intervals in scientific practice: a tutorial on binary variables.

BACKGROUND: One of the emerging themes in epidemiology is the use of interval estimates. Currently, three interval estimates for confidence (CI), prediction (PI), and tolerance (TI) are at a researcher's disposal and are accessible within the open access framework in R. These three types of statistical intervals serve different purposes. Confidence intervals are designed to describe a parameter with some uncertainty due to sampling errors. Prediction intervals aim to predict future observation(s), including some uncertainty present in the actual and future samples. Tolerance intervals are constructed to capture a specified proportion of a population with a defined confidence. It is well known that interval estimates support a greater knowledge gain than point estimates. Thus, a good understanding and the use of CI, PI, and TI underlie good statistical practice. While CIs are taught in introductory statistical classes, PIs and TIs are less familiar. RESULTS: In this paper, we provide a concise tutorial on two-sided CI, PI and TI for binary variables. This hands-on tutorial is based on our teaching materials. It contains an overview of the meaning and applicability from both a classical and a Bayesian perspective. Based on a worked-out example from veterinary medicine, we provide guidance and code that can be directly applied in R. CONCLUSIONS: This tutorial can be used by others for teaching, either in a class or for self-instruction of students and senior researchers.

Sensitivity and identification quantification by a relative latent model complexity perturbation in Bayesian meta-analysis.

In recent years, Bayesian meta-analysis expressed by a normal-normal hierarchical model (NNHM) has been widely used for combining evidence from multiple studies. Data provided for the NNHM are frequently based on a small number of studies and on uncertain within-study standard deviation values. Despite the widespread use of Bayesian NNHM, it has always been unclear to what extent the posterior inference is impacted by the heterogeneity prior (sensitivity S ) and by the uncertainty in the within-study standard deviation values (identification I ). Thus, to answer this question, we developed a unified method to simultaneously quantify both sensitivity and identification ( S - I ) for all model parameters in a Bayesian NNHM, based on derivatives of the Bhattacharyya coefficient with respect to relative latent model complexity (RLMC) perturbations. Three case studies exemplify the applicability of the method proposed: historical data for a conventional therapy, data from which one large study is first included and then excluded, and two subgroup meta-analyses specified by their randomization status. We analyzed six scenarios, crossing three RLMC targets with two heterogeneity priors (half-normal, half-Cauchy). The results show that S - I explicitly reveals which parameters are affected by the heterogeneity prior and by the uncertainty in the within-study standard deviation values. In addition, we compare the impact of both heterogeneity priors and quantify how S - I values are affected by omitting one large study and by the randomization status. Finally, the range of applicability of S - I is extended to Bayesian NtHM. A dedicated R package facilitates automatic S - I quantification in applied Bayesian meta-analyses.

How vague is vague? How informative is informative? Reference analysis for Bayesian meta-analysis.

Meta-analysis provides important insights for evidence-based medicine by synthesizing evidence from multiple studies which address the same research question. Within the Bayesian framework, meta-analysis is frequently expressed by a Bayesian normal-normal hierarchical model (NNHM). Recently, several publications have discussed the choice of the prior distribution for the between-study heterogeneity in the Bayesian NNHM and used several "vague" priors. However, no approach exists to quantify the informativeness of such priors, and thus, we develop a principled reference analysis framework for the Bayesian NNHM acting at the posterior level. The posterior reference analysis (post-RA) is based on two posterior benchmarks: one induced by the improper reference prior, which is minimally informative for the data, and the other induced by a highly anticonservative proper prior. This approach applies the Hellinger distance to quantify the informativeness of a heterogeneity prior of interest by comparing the corresponding marginal posteriors with both posterior benchmarks. The post-RA is implemented in the freely accessible R package ra4bayesmeta and is applied to two medical case studies. Our findings show that anticonservative heterogeneity priors produce platykurtic posteriors compared with the reference posterior, and they produce shorter 95% credible intervals (CrI) and optimistic inference compared with the reference prior. Conservative heterogeneity priors produce leptokurtic posteriors, longer 95% CrI and cautious inference. The novel post-RA framework could support numerous Bayesian meta-analyses in many research fields, as it determines how informative a heterogeneity prior is for the actual data as compared with the minimally informative reference prior.

Bonding Behavior Between Polyetheretherketone and Polymethylmethacrylate Acrylic Denture Polymer.

PURPOSE: To investigate the impact of pretreatment and conditioning on shear bond strength (SBS), surface free energy (SFE) and surface roughness (SR) between polyetheretherketone (PEEK) and cold-cured polymethylmethacrylate (PMMA). MATERIALS AND METHODS: PEEK substrates (Dentokeep PEEK Disc, nt-trading) were air abraded with Al2O3 particles of different grain sizes applied with varying pressure at 1) 0.2 MPa - 50 µm Al2O3; 2) 0.4 MPa - 50 µm Al2O3; 3) 0.2 MPa - 110 µm Al2O3; 4) 0.4 MPa - 110 µm Al2O3; or 5) without air abrasion (n = 172/group). Surface properties were quantified using SFE and SR (n = 10/group), and scanning electron microscope imaging (n = 2/group). Substrates were conditioned with a) Visio.link (VL, Bredent); b) Scotchbond Universal (SU, 3M Oral Care); c) Bonding Fluid (BF, Schütz Dental); or d) without conditioning (WC; n = 40/subgroup) and bonded to the polymer (Futura Jet, Schütz Dental). SBS and fracture types were determined before and after 10,000 thermal cycles (n = 20/subgroup). Univariate ANOVA, Kruskal-Wallis test, Mann-Whitney U-test, Kaplan-Meier survival estimates, and Weibull distribution were computed (p < 0.05). Ciba-Geigy tables and the chi-squared test were used to analyze fracture type distributions. RESULTS: An increase in particle size and pressure resulted in similar or increased SBS, Weibull characteristic strength, and Weibull moduli (p < 0.001 - 0.046). The lowest results were observed for the control group (without air abrasion), while pretreatment with 0.4 MPa - 110 µm Al2O3 presented the highest values (p < 0.001). In comparison with the other conditioning procedures, VL showed high (p < 0.001 - 0.03), and SU and WC low SBS (p < 0.001 - 0.006). Although it did not influence SFE, an increase in particle size and pressure led to an increased SR (p < 0.001). CONCLUSION: Pretreatment with 0.4 MPa - 110 µm Al2O3 can be recommended to increase bonding properties between PEEK and PMMA. Application of adhesives such as VL can enhance SBS further.

Retention force of polyetheretherketone and cobalt-chrome-molybdenum removable dental prosthesis clasps after artificial aging.

OBJECTIVES: To examine the retention force of removable dental prosthesis (RDP) clasps made from polyetheretherketone (PEEK) and cobalt-chrome-molybdenum (CoCrMo, control group) after storage in water and artificial aging. MATERIALS AND METHODS: For each material, 15 Bonwill clasps with retentive buccal and reciprocal lingual arms situated between the second pre- and first molar were manufactured by milling (Dentokeep [PEEKmilled1], NT digital implant technology; breCAM BioHPP Blank [PEEKmilled2], bredent), pressing (BioHPP Granulat for 2 press [PEEKpressed], bredent), or casting (remanium GM 800+ [CoCrMo], Dentaurum); N = 60, n = 15/subgroup. A total of 50 retention force measurements were performed for each specimen per aging level (initial; after storage [30 days, 37 °C] and 10,000 thermal cycles; after storage [60 days, 37 °C] and 20,000 thermal cycles) in a pull-off test. Data were statistically analyzed using one-way ANOVA, post hoc Scheffé and mixed models (p < 0.05). RESULTS: Initial, PEEKpressed (80.2 ± 35.2) and PEEKmilled1 (98.9 ± 40.3) presented the lowest results, while PEEKmilled2 (170.2 ± 51.8) showed the highest values. After artificial aging, the highest retention force was observed for the control group (131.4 ± 56.8). The influence of artificial aging was significantly higher for PEEK-based materials. While PEEKmilled2 and PEEKpressed showed an initial decline in retention force, all other groups presented no impact or an increase in retention force over a repetitive insertion and removal of the clasps. CONCLUSIONS: Within the tested PEEK materials, PEEKmilled2 presented superior results than PEEKpressed. Although CoCrMo showed higher values after artificial aging, all materials exhibited sufficient retention to recommend usage under clinical conditions. CLINICAL RELEVANCE: As RDPs are still employed for a wide range of indications, esthetic alternatives to conventional CoCrMo clasps are sought.

Is the high-performance thermoplastic polyetheretherketone indicated as a clasp material for removable dental prostheses?

OBJECTIVES: To investigate the retention force of polyetheretherketone (PEEK) removable dental prosthesis clasps in comparison with a cobalt-chrome-molybdenum control group after storage in artificial saliva. MATERIALS AND METHODS: Clasps were milled (Dentokeep (PEEKmilled1), NT digital implant technology; breCAM BioHPP Blank (PEEKmilled2), bredent), pressed (BioHPP Granulat for 2 press (PEEKpressed), bredent), or cast (remanium GM 800+ (cobalt-chrome-molybdenum), Dentaurum); N = 60, n = 15/subgroup. Retention force was examined 50 times/specimen in a pull-off test using the universal testing machine (Zwick 1445), where pull-off force was applied with a crosshead speed of 5 mm/minute until the maximum force dropped by 10%, at different aging levels: (1) initial, after storage in artificial saliva for (2) 90 and (3) 180 days. Statistical analysis was performed using one-way ANOVA followed by post hoc Scheffé-test and mixed models (p < 0.05). RESULTS: Cobalt-chrome-molybdenum presented the highest retention force. No differences were observed between polyetheretherketone materials. Cobalt-chrome-molybdenum showed a significant decrease of its values after artificial aging, while polyetheretherketone materials presented similar results over the course of aging. Regarding a repetitive insertion and removal, even though PEEKmilled2 and cobalt-chrome-molybdenum showed an initial increase, ultimately, a decrease in retention force was observed for all tested groups. CONCLUSIONS: Although the control group showed significantly higher results, the retention force of polyetheretherketone materials indicate a potential clinical application. Neither the manufacturing process nor artificial aging showed an impact on the retention force of polyetheretherketone clasps. CLINICAL RELEVANCE: Mechanical properties of novel removable dental prosthesis clasp materials devised to meet the growing esthetic demands of patients need to be investigated to ensure a successful long-term clinical application.

Tailored immunosuppression after kidney transplantation - a single center real-life experience.

BACKGROUND: Kidney allograft survival continuously improved with introduction of novel immunosuppressants. However, also immunologically challenging transplants (blood group incompatibility and sensitized recipients) increase. Between 2006 and 2008, a new tailored immunosuppression scheme for kidney transplantation was implemented at the University Hospital in Zurich, together with an ABO-incompatible transplant program and systematic pre- and posttransplant anti-human leukocyte antigen (HLA) antibody screening by Luminex technology. This study retrospectively evaluated the results of this tailored immunosuppression approach with a particular focus on immunologically higher risk transplants. METHODS: A total of 204 consecutive kidney transplantations were analyzed, of whom 14 were ABO-incompatible and 35 recipients were donor-specific anti-HLA antibodies (DSA) positive, but complement-dependent cytotoxicity crossmatch (CDC-XM) negative. We analyzed patient and graft survival, acute rejection rates and infectious complications in ABO-compatible versus -incompatible and in DSA positive versus negative patients and compared those with a historical control group. RESULTS: Overall patient, death-censored allograft survival and non-death-censored allograft survival at 4 years were 92, 91 and 87%, respectively. We found that (1) there were no differences between ABO-compatible and -incompatible and between DSA positive and DSA negative patients concerning acute rejection rate and graft survival; (2) compared with the historical control group there was a significant decrease of acute rejection rates in sensitized patients who received an induction with thymoglobulin; (3) there was no increased rate of infection among the patients who received induction with thymoglobulin compared to no induction therapy. CONCLUSIONS: We observed excellent overall mid-term patient and graft survival rates with our tailored immunosuppression approach. Induction with thymoglobulin was efficient and safe in keeping rejection rates low in DSA positive patients with a negative CDC-XM.

Medication as a risk factor for hospitalization due to heart failure and shock: a series of case-crossover studies in Swiss claims data.

PURPOSE: Heart failure is among the leading causes for hospitalization in Europe. In this study, we evaluate potential precipitating factors for hospitalization for heart failure and shock. METHODS: Using Swiss claims data (2014-2015), we evaluated the association between hospitalization for heart failure and shock, and prescription of oral potassium supplements, non-steroidal anti-inflammatory drugs (NSAIDs), and amoxicillin/clavulanic acid. We conducted case-crossover analyses, where exposure was compared for the hazard period and the primary control period (e.g., 1-30 days before hospitalization vs. 31-60 days, respectively). Conditional logistic regression was applied and subsequently adjusted for addressing potential confounding by disease progression. Sensitivity analyses were conducted and stratification for co-medication was performed. RESULTS: We identified 2185 patients hospitalized with heart failure or shock. Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid was significantly associated with an increased risk for hospitalization for heart failure and shock with crude odds ratios (OR) of 2.04 for potassium (95% CI 1.24-3.36, p = 0.005, 30 days), OR 1.8 for NSAIDs (95% CI 1.39-2.33, p < 0.0001, 30 days), and OR 3.25 for amoxicillin/clavulanic acid (95% CI 2.06-5.14, p < 0.0001, 15 days), respectively. Adjustment attenuated odds ratios, while the significant positive association remained (potassium OR 1.70 (95% CI 1.01-2.86, p = 0.046), NSAIDs OR 1.50 (95% CI 1.14-1.97, p = 0.003), and amoxicillin/clavulanic acid OR 2.26 (95% CI 1.41-3.62, p = 0.001). CONCLUSION: Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid is associated with increased risk for hospitalization. Underlying conditions such as pain, electrolyte imbalances, and infections are likely contributing risk factors. Physicians may use this knowledge to better identify patients at risk and adapt patient management.

Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial.

INTRODUCTION: Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA. MATERIAL AND METHODS: In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score >10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3-4 h). Patients were allocated through minimisation to either subtherapeutic CPAP ("sham CPAP") or continuation of CPAP ("therapeutic CPAP"). A Bayesian analysis with historical priors calculated the posterior probability of superiority. RESULTS: Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6-4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure. CONCLUSIONS: Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.

Prediction of health care expenditure increase: how does pharmacotherapy contribute?

BACKGROUND: Rising health care costs are a major public health issue. Thus, accurately predicting future costs and understanding which factors contribute to increases in health care expenditures are important. The objective of this project was to predict patients healthcare costs development in the subsequent year and to identify factors contributing to this prediction, with a particular focus on the role of pharmacotherapy. METHODS: We used 2014-2015 Swiss health insurance claims data on 373'264 adult patients to classify individuals' changes in health care costs. We performed extensive feature generation and developed predictive models using logistic regression, boosted decision trees and neural networks. Based on the decision tree model, we performed a detailed feature importance analysis and subgroup analysis, with an emphasis on drug classes. RESULTS: The boosted decision tree model achieved an overall accuracy of 67.6% and an area under the curve-score of 0.74; the neural network and logistic regression models performed 0.4 and 1.9% worse, respectively. Feature engineering played a key role in capturing temporal patterns in the data. The number of features was reduced from 747 to 36 with only a 0.5% loss in the accuracy. In addition to hospitalisation and outpatient physician visits, 6 drug classes and the mode of drug administration were among the most important features. Patient subgroups with a high probability of increase (up to 88%) and decrease (up to 92%) were identified. CONCLUSIONS: Pharmacotherapy provides important information for predicting cost increases in the total population. Moreover, its relative importance increases in combination with other features, including health care utilisation.

Fracture resistance and 2-body wear of 3-dimensional-printed occlusal devices.

STATEMENT OF PROBLEM: Polymeric material for 3-dimensional printing can be used to fabricate occlusal devices. However, information about fracture resistance and wear is scarce. PURPOSE: The purpose of this in vitro study was to investigate the fracture resistance and 2-body wear of 3-dimensional-printed (3DP) (FotoDent splint; Dreve Dentamid GmbH), milled polymethylmethacrylate (CAM) (Temp Basic; Transpa 95H16, Zirkonzahn GmbH), and conventionally fabricated polymethylmethacrylate (CAST) (Castdon; Dreve Dentamid GmbH) occlusal devices. MATERIAL AND METHODS: A total of 96 occlusal devices were prepared according to the 3 different manufacturing techniques 3DP, CAM, and CAST (n=32). For each manufacturing technique, specimens were further divided into initial fracture resistance tests (n=16) and artificial aging in the mastication simulator (50 N, 37°C) with 2-body wear followed by fracture resistance tests (n=16). The fracture resistance was determined using a universal testing machine (1 mm/min). The wear was measured after 20 000 and 120 000 mastication cycles with the replica technique, mapped with a laser scanner, and quantified in R software. Data were analyzed using a 2-way ANOVA followed by a 1-way ANOVA with Scheffé or Games-Howell post hoc tests, repeated measures ANOVA with corrected Greenhouse-Geisser P values, and the Levene, Mann-Whitney, and paired t tests (α=.05). RESULTS: CAM presented higher initial fracture resistance than 3DP or CAST (P<.001). After mastication simulation, CAM followed by 3DP showed higher fracture resistance than CAST (P<.001). Mastication simulation decreased the fracture resistance for CAM and CAST (P<.001) but not for 3DP (P=.78). Three-dimensional-printed occlusal devices showed the highest material volume loss, followed by CAM and the lowest in CAST (P<.001). CONCLUSIONS: Three-dimensional-printed occlusal devices showed lower wear resistance and lower fracture resistance than those milled or conventionally fabricated. Therefore, only short-term application in the mouth is recommended. Further developments of occlusal device material for 3-dimensional printing are necessary.

Bonding to new CAD/CAM resin composites: influence of air abrasion and conditioning agents as pretreatment strategy.

OBJECTIVES: Because of their industrially standardized process of manufacturing, CAD/CAM resin composites show a high degree of conversion, making a reliable bond difficult to achieve. PURPOSE: The purpose of this experiment was to investigate the tensile bond strength (TBS) of luting composite to CAD/CAM resin composite materials as influenced by air abrasion and pretreatment strategies. MATERIAL AND METHODS: The treatment factors of the present study were (1) brand of the CAD/CAM resin composite (Brilliant Crios [Coltene/Whaledent], Cerasmart [GC Europe], Shofu Block HC [Shofu], and Lava Ultimate [3M]); (2) air abrasion vs. no air abrasion; and (3) pretreatment using a silane primer (Clearfil Ceramic Primer, Kuraray) vs. a resin primer (One Coat 7 Universal, Coltene/Whaledent). Subsequently, luting composite (DuoCem, Coltene/Whaledent) was polymerized onto the substrate surface using a mold. For each combination of the levels of the three treatment factors (4 (materials) × 2 (air abrasion vs. no air abrasion; resin) × 2 (primer vs. silane primer)), n = 15, specimens were prepared. After 24 h of water storage at 37 °C and 5000 thermo-cycles (5/55 °C), TBS was measured and failure types were examined. The resulting data was analyzed using Kaplan-Meier estimates of the cumulative failure distribution function with Breslow-Gehan tests and non-parametric ANOVA (Kruskal-Wallis test) followed by the multiple pairwise Mann-Whitney U test with α-error adjustment using the Benjamini-Hochberg procedure and chi-square test (p < 0.05). RESULTS: The additional air abrasion step increased TBS values and lowered failure rates. Specimens pretreated using a resin primer showed significantly higher TBS and lower failure rates than those pretreated using a silane primer. The highest failure rates were observed for groups pretreated with a silane primer. Within the Shofu Block HC group, all specimens without air abrasion and pretreatment with a silane primer debonded during the aging procedure. CONCLUSIONS: Before fixation of CAD/CAM resin composites, the restorations should be air abraded and pretreated using a resin primer containing methyl-methacrylate to successfully bond to the luting composite. The pretreatment of the CAD/CAM resin composite using merely a silane primer results in deficient adhesion. CLINICAL RELEVANCE: For a reliable bond of CAD/CAM resin composites to the luting composite, air abrasion and a special pretreatment strategy are necessary in order to achieve promising long-term results.

A complication probability study for a definitive-intent, moderately hypofractionated image-guided intensity-modulated radiotherapy protocol for anal sac adenocarcinoma in dogs.

Previous trials showed the importance of administering radiation therapy (RT) with small doses per fraction in canine pelvic tumours to maintain acceptable toxicity levels. With increased accuracy/precision of RT, namely intensity-modulated RT (IMRT), this approach might be challenged. Theoretical toxicity calculations for a new definitive-intent moderately hypofractionated RT protocol for canine anal sac adenocarcinomas (ASAC) were performed, focussing on the risk of toxicity in pelvic organs at risk (OAR). Computed tomography datasets of 18 dogs with stage 3b ASAC were included. Re-planning with margins for daily image-guidance/IMRT was performed and a new protocol isoeffective to previously described definitive-intent protocols was computed. Dose-volume information were derived from individual plans and used for normal tissue complication probability (NTCP) computations. A 12 × 3.8 Gy protocol was computed for risk estimation. Tumour volumes ranged from 27.9 to 820.4 cm3 (mean 221.3 cm3 ± 188.9). For late rectal toxicity/bleeding ≥grade 2, median risk probability was 2.3% inter quartile range (IQR: 5.9; 95% confidence interval (CI): 1.2, 8.4) (rho = 0.436) and 3.4% (IQR: 0.96; 95%CI: 3.1, 4.0) (rho = 0.565), respectively. Median late toxicities in urinary bladder, kidneys and small bowel were <1%, except in one kidney. Myelopathy/myelonecrosis had a median risk probability of 4.1% (IQR: 23.5; 95%CI: 2.1, 25.2) (rho = 0.366) and 5.6% (IQR: 13.5; 95%CI: 3.1, 14.1) (rho = 0.363), respectively. However, graded risk showed a probability estimate for late spinal cord toxicity of ≥5% in 8/18 patients. The daily-imaging IMRT 12 × 3.8 Gy protocol for canine ASAC seems tolerable for most cases, even in advanced disease. Theoretical dose computations serve as estimate, but are safe measures before implementing new protocols into clinical use.

Radiation therapy for intracranial tumours in cats with neurological signs.

OBJECTIVES: The aim of this study was to evaluate the outcome of cats with intracranial tumours presenting with neurological signs treated with radiation therapy. METHODS: This study comprised a retrospective multicentre case series. Medical records of a total of 22 cats with intracranial space-occupying lesions, presenting with neurological signs and/or epileptic seizures and treated with external beam radiation therapy, were reviewed. In the treated cats, patient-, tumour- and treatment-related variables were investigated, including age, sex, tumour location, tumour volume, total radiation dose, equivalent dose in 2 Gy fractions (EQD2), corticosteroid dose, overall treatment time and institution for influence on local tumour control and survival. RESULTS: Based on advanced imaging characteristics, the 22 treated cats presented with meningioma (n = 11), pituitary tumour (n = 8), choroid plexus tumour (n = 2) or glioma (n = 1). Allocated to the neuraxis, 11 lesions were extra-axial, three were intra-axial and eight were located in the pituitary region. At diagnosis, 21 cats exhibited altered neurological status. One cat presented with epileptic seizures and another cat had both seizures and altered neurological status. The mean total physical dose of radiation was 41.63 Gy (± 4.33), range 24-45 Gy. In all but one cat (95.5%), neurological signs improved after radiation therapy. The median progression-free survival was 510 days (95% confidence interval [CI]: 51-969). The proportion free of progression at 1 year was 55.7% (95% CI: 33-78). Fourteen cats died (only in five cases was death related to the intracranial tumour) and eight cats were still alive or lost to follow-up. The median overall survival time was 515 days (95% CI: 66-964). None of the tested variables influenced outcome. CONCLUSIONS AND RELEVANCE: Radiation therapy seems to represent a viable treatment option in cats with intracranial tumours, relieving neurological signs and improving local tumour control. Radiation therapy may be considered for cats with tumours in complicated/inoperable localisations or for cases with a high peri- and postoperative risk.

Comparative evaluation of a novel, moderately hypofractionated radiation protocol in 56 dogs with symptomatic intracranial neoplasia.

BACKGROUND: Use of strongly hypofractionated radiation treatments in dogs with intracranial neoplasia did not improve outcomes and yielded increased rates of toxicosis. OBJECTIVES: To evaluate safety and efficacy of a new, moderately hypofractionated radiation protocol of 10 × 4 Gy compared to a standard protocol. ANIMALS: Convenience sample of 56 client-owned dogs with primary symptomatic brain tumors. METHODS: Retrospective observational study. Twenty-six dogs were assigned to the control standard protocol of 20 × 2.5 Gy (group A) and 30 dogs to the new protocol of 10 × 4 Gy (group B), assigned on owners' informed consent. Statistical analysis was conducted under the "as treated" regime, using Kaplan-Meier and Cox-regression analysis. Treatment was delivered with technically advanced image-guided radiation therapy. The 2 treatment groups were compared in terms of outcome and signs of toxicosis. RESULTS: Overall progression-free interval (PFI) and overall survival (OS) time were favorable, with 663 (95%CI: 497;828) and 637 (95%CI: 403;870) days, respectively. We found no significant difference between the two groups: PFI for dogs in group A vs B was 608 (95%CI: 437;779) days and mean (median not reached) 863 (95%CI: 644;1083) days, respectively (P = .89), and OS for dogs in group A vs B 610 (95%CI: 404;816) and mean (median not reached) 796 (95%CI: 586;1007) days (P = .83). CONCLUSION AND CLINICAL IMPORTANCE: In conclusion, 10 × 4 Gy is a safe and efficient protocol for treatment of primary intracranial neoplasia and future dose escalation can be considered.

Reliability of wear measurements of CAD-CAM restorative materials after artificial aging in a mastication simulator.

OBJECTIVES: The purpose of this in vitro study was to assess the 2-body wear behavior of computer-aided design and computer-aided manufacturing (CAD-CAM) restorative materials and additionally to validate an automatic approach to wear quantification as provided by newly developed software. MATERIALS AND METHODS: Two composite resins (Experimental Composite, Shofu Block HC), 1 polymethyl methacrylate- (PMMA)-based material (Telio CAD), and 1 dual-network material (VITA Enamic) were tested (n = 12). The materials were stored in distilled water at 37 °C for 14 days, then aged in a mastication simulator (cycles: 400 000, 50 N, 1.2 Hz, 5/55 °C) for 2-body wear testing with human molars as antagonists. Software was developed as a freely available function in R for automatic wear quantification and was applied to 2 (vertical and horizontal) images obtained by an optical laser scanner (SDM). Wear measurements were validated with a reference confocal laser scanning microscope (LSM) system. The Kruskal-Wallis with Tukey-Kramer post hoc test (α = 0.05), coefficient of variation, Bland-Altman method, and intraclass correlation were applied. RESULTS: Shofu Block HC showed the greatest wear, and no differences were found among other materials. The automatic wear measurements agreed well with the reference LSM system. The reliability of the SDM scans was 98.5%. CONCLUSIONS: The wear resistance caused by two-body wear differed among the restorative materials tested, with the mean wear resistance of the 2 composite resin materials differing significantly. Wear quantification with R software based on SDM scans showed satisfactory agreement with the reference LSM system.

Analysis of Drug-Drug Interactions in Swiss Claims Data Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated Combination.

BACKGROUND: Potential drug-drug interactions (pDDIs) are described in various case reports, but few studies have evaluated the impact of specific combinations on a population level. OBJECTIVE: To analyze the type and frequency of multiple contraindicated (X-pDDIs) and major interactions (D-pDDIs) and to subsequently assess the impact of the particular combination of tizanidine and ciprofloxacin on outpatient physician visits and hospitalizations. METHODS: Anonymized Swiss claims data from 524 797 patients in 2014-2015 were analyzed. First, frequencies of X- and D-pDDIs were calculated. Next, a retrospective cohort study was conducted among patients prescribed tizanidine and ciprofloxacin (exposed, n = 199) or tizanidine and other antibiotics (unexposed, n = 960). Hospitalizations and outpatient physician visits within 7, 14, and 30 days after initiation of antibiotic therapy were evaluated using multiple binary logistic regression and multiple linear regression. RESULTS: The relative frequencies of X- and D-pDDIs were 0.4% and 6.65%, respectively. In the cohort study, significant associations between exposure to tizanidine and ciprofloxacin and outpatient physician visits were identified for 14 and 30 days (odds ratio [OR] = 1.61 [95% CI = 1.17-2.24], P = 0.004, and OR = 1.59 [95% CI = 1.1-2.34], P = 0.016). A trend for increased risk of hospitalization was found for all evaluated time periods (OR = 1.68 [95% CI = 0.84-3.17], OR = 1.52 [95% CI = 0.63-3.33], and OR = 2.19 [95% CI = 0.88-5.02]). Conclusion and Relevance: The interaction between tizanidine and ciprofloxacin is not only relevant for individual patients, but also at the population level. Further investigation of the impact of other clinically relevant DDIs is necessary to improve patient safety and reduce avoidable health care utilization.

Macro- and microtopographical examination and quantification of CAD-CAM composite resin 2- and 3-body wear.

STATEMENT OF PROBLEM: The selection of an appropriate restorative material based on wear behavior is important for the long-term success of a dental restoration. For computer-aided design and computer-aided manufacturing (CAD-CAM) composite resins, information about their wear resistance and wear mechanism is scarce. PURPOSE: The purpose of this in vitro study was to compare the 2- and 3-body wear of CAD-CAM composite resins with that of lithium disilicate ceramic and to develop analysis software. MATERIAL AND METHODS: Flat specimens were prepared from the following CAD-CAM composite resins: Cerasmart (CS), SHOFU Block HC (SH), Katana Avencia (KA), Brilliant Crios (BC), an experimental composite resin (EXP), and lithium disilicate ceramic IPS e.max CAD (REF). The specimens underwent 2-body wear (50 N, 5/55°C, 400 000 cycles) opposed by human enamel antagonists. Specimen wheels were prepared with each material on each wheel for 3-body wear with a millet slurry (15 N, 15% slip, 200 000 cycles). All specimens were digitized by using a dedicated laser scanner. Analysis software was developed to calculate macrotopographical examination of volume loss. The microtopography of the surfaces was examined by using scanning electron microscopy. For data analysis, the Kruskal-Wallis test with the Tukey-Kramer post hoc test and the 1-sample Wilcoxon test were used (α=.05). RESULTS: After 2-body wear simulation, SH and KA presented higher volume loss than the other CAD-CAM materials. For 3-body wear, REF had lower volume loss than CS, SH, or BC. In addition, BC led to higher volume loss than EXP. The patterns of 2- and 3-body wear were different. CONCLUSIONS: The ceramic showed good global wear resistance. The volume loss of the CAD-CAM composite resins differed and depended on the material. The 2- and 3-body wear test methods tended to differ with regard to volume loss. Examination of the worn surfaces revealed different mechanisms acting in 2- and 3-body wear test.