Administration of an adeno-associated viral vector expressing interferon-ß in patients with inflammatory hand arthritis, results of a phase I/II study.

OBJECTIVE: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-ß, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. METHODS: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-ß immune responses were evaluated. A data review committee provided safety recommendations. RESULTS: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-ß, nor IFN-ß antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. CONCLUSION: Single IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. TRIAL REGISTRATION: NCT02727764.

Using machine learning techniques to characterize sleep-deprived driving behavior.

OBJECTIVE: Sleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present study, we extend this approach to sleep deprivation and test the model for characterization of new interventions. We aimed to classify abnormal driving behavior after sleep deprivation, and, by using a machine learning model, we tested if this model could also pick up abnormal driving behavior resulting from other interventions. METHODS: Data were collected during a previous study, in which 24 subjects were tested after being sleep-deprived and after a well-rested night. Features were calculated from several driving parameters, such as the lateral position, speed of the car, and steering speed. In the present study, we used a gradient boosting model to classify sleep deprivation. The model was validated using a 5-fold cross validation technique. Next, probability scores were used to identify the overlap of driving behavior after sleep deprivation and driving behavior affected by other interventions. In the current study alprazolam, alcohol, and placebo are used to test/validate the approach. RESULTS: The sleep deprivation model detected abnormal driving behavior in the simulator with an accuracy of 77 ± 9%. Abnormal driving behavior after alprazolam, and to a lesser extent also after alcohol intake, showed remarkably similar characteristics to sleep deprivation. The average probability score for alprazolam and alcohol measurements was 0.79, for alcohol 0.63, and for placebo only 0.27 and 0.30, matching the expected relative drowsiness. CONCLUSION: We developed a model detecting abnormal driving induced by sleep deprivation. The model shows the similarities in driving characteristics between sleep deprivation and other interventions, i.e., alcohol and alprazolam. Consequently, our model for sleep deprivation may serve as a next reference point for a driving test battery of newly developed drugs.

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.

Challenges and opportunities of pharmacological interventions for osteoarthritis: A review of current clinical trials and developments.

Objective: Osteoarthritis (OA) is the most common cause of disability in older adults, and leads to a huge unmet medical need, as no registered disease modifying OA drugs (DMOADs), but only symptomatic treatments, are available. New targets and compounds for these targets, are currently under investigation. The objective of this paper is to provide an overview of compounds under investigation for OA in phase II and III. Design: We performed a review of OA trials for pharmacological interventions registered on the National Library of Medicine ClinicalTrials.gov website with a completion date in 2017 or later. Results: The database search yielded 255 results, of which 184 studies were included in this review. These were structured in compounds targeting pain, immunomodulators, stem cell therapy, platelet rich plasma and DMOADs with cartilage and/or bone resorption modifying properties. Conclusions: The results provide an overview of the fields in development and may include future treatment options for OA, by which a registered DMOADs may become more than a utopic vista. Further knowledge on pathophysiology and new approaches of value-based drug development could be an opportunity for the optimization of drug development in OA.

Clinical translation and implementation of optical imaging agents for precision image-guided cancer surgery.

INTRODUCTION: The field of tumor-specific fluorescence-guided surgery has seen a significant increase in the development of novel tumor-targeted imaging agents. Studying patient benefit using intraoperative fluorescence-guided imaging for cancer surgery is the final step needed for implementation in standard treatment protocols. Translation into phase III clinical trials can be challenging and time consuming. Recent studies have helped to identify certain waypoints in this transition phase between studying imaging agent efficacy (phase I-II) and proving patient benefit (phase III). TRIAL INITIATION: Performing these trials outside centers of expertise, thus involving motivated clinicians, training them, and providing feedback on data quality, increases the translatability of imaging agents and the surgical technique. Furthermore, timely formation of a trial team which oversees the translational process is vital. They are responsible for establishing an imaging framework (camera system, imaging protocol, surgical workflow) and clinical framework (disease stage, procedure type, clinical research question) in which the trial is executed. Providing participating clinicians with well-defined protocols with the aim to answer clinically relevant research questions within the context of care is the pinnacle in gathering reliable trial data. OUTLOOK: If all these aspects are taken into consideration, tumor-specific fluorescence-guided surgery is expected be of significant value when integrated into the diagnostic work-up, surgical procedure, and follow-up of cancer patients. It is only by involving and collaborating with all stakeholders involved in this process that successful clinical translation can occur. AIM: Here, we discuss the challenges faced during this important translational phase and present potential solutions to enable final clinical translation and implementation of imaging agents for image-guided cancer surgery.

The use of machine learning improves the assessment of drug-induced driving behaviour.

RATIONALE: Car-driving performance is negatively affected by the intake of alcohol, tranquillizers, sedatives and sleep deprivation. Although several studies have shown that the standard deviation of the lateral position on the road (SDLP) is sensitive to drug-induced changes in simulated and real driving performance tests, this parameter alone might not fully assess and quantify deviant or unsafe driving. OBJECTIVE: Using machine learning we investigated if including multiple simulator-derived parameters, rather than the SDLP alone would provide a more accurate assessment of the effect of substances affecting driving performance. We specifically analysed the effects of alcohol and alprazolam. METHODS: The data used in the present study were collected during a previous study on driving effects of alcohol and alprazolam in 24 healthy subjects (12 M, 12 F, mean age 26 years, range 20-43 years). Various driving features, such as speed and steering variations, were quantified and the influence of administration of alcohol or alprazolam was assessed to assist in designing a predictive model for abnormal driving behaviour. RESULTS: Adding additional features besides the SDLP increased the model performance for prediction of drug-induced abnormal driving behaviour (from an accuracy of 65 %-83 % after alprazolam intake and from 50 % to 76 % after alcohol ingestion). Driving behaviour influenced by alcohol and alprazolam was characterised by different feature importance, indicating that the two interventions influenced driving behaviour in a different way. CONCLUSION: Machine learning using multiple driving features in addition to the state-of-the-art SDLP improves the assessment of drug-induced abnormal driving behaviour. The created models may facilitate quantitative description of abnormal driving behaviour in the development and application of psychopharmacological medicines. Our models require further validation using similar and unknown interventions.

Perioperative Management in Patients Using Vitamin K Antagonists: Observational Cohort Study.

BACKGROUND: The benefit of periprocedural bridging with low-molecular-weight heparin (LMWH) in patients with atrial fibrillation has been contested by the publication of the BRIDGE trial. OBJECTIVE: This article determines whether publication of the BRIDGE trial has led to less bridging procedures and better patient outcomes (i.e., a composite of thromboembolism, major bleeding, and death) in patients undergoing invasive procedures at the Leiden Anticoagulation Clinic, the Netherlands. METHODS: We identified all procedures that required vitamin K antagonist interruption. Procedures were divided in a period before (2014-2016; 22 months) and after the publication of the BRIDGE trial (2016-2017; 22 months). Cumulative incidences 30 days postprocedure and relative risks of thromboembolic events, major bleeding, and mortality were calculated. RESULTS: A total of 4,892 and 4,237 eligible procedures were performed in 2014 to 2016 and 2016 to 2017, respectively. The cumulative incidence of thromboembolism was 0.5% in 2014 to 2016 compared with 0.3% in 2016 to 2017; adjusted odds ratio (OR) 0.60 (95% confidence interval [CI] 0.30-1.21). The cumulative incidence of major bleeding was 1.0% in the 2014 to 2016 period as compared with 1.3% in the 2016 to 2017 period; adjusted OR was 1.27 (95% CI 0.85-1.90). The adjusted OR of the composite endpoint was 1.05 (95% CI 0.74-1.48). The frequency of bridging with LMWH (14.8% in 2014-2016 vs. 16.6% in 2016-2017) as well as mean CHA2DS2-VASc scores of patients receiving bridging did not change after publication of the BRIDGE trial. CONCLUSION: We showed that despite publication of the BRIDGE trial, the frequency of bridging with LMWH and patient outcomes regarding bleeding complications did not change.

Carcinoembryonic antigen-specific, fluorescent image-guided cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for metastatic colorectal cancer.

This multicentre pilot study investigated the role of peroperative carcinoembryonic antigen (CEA)-specific fluorescence imaging during cytoreductive surgery-hyperthermic intraperitoneal chemotherapy surgery in peritoneal metastasized colorectal cancer. A correct change in peritoneal carcinomatosis index (PCI) owing to fluorescence imaging was seen in four of the 14 included patients. The use of SGM-101 in patients with peritoneally metastasized colorectal carcinoma is feasible, and allows intraoperative detection of tumour deposits and alteration of the PCI. Augmented reality guidance.

Potential targets for tumor-specific imaging of vulvar squamous cell carcinoma: A systematic review of candidate biomarkers.

INTRODUCTION: Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC. METHODS: Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and III) in vivo application. RESULTS: In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A. DISCUSSION: This overview identified 7 potential biomarkers that can be used in the development of VSCC-specific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions.

Mobile e-diary application facilitates the monitoring of patient-reported outcomes and a high treatment adherence for clinical trials in dermatology.

BACKGROUND: Assessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have limited reliability, particularly for outpatient trials. OBJECTIVES: To investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials. METHODS: An e-diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient-reported outcomes, i.e. pain and itch, were evaluated by the e-diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e-diary adherence, and patients' perception of usefulness and acceptability of the e-diary were evaluated. RESULTS: Treatment adherence rates of the included 256 patients were high (median 98%, range 97-99%). E-diary adherence was also high with a median of 93% (range 87-97%) for capturing the applied drug by camera, and 89% (range 87-96%) and 94% (range 87-96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e-diary as good to excellent with respect to user acceptability. CONCLUSIONS: The results suggest that the e-diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e-diary may also be valuable for frequent and reliable monitoring of patient-reported outcomes in daily clinical practice.

The simplified oral flucloxacillin absorption test: an accurate method to identify patients with inadequate oral flucloxacillin absorption.

BACKGROUND: The preferred treatment for severe methicillin-sensitive Staphylococcus aureus infections is flucloxacillin, a small-spectrum antibiotic administered intravenously (IV) and orally. However, clinicians switch to the less preferred broad-spectrum antibiotics because of the variable absorption after oral administration of flucloxacillin. A classical oral absorption test (OAT) requires overnight fasting and interruption of IV therapy, and is laborious. In the current study, we investigated whether a simplified OAT can be utilized in a clinical setting to guide antibiotic treatment in patients with severe S. aureus infections. For this, OAT IV therapy is continued and oral dosing is performed after a one-hour fast and implemented after a small study. METHODS: In 196 patients receiving IV flucloxacillin by continuous infusion, a classical OAT (test A) or simplified version of the OAT (test B) was performed. In both tests, 1 g oral flucloxacillin was given and serum samples were taken prior to intake and at one and two hours after administration. Flucloxacillin concentrations were determined by high-performance liquid chromatography. Adequate absorption was defined as an increase of flucloxacillin concentration of at least 10 mg/l after one or two hours compared to baseline. RESULTS: In a sample of 196 patients (85 F/111 M), test A was performed in 28 patients, and test B in 168 patients. Age, gender, and baseline values of creatinine and albumin were similar in both groups. The maximal increase of flucloxacillin absorption was highly variable between patients. In 26 (13%) of the 196 patients, the flucloxacillin increase did not reach the value of 10 mg/l. The median (interquartile range, IQR) maximal increase of flucloxacillin absorption was 22.0 (15-31.25) mg/l for test A and 21.5 (13-32.25) mg/l for test B. There was no significant difference in maximal increase of flucloxacillin absorption between test A and B (p = 0.74), nor between males and females (p = 0.95). Age, creatinine, and albumin were not correlated with flucloxacillin levels. CONCLUSIONS: The simplified version of the OAT is useful to identify patients with adequate oral flucloxacillin absorption, and to ensure the effective continuation of an oral small-spectrum treatment.

Body mass index related electrocardiographic findings in healthy young individuals with a normal body mass index.

INTRODUCTION: An increased body mass index (BMI) (>25 kg/m2) is associated with a wide range of electrocardiographic changes. However, the association between electrocardiographic changes and BMI in healthy young individuals with a normal BMI (18.5-25 kg/m2) is unknown. The aim of this study was to evaluate the association between BMI and electrocardiographic parameters. METHODS: Data from 1,290 volunteers aged 18 to 30 years collected at our centre were analysed. Only subjects considered healthy by a physician after review of collected data with a normal BMI and in sinus rhythm were included in the analysis. Subjects with a normal BMI (18.5-25 kg/m2) were divided into BMI quartiles analysis and a backward multivariate regression analysis with a normal BMI as a continuous variable was performed. RESULTS: Mean age was 22.7 ± 3.0 years, mean BMI was 22.0, and 73.4% were male. There were significant differences between the BMI quartiles in terms of maximum P-wave duration, P-wave balance, total P-wave area in lead V1, PR-interval duration, and heart axis. In the multivariate model maximum P-wave duration (standardised coefficient (SC) = +0.112, P < 0.001), P-wave balance in lead V1 (SC = +0.072, P < 0.001), heart axis (SC = -0.164, P < 0.001), and Sokolow-Lyon voltage (SC = -0.097, P < 0.001) were independently associated with BMI. CONCLUSION: Increased BMI was related with discrete electrocardiographic alterations including an increased P-wave duration, increased P-wave balance, a leftward shift of the heart axis, and decreased Sokolow-Lyon voltage on a standard twelve lead electrocardiogram in healthy young individuals with a normal BMI.

Stereophotogrammetric three-dimensional photography is an accurate and precise planimetric method for the clinical visualization and quantification of human papilloma virus-induced skin lesions.

BACKGROUND: The quantification of human papilloma virus (HPV)-induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical assessments that measure dimensions of lesions using a caliper do not provide complete insight into three-dimensional (3D) lesions, and its inter-rater variability is often poor. OBJECTIVE: The aim of this study was to validate a stereophotogrammetric 3D camera system for the quantification of HPV-induced lesions. METHODS: The camera system was validated for accuracy, precision and interoperator and inter-rater variability. Subsequently, 3D photographs were quantified and compared to caliper measurements for clinical validation by Bland-Altman modelling, based on data from 80 patients with cutaneous warts (CW), 24 with anogenital warts (AGW) patients and 12 with high-grade squamous intraepithelial lesions of the vulva (vulvar HSIL) with a total lesion count of 220 CW, 74 AGW and 31 vulvar HSIL. RESULTS: Technical validation showed excellent accuracy [coefficients of variation (CV) ≤ 0.68%] and reproducibility (CVs ≤ 2%), a good to excellent agreement between operators (CVs ≤ 8.7%) and a good to excellent agreement between different raters for all three lesion types (ICCs ≥ 0.86). When comparing 3D with caliper measurements, excellent biases were found for diameter of AGW (long diameter 5%), good biases were found for diameter of AGW (short diameter 10%) and height of CW (8%), and acceptable biases were found for the diameter of CW (11%) and vulvar HSIL (short diameter 14%, long diameter 16%). An unfavourable difference between these methods (bias 25%) was found for the assessment of height of AGWs. CONCLUSION: Stereophotogrammetric 3D imaging is an accurate and reliable method for the clinical visualization and quantification of HPV-induced skin lesions.

Number of ECG Replicates and QT Correction Formula Influences the Estimated QT Prolonging Effect of a Drug.

INTRODUCTION: The present analysis addressed the effect of the number of ECG replicates extracted from a continuous ECG on estimated QT interval prolongation for different QT correction formulas. METHODS: For 100 healthy volunteers, who received a compound prolonging the QT interval, 18 ECG replicates within a 3-minute window were extracted from 12-lead Holter ECGs. Ten QT correction formulas were deployed, and the QTc interval was controlled for baseline and placebo and averaged per dose level. RESULTS: The mean prolongation difference was >4 ms for single and >2 ms for triplicate ECG measurements compared with the 18 ECG replicate mean values. The difference was <0.5 ms after 14 replicates. By contrast, concentration-effect analysis was independent of replicate count and also of the QT correction formula. CONCLUSION: The number of ECG replicates impacted the estimated QT interval prolongation for all deployed QT correction formulas. However, concentration-effect analysis was independent of both the replicate number and correction formula.

A randomized controlled proof-of-concept trial of digoxin and furosemide in adults with cutaneous warts.

BACKGROUND: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts. OBJECTIVES: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT. METHODS: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643. RESULTS: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts. CONCLUSIONS: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers.

BACKGROUND: We investigated potential for hypersensitivity reactions after repeated sugammadex administration and explored the mechanism of hypersensitivity. METHODS: In this double-blind, placebo-controlled study (NCT00988065), 448 healthy volunteers were randomised to one of three arms to receive three repeat i.v. administrations of either sugammadex 4 mg kg-1, 16 mg kg-1, or placebo. Primary endpoint was percentage of subjects with hypersensitivity (assessed by an independent adjudication committee). Secondary endpoint of anaphylaxis was classified per Sampson and Brighton criteria. Exploratory endpoints included skin testing, serum tryptase, anti-sugammadex antibodies [immunoglobulin (Ig) E/IgG], and other immunologic parameters. RESULTS: Hypersensitivity was adjudicated for 1/148 (0.7%), 7/150 (4.7%), and 0/150 (0.0%) subjects after sugammadex 4 mg kg-1, 16 mg kg-1, and placebo, respectively. After sugammadex 16 mg kg-1, one subject met Sampson criterion 1 and Brighton level 1 (highest certainty) anaphylaxis criteria; two met Brighton level 2 criteria. After database lock it was determined that certain protocol deviations could have introduced bias in the reporting of hypersensitivity signs/symptoms in a subject subset. Objective laboratory investigations indicated that potential underlying hypersensitivity mechanisms were unlikely to have been activated; the results suggest that most of the observed hypersensitivity reactions were unlikely IgE/IgG-mediated. CONCLUSION: Dose-dependent hypersensitivity or anaphylaxis reactions to sugammadex were observed when administered without prior neuromuscular blocking agent. Laboratory investigations do not suggest prevalent allergen-specific IgE/IgG-mediated immunologic hypersensitivity. Because it could not be fully excluded that estimates of hypersensitivity/anaphylaxis incidence were unbiased, an additional study was conducted to characterise the potential for hypersensitivity reactions and is described in a companion report. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00988065; Protocol number P06042.

Malleostapedotomy with the self-fixing and articulated titanium piston.

OBJECTIVE: To analyze the results of malleostapedotomy performed by applying the self-fixing and articulated titanium piston according to Häusler. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: This study concerns a retrospective analysis of the results of malleostapedotomy with the use of a self-fixing articulated titanium piston in 16 ears of 16 consecutively treated patients between 2005 and 2009. The medical files were used for the acquisition of data on medical and surgical history and to obtain pre- and postoperative audiometry. Diagnosis and outcomes of mainly revision surgeries are presented and compared to the literature. MAIN OUTCOME MEASURES: Effect of (revision) malleostapedotomy by evaluating postoperative audiometry and air-bone gap closure. RESULTS: The postoperative air-bone gap closure was ≤ 10 dB in 9/16 (56%) ears and within ≤ 20 dB in 13/16 (81%) ears. The mean postoperative air-bone gap was 14.3 dB HL (0.5-2.0 kHz) and 17.3 dB HL (0.5-4.0 kHz). Postoperatively, there was no increase in bone conduction thresholds larger than 3 dB (0.5-2.0 kHz) and postoperative dizziness was absent or very limited and transient. CONCLUSIONS: The malleostapedotomy procedure has become surgically less demanding over time by the technical improvements present in the nowadays available pistons. The design of the self-fixing and articulated titanium piston used in the present group of patients allows a safe and straight-forward malleostapedotomy procedure. Present hearing outcomes match with results presented in the literature.

Developing and validating the Cutaneous WARTS (CWARTS) diagnostic tool: a novel clinical assessment and classification system for cutaneous warts.

BACKGROUND: The clinical appearance of cutaneous warts is highly variable and not standardized. OBJECTIVES: To develop and validate a reproducible clinical tool for the standardized assessment of cutaneous warts to distinguish these lesions accurately. METHODS: Nine morphological characteristics were defined and validated regarding intra- and interobserver agreement. Based on literature and semistructured interviews, a systematic dichotomous assessment tool, the Cutaneous WARTS (CWARTS) diagnostic tool was developed. The validation consisted of two independent parts performed with photographs from the recent WARTS-2 trial. In part A, the CWARTS diagnostic tool was tested by 28 experienced physicians who assessed photographs of 10 different warts to investigate interobserver concordance. In part B, morphological characteristics were validated by masked and independent scoring of 299 photographs by six different observers. Part B also entailed reassessment of the photographs after at least 1 week. The primary outcome measurement was the intraclass correlation coefficient (ICC). RESULTS: Presence of black dots (capillary thrombosis) had the greatest ICC (0·85) for interobserver agreement in part A, followed by arrangement (0·65), presence of border erythema (0·64) and sharpness of the border (0·60). In part B, results were similar for interobserver agreement with presence of black dots having the highest ICC (0·68), followed by border erythema (0·64), arrangement (0·58) and colour (0·55). For intraobserver agreement, presence of black dots had the highest agreement (0·70), followed by presence of border erythema (0·694) and colour (0·59). CONCLUSIONS: Wart phenotype can be reliably assessed using the CWARTS diagnostic tool.