Federated electronic data capture (fEDC): Architecture and prototype.

In clinical research as well as patient care, structured documentation of findings is an important task. In many cases, this is achieved by means of electronic case report forms (eCRF) using corresponding information technology systems. To avoid double data entry, eCRF systems can be integrated with electronic health records (EHR). However, when researchers from different institutions collaborate in collecting data, they often use a single joint eCRF system on the Internet. In this case, integration with EHR systems is not possible in most cases due to information security and data protection restrictions. To overcome this shortcoming, we propose a novel architecture for a federated electronic data capture system (fEDC). Four key requirements were identified for fEDC: Definitions of forms have to be available in a reliable and controlled fashion, integration with electronic health record systems must be possible, patient data should be under full local control until they are explicitly transferred for joint analysis, and the system must support data sharing principles accepted by the scientific community for both data model and data captured. With our approach, sites participating in a joint study can run their own instance of an fEDC system that complies with local standards (such as being behind a network firewall) while also being able to benefit from using identical form definitions by sharing metadata in the Operational Data Model (ODM) format published by the Clinical Data Interchange Standards Consortium (CDISC) throughout the collaboration. The fEDC architecture was validated with a working open-source prototype at five German university hospitals. The fEDC architecture provides a novel approach with the potential to significantly improve collaborative data capture: Efforts for data entry are reduced and at the same time, data quality is increased since barriers for integrating with local electronic health record systems are lowered. Further, metadata are shared and patient privacy is ensured at a high level.

Inhibition of SARS-CoV-2 coronavirus proliferation by designer antisense-circRNAs.

Circular RNAs (circRNAs) are noncoding RNAs that exist in all eukaryotes investigated and are derived from back-splicing of certain pre-mRNA exons. Here, we report the application of artificial circRNAs designed to act as antisense-RNAs. We systematically tested a series of antisense-circRNAs targeted to the SARS-CoV-2 genome RNA, in particular its structurally conserved 5'-untranslated region. Functional assays with both reporter transfections as well as with SARS-CoV-2 infections revealed that specific segments of the SARS-CoV-2 5'-untranslated region can be efficiently accessed by specific antisense-circRNAs, resulting in up to 90% reduction of virus proliferation in cell culture, and with a durability of at least 48 h. Presenting the antisense sequence within a circRNA clearly proved more efficient than in the corresponding linear configuration and is superior to modified antisense oligonucleotides. The activity of the antisense-circRNA is surprisingly robust towards point mutations in the target sequence. This strategy opens up novel applications for designer circRNAs and promising therapeutic strategies in molecular medicine.

Methods to study circRNA-protein interactions.

Circular RNAs (circRNAs) have been studied extensively in the last few years, uncovering functional roles in a diverse range of cell types and organisms. As shown for a few cases, these functions may be mediated by trans-acting factors, in particular RNA-binding proteins (RBPs). However, the specific interaction partners for most circRNAs remain unknown. This is mainly due to technical difficulties in their identification and in differentiating between interactors of circRNAs and their linear counterparts. Here we review the currently used methodology to systematically study circRNA-protein complexes (circRNPs), focusing either on a specific RNA or protein, both on the gene-specific or global level, and discuss advantages and challenges of the available approaches.

Personal social capital and self-rated health among middle-aged and older adults: a cross-sectional study exploring the roles of leisure-time physical activity and socioeconomic status.

BACKGROUND: Personal social capital, which refers to the scope and quality of an individual's social networks within a community, has received increasing attention as a potential sociological factor associated with better individual health; yet, the mechanism relating social capital to health is still not fully understood. This study examined the associations between social capital and self-rated health while exploring the roles of leisure-time physical activity (LTPA) and socioeconomic status (SES) among middle-aged and older adults. METHODS: Cross-sectional data were collected from 662 middle-aged and older adults (Mean age: 58.11 ± 10.59 years old) using the Qualtrics survey panel. Personal Social Capital Scale was used to measure bonding and bridging social capital and the International Physical Activity Questionnaire was used to assess LTPA levels. SES was assessed by education and household income levels. Self-rated health was assessed using a single item, by which the participants were categorized into the two groups, having 'good' vs. 'not good' self-rated health. A series of univariate and multivariate logistic regression models were established to examine the independent and adjusted associations of social capital with self-rated health and to test mediating and moderating roles of LTPA and SES, respectively. RESULTS: Bonding and bridging social capital were positively associated with self-rated health (Odds ratios = 1.11 and 1.09; P's < .05, respectively), independent of LTPA that was also significantly associated with greater self-rated health (P-for-linear trends = .007). After adjusting SES, the associations of social capital were significantly attenuated and there was a significant interaction effect by household income (P-for-interaction = .012). Follow-up analyses stratified by household income showed that beneficial associations of social capital with self-rated health were more apparent among the people with low and high levels of household income; yet, LTPA was the stronger predictor of self-rated health among those in the middle class of household income. CONCLUSIONS: Findings suggest that both social capital and LTPA are associated with better self-rated health; yet, these associations vary by SES. The health policymakers should address both social capital and LTPA for enhancing perceived health among aging populations but may need to consider varying SES backgrounds.

INS/GNSS Integration for Aerobatic Flight Applications and Aircraft Motion Surveying.

This paper presents field tests of challenging flight applications obtained with a new family of lightweight low-power INS/GNSS (inertial navigation system/global satellite navigation system) solutions based on MEMS (micro-electro-mechanical- sensor) machined sensors, being used for UAV (unmanned aerial vehicle) navigation and control as well as for aircraft motion dynamics analysis and trajectory surveying. One key is a 42+ state extended Kalman-filter-based powerful data fusion, which also allows the estimation and correction of parameters that are typically affected by sensor aging, especially when applying MEMS-based inertial sensors, and which is not yet deeply considered in the literature. The paper presents the general system architecture, which allows iMAR Navigation the integration of all classes of inertial sensors and GNSS (global navigation satellite system) receivers from very-low-cost MEMS and high performance MEMS over FOG (fiber optical gyro) and RLG (ring laser gyro) up to HRG (hemispherical resonator gyro) technology, and presents detailed flight test results obtained under extreme flight conditions. As a real-world example, the aerobatic maneuvers of the World Champion 2016 (Red Bull Air Race) are presented. Short consideration is also given to surveying applications, where the ultimate performance of the same data fusion, but applied on gravimetric surveying, is discussed.

Superiority of fesoterodine 8 mg vs 4 mg in reducing urgency urinary incontinence episodes in patients with overactive bladder: results of the randomised, double-blind, placebo-controlled EIGHT trial.

OBJECTIVE: To assess the superiority of fesoterodine 8 mg vs 4 mg for improvement in urgency urinary incontinence (UUI) episodes and other diary variables, diary-dry rate (proportion of patients with >0 UUI episodes on baseline diary and 0 UUI episodes on post-baseline diary), and improvements in measures of symptom bother, health-related quality of life (HRQL), and other patient-reported outcomes (PROs). PATIENTS AND METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, multinational trial of men and women aged ≥18 years with overactive bladder (OAB) symptoms including UUI (ClinicalTrials.gov ID NCT01302067). Patients were randomised (2:2:1) to receive fesoterodine 8 mg, fesoterodine 4 mg, or placebo once daily; those randomised to fesoterodine 8 mg started with fesoterodine 4 mg once daily for 1 week, then 8 mg once daily for the remaining 11 weeks. Patients completed bladder diaries at baseline and weeks 4 and 12 and the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. The primary endpoint was change from baseline to week 12 in UUI episodes per 24 h. RESULTS: At week 12, patients receiving fesoterodine 8 mg (779 patients) had significantly greater reductions from baseline in UUI episodes, micturitions, and urgency episodes than patients receiving fesoterodine 4 mg (790) or placebo (386); diary-dry rate was significantly higher in the fesoterodine 8-mg group vs the fesoterodine 4-mg and placebo groups (all P < 0.05). At week 12, patients receiving fesoterodine 8 mg also had significantly greater improvements in scores on the PPBC, UPS, and all OAB-q scales and domains than patients receiving fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving fesoterodine 4 mg had significantly greater improvements in UUI episodes, urgency episodes, and micturitions; significantly higher diary-dry rates; and significantly greater improvement in PPBC scores and OAB-q scores than patients receiving placebo (all P < 0.05). Dry mouth was the most commonly reported adverse event (AE) in the fesoterodine groups (placebo group, 3.4%; fesoterodine 4-mg group, 12.9%; fesoterodine 8-mg group, 26.1%); most cases were mild or moderate in all treatment groups. Rates of serious AEs and discontinuations due to AEs were low in all groups. CONCLUSIONS: In a 12-week, prospectively designed, superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy vs fesoterodine 4 mg and placebo, as measured by reductions in UUI episodes and other diary variables, diary-dry dry rate, and improvements in measures of symptom bother, HRQL, and other PROs; clear evidence of dose-dependent efficacy is unique to fesoterodine among antimuscarinics and other oral agents for the treatment of OAB. Fesoterodine 4 mg was significantly more effective than placebo on all outcomes except for improvements in UPS scores. These data support the benefit of having two doses of fesoterodine in clinical practice, with the recommended starting dose of 4 mg for all patients and the fesoterodine 8-mg dose available for patients who require a higher dose to achieve optimal symptom relief.

Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies.

OBJECTIVES: Nocturia is prevalent and bothersome in men with lower urinary tract symptoms suggestive of BPH (LUTS/BPH). α-Adrenoceptor antagonists without subtype selectivity have inconsistently shown significant effects on nocturia in these patients. We explored the effects of the α1A-adrenoceptor subtype-selective antagonist silodosin on nocturia by analyzing three placebo-controlled registration studies. METHODS: Responses to question 7 of the IPSS questionnaire were analyzed for the entire study population and patients with ≥ 2 voids/night at baseline. Improvement/worsening rates for nocturia were calculated for once-daily silodosin 8 mg and placebo. Silodosin effects on the mean number of nocturnal voids were compared with placebo, and the number of patients in whom nocturia was reduced to <2 times was calculated. RESULTS: In total, 1,479 men were treated with silodosin or placebo; 1,266 men (85 %) had ≥ 2 voids/night at baseline. Compared to placebo, more men treated with silodosin reported about nocturia improvement (53.4 vs. 42.8 %, p < 0.0001) and fewer patients about worsening (9.0 vs. 14.3 %, p < 0.0001). Silodosin significantly reduced nocturia within each study and pooled cohort compared to placebo (p < 0.001). In men with ≥ 2 nocturnal voids at baseline, 61 and 49 % of patients with silodosin and placebo had reductions of ≥ 1 voids/night, respectively (p = 0.0003), and significantly more patients with silodosin had <2 nocturia episodes at study end compared to placebo (29.3 vs. 19.0 %; p = 0.0002). CONCLUSIONS: Although a weak impact on nocturia is already known from α-adrenoceptor antagonists without subtype selectivity, the individual placebo-controlled studies and the pooled data analysis showed that the α1A-adrenoceptor subtype-selective antagonist silodosin consistently and significantly improves nocturia in men with LUTS/BPH.

Lack of Consensus on the Definition of Aseptic Loosening in Total Ankle Replacement: A Narrative Systematic Review.

Background: Aseptic loosening is one of the most common modes of failure of total ankle replacement (TAR). However, a precise definition of aseptic loosening is still lacking. This systematic review aimed to identify the variations of applied definitions and offer insights into the lack of consensus. Methods: Human studies reporting aseptic loosening of TAR published in peer-reviewed journals within the last decade were considered. The search strategy involved specific terms in Embase, MEDLINE ALL, and the Cochrane Library. Variations in aseptic loosening definitions were analysed. Results: Of 767 studies, 88 were included in this study. Only nine studies precisely defined aseptic loosening with significant variations. Twenty-two studies referenced the term and fifty-seven reported it as a complication but neither defined nor referenced it. Conclusions: Significant uncertainty exists regarding the universal definition of aseptic loosening of TAR, and many variations occur in terms of the assessment approach and criteria.

Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder.

OBJECTIVE: To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men. SUBJECTS AND METHODS: Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed. Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h. Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo. Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the 'diary-dry' rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary). The primary endpoint was the change from baseline to week 12 in UUI episodes. RESULTS: At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n = 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005). Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001). In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04). The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%). Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%). CONCLUSION: This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women. In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

Pudendal nerve block in HDR-brachytherapy patients: do we really need general or regional anesthesia?

PURPOSE: In male patients, the pudendal block was applied only in rare cases as a therapy of neuralgia of the pudendal nerve. We compared pudendal nerve block (NPB) and combined spinal-epidural anesthesia (CSE) in order to perform a pain-free high-dose-rate (HDR) brachytherapy in a former pilot study in 2010. Regarding this background, in the present study, we only performed the bilateral perineal infiltration of the pudendal nerve. METHODS: In 25 patients (71.8 ± 4.18 years) suffering from a high-risk prostate carcinoma, we performed the HDR-brachytherapy with the NPB. The perioperative compatibility, the subjective feeling (German school marks principle 1-6), subjective pain (VAS 1-10) and the early postoperative course (mobility, complications) were examined. RESULTS: All patients preferred the NPB. There was no change of anesthesia form necessary. The expense time of NPB was 10.68 ± 2.34 min. The hollow needles (mean 24, range 13-27) for the HDR-brachytherapy remained on average 79.92 ± 12.41 min. During and postoperative, pain feeling was between 1.4 ± 1.08 and 1.08 ± 1.00. A transurethral 22 French Foley catheter was left in place for 6 h. All patients felt the bladder catheter as annoying, but they considered postoperative mobility as more important as complete lack of pain. The subjective feeling was described as 2.28 ± 0.74. Any side effects or complications did not appear. CONCLUSIONS: Bilateral NPB is a safe and effective analgesic option in HDR-brachytherapy and can replace CSE. It offers the advantage of almost no impaired mobility of the patient and can be performed by the urologist himself. Using transrectal ultrasound guidance, the method can be learned quickly.

Biomechanical comparison of metatarsal head designs in first metatarsophalangeal joint arthroplasty.

BACKGROUND: Arthritis of the metatarsophalangeal (MTP) joint is characterized by loss of MTP joint range of motion (ROM) and pain. Joint arthroplasty is one treatment option, and while results can be satisfactory, there is still room for improvement. The aim was to use cadaveric model to compare the sagittal kinematics and articulating contact properties of 4 different first metatarsal head designs of an MTP joint implant. METHODS: Six cadaveric feet were each prepared with a single modular first MTP joint total arthroplasty. A standard cyclic load, which induced hallux dorsiflexion, was applied and motion measured from high resolution images. Contact behavior was collected simultaneously using a pressure transducer. Data collected compared the native joint with 4 different reconstructed cases. Each reconstructed joint used a different metatarsal-head-component while reusing the same phalangeal component to compare the 4 alternative metatarsal head designs. RESULTS: All reconstructed joints displayed greater ROM compared with the intact joint. Of the 4 metatarsal head components, the grooved, anatomical design demonstrated the greatest dorsiflexion when compared to the standard design, 31.6 degrees (SD ± 8.6 degrees), P < .05. All reconstructed joints displayed contact areas lower than the intact (~50%, P < .001). The grooved metatarsal-head-component experienced the least contact force (P < .015), and the eccentric component underwent the greatest contact pressure (P < .05) when compared to the intact case. CONCLUSIONS: In this study of a first metatarsophalangeal joint replacement design, ROM was shown to be better for the more anatomically designed metatarsal head, while contact properties did not vary across different designs. CLINICAL RELEVANCE: This information may be useful in the development of new metatarsal components.

Orthovoltage X-ray Minibeam Radiation Therapy for the Treatment of Ocular Tumours-An In Silico Evaluation.

(1) Background: Radiotherapeutic treatments of ocular tumors are often challenging because of nearby radiosensitive structures and the high doses required to treat radioresistant cancers such as uveal melanomas. Although increased local control rates can be obtained with advanced techniques such as proton therapy and stereotactic radiosurgery, these modalities are not always accessible to patients (due to high costs or low availability) and side effects in structures such as the lens, eyelids or anterior chamber remain an issue. Minibeam radiation therapy (MBRT) could represent a promising alternative in this regard. MBRT is an innovative new treatment approach where the irradiation field is composed of multiple sub-millimetric beamlets, spaced apart by a few millimetres. This creates a so-called spatial fractionation of the dose which, in small animal experiments, has been shown to increase normal tissue sparing while simultaneously providing high tumour control rates. Moreover, MBRT with orthovoltage X-rays could be easily implemented in widely available and comparably inexpensive irradiation platforms. (2) Methods: Monte Carlo simulations were performed using the TOPAS toolkit to evaluate orthovoltage X-ray MBRT as a potential alternative for treating ocular tumours. Dose distributions were simulated in CT images of a human head, considering six different irradiation configurations. (3) Results: The mean, peak and valley doses were assessed in a generic target region and in different organs at risk. The obtained doses were comparable to those reported in previous X-ray MBRT animal studies where good normal tissue sparing and tumour control (rat glioma models) were found. (4) Conclusions: A proof-of-concept study for the application of orthovoltage X-ray MBRT to ocular tumours was performed. The simulation results encourage the realisation of dedicated animal studies considering minibeam irradiations of the eye to specifically assess ocular and orbital toxicities as well as tumour response. If proven successful, orthovoltage X-ray minibeams could become a cost-effective treatment alternative, in particular for developing countries.

TrustNShare: Development of a Blockchain-Based Data Trust Model for Secure and Controlled Health Data Sharing Grounded on Empirical Research.

Ensuring data quality and protecting data are key requirements when working with health-related data. Re-identification risks of feature-rich data sets have led to the dissolution of the hard boundary between data protected by data protection laws (GDPR) and anonymized data sets. To solve this problem, the TrustNShare project is creating a transparent data trust that acts as a trusted intermediary. This allows for secure and controlled data exchange, while offering flexible datasharing options, considering trustworthiness, risk tolerance, and healthcare interoperability. Empirical studies and participatory research will be conducted to develop a trustworthy and effective data trust model.

What does high value care for musculoskeletal conditions mean and how do you apply it in practice? A consensus statement from a research network of physiotherapists in New South Wales, Australia.

OBJECTIVES: To develop a physiotherapist-led consensus statement on the definition and provision of high-value care for people with musculoskeletal conditions. DESIGN: We performed a three-stage study using Research And Development/University of California Los Angeles Appropriateness Method methodology. We reviewed evidence about current definitions through a rapid literature review and then performed a survey and interviews with network members to gather consensus. Consensus was finalised in a face-to-face meeting. SETTING: Australian primary care. PARTICIPANTS: Registered physiotherapists who are members of a practice-based research network (n=31). RESULTS: The rapid review revealed two definitions, four domains of high value care and seven themes of high-quality care. Online survey responses (n=26) and interviews (n=9) generated two additional high-quality care themes, a definition of low-value care, and 21 statements on the application of high value care. Consensus was reached for three working definitions (high value, high-quality and low value care), a final model of four high value care domains (high-quality care, patient values, cost-effectiveness, reducing waste), nine high-quality care themes and 15 statements on application. CONCLUSION: High value care for musculoskeletal conditions delivers most value for the patient, and the clinical benefits outweigh the costs to the individual or system providing the care. High-quality care is evidence based, effective and safe care that is patient-centred, consistent, accountable, timely, equitable and allows easy interaction with healthcare providers and healthcare systems.

Central venous port implantations via the cephalic vein applying an intravasal electrographic control of the catheter tip position: a single-center experience of 316 cases.

PURPOSE: The aim of this study was the analysis of the feasibility and complication rate of central venous port implantation with the surgical cut-down technique applying an intravasal electrographic control of the catheter tip position performed by urologists. PATIENTS AND METHODS: In the time from December 1999 to November 2010, implantation of 324 subcutaneously implanted venous port systems (NuPort-System) has been performed in 316 patients, 221 men (mean age 59.5 years, range 11-87 years) and 95 women (mean age 57.6 years, range 7-85 years). Two hundred and fifty-nine (79.9%) port systems were placed under electrographic control of the catheter tip position. Duration of procedure, long-term device function, and complications such as infections, occlusions, dislocations, and thrombosis were all retrospectively measured and recorded until removal of the device, patient's death or the last known recorded documentation. RESULTS: In total, 359 devices have been used in 348 surgical procedures, 324 implantations (90.25%), and 35 explantations (9.75%). Port systems were implanted using the cephalic vein in 275 patients (84.9%), and in 49 (15.1%), the subclavian vein was used for insertion of the catheter. Mean surgical implantation time was 38.8 min (15-85 min). The median follow-up was 490.6 days (range 2-2,568); 159,764 catheter days (mean, 234 days, range 2-2,604) were documented. Of 35 explanted devices, the explantation was necessary due to complications in 28 cases (8.6%) with infection n = 6 (1.9%, 0.037 per 1,000 catheter days), occlusion n = 8 (2.5%, 0.050 per 1,000 catheter days), dislocation n = 7 (2.2%, 0.044 per 1,000 catheter days), deep vein thrombosis of the upper extremity n = 6 (1.9%, 0.037 per 1,000 catheter days), and clotting n = 1 (0.3%, 0.006 per 1,000 catheter days). Premature catheter removal (<30d post-operatively) was required in 6 patients (1.9%, 0.037 per 1,000 catheter days) due to complications: 3 catheter dislocations/malfunctions (0.9%, 0.019 per 1,000 catheter days), one port related infection, one pocket port infection, and one deep vein thrombosis of the upper extremity (0.3%, 0.006 per 1,000 catheter days). CONCLUSIONS: The intra-atrial ECG techniques to judge correct tip positioning for central venous port implantations are simple and economical. The exact position can be determined intraoperatively. It can justify a delayed postoperative chest X-ray to confirm CVC line tip placement. Nevertheless, the procedure and handling of the device later on has to be performed with care in order to avoid infections and technical problems.

Technical aspects of proton minibeam radiation therapy: Minibeam generation and delivery.

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that combines the normal tissue sparing of sub-millimetric, spatially fractionated beams with the improved ballistics of protons. This may allow a safe dose escalation in the tumour and has already proven to provide a remarkable increase of the therapeutic index for high-grade gliomas in animal experiments. One of the main challenges in pMBRT concerns the generation of minibeams and the implementation in a clinical environment. This article reviews the different approaches for generating minibeams, using mechanical collimators and focussing magnets, and discusses the technical aspects of the implementation and delivery of pMBRT.

What Are Realistic Expectations to Become Free of Overactive Bladder Symptoms? Experience from Non-interventional Studies with Propiverine.

INTRODUCTION: Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting. METHODS: Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution. RESULTS: The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials. CONCLUSION: These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.

Unmet expectations are a major reason why patients with overactive bladder syndrome discontinue treatment. To enable evidence-based counselling of patients on realistic expectations, we have determined the chance that patients with overactive bladder become free of urgency, incontinence, voiding frequency, and nocturia. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. The probability of becoming symptom-free was largest for incontinence and voiding frequency (about 50%), but lesser for urgency and nocturia (about 20%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.

Combining FLASH and spatially fractionated radiation therapy: The best of both worlds.

FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new therapeutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. With the therapeutic potential having been established separately for each technique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future.

Early onset of fesoterodine efficacy in subjects with overactive bladder.

OBJECTIVE: To assess the onset of efficacy of fesoterodine 4 mg once daily on overactive bladder (OAB) symptoms after 1 week of treatment. PATIENTS AND METHODS: This was a prespecified analysis of data collected during the first week of a 12-week, open-label, single-arm, flexible-dose study of fesoterodine. Eligible subjects were adult men and women (aged ≥ 18 years) who reported urinary frequency (eight or more micturitions per 24 h) and urgency (three or more episodes per 24 h) in 5-day bladder diaries at baseline, and dissatisfaction with previous tolterodine or tolterodine extended-release treatment received within 2 years of screening. All subjects received fesoterodine 4 mg once daily during the first 4 weeks of treatment (with an optional dose increase to fesoterodine 8 mg after week 4). Early onset of efficacy of fesoterodine 4 mg was assessed based on changes from baseline to week 1 in variables recorded in 5-day bladder diaries, including total micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes and nocturnal micturitions. Urgency and severe urgency episodes were defined as those rated ≥ 3 and ≥ 4, respectively, on the five-point Urinary Sensation Scale (USS) (1 = no urgency, 5 = UUI); frequency-urgency sum (a combined measure of micturition frequency and urgency) was defined as the sum of all USS ratings. RESULTS: All bladder diary variables, including total and nocturnal micturitions, UUI episodes, urgency episodes, severe urgency episodes and frequency-urgency sum per 24 h, were significantly improved (all P < 0.0001) after 1 week of treatment with fesoterodine 4 mg compared to baseline. The diary-dry rate at week 1 (i.e. subjects with at least one UUI episode at baseline who subsequently reported no UUI episodes on week 1 diary) was 38%. CONCLUSION: In this open-label study of subjects with OAB who had been previously treated and dissatisfied with tolterodine, fesoterodine 4 mg showed a rapid onset of efficacy at 1 week.

Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective, head-to-head, placebo-controlled trial.

OBJECTIVE: • To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo-controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient-reported outcomes. MATERIALS AND METHODS: • In this 12-week, double-blind, double-dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. • Subjects completed 3-day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12. RESULTS: • A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). • Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. • Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively. CONCLUSIONS: • In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self-reported patient assessments of bladder-related problems, urgency, symptom bother and health-related quality of life. • The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER.