Safety Assessment Studies Research Articles

A New Evidential Reasoning Rule-Based Safety Assessment Method With Sensor Reliability for Complex Systems.

In current studies of safety assessment for complex systems with the evidential reasoning (ER) rule, the evidence reliability is generally given by experts, which makes the observation data by sensors ignored. However, sensors are inevitably affected by such various uncertainties as perturbations in engineering practice, which can reduce their quality and tracking ability. As such, the observation data may become unreliable, and the modeling accuracy of the ER rule is decreased. In this article, a new ER rule-based safety assessment method with sensor reliability for complex systems is proposed, where sensor reliability and perturbation are considered. The coefficient of the variation-based weighting (CVBW) method is employed to obtain sensor weight. The sensor reliability is calculated by static reliability and dynamic reliability, which are determined by experts and the distance-based method, respectively. The perturbation is quantified as a bounded parameter defined as the perturbation factor, which is used to describe uncertainties and aggregate static reliability and dynamic reliability. The performance analysis of safety assessment is conducted to demonstrate the rationality of perturbation and position poor sensors, followed by a safety assessment algorithm. A case study is carried out to validate the effectiveness of the proposed method.

Evaluation of Cell Proliferation in Rat Mammary Glands Is Not Predictive of the Carcinogenic Potential of Insulin In Vivo.

For nonclinical safety-assessment of insulin analogues in vivo, mitogenic effects are compared to that of human insulin. Besides histopathologic evaluation, this usually includes assessment of cell proliferation (CP) in mammary glands. Insulin analogue X10 is recommended as positive control, due to its known carcinogenic effect in rat mammary glands. Here, we discuss the mitogenic effect of insulin in vivo and use of X10 as positive control. We present results from 4 nonclinical rat studies evaluating effects of repeated dosing with insulin detemir (≤26 weeks) or degludec (52 weeks) in mammary glands. Studies included human insulin-dosed groups as comparators, CP, and histopathologic evaluation. One study included an X10-dosed group (26 weeks), another ≤3 weeks of dosing with X10 or human insulin evaluating effects of these comparators. Neither human insulin, insulin detemir, degludec, nor X10 induced mammary tumors or increased CP in the studies. The CP marker proliferating cell nuclear antigen varied within/between studies and was not correlated with the remaining markers or CP fluctuations during estrous cycle, whereas the other CP markers, Ki-67 and 5-bromo-2'-deoxyuridine (BrdU), correlated with estrous cycle changes and each other. In conclusion, we propose that the mitogenic effect of insulin in rat mammary glands is weak in vivo. Cell proliferation evaluation in nonclinical safety assessment studies is not predictive of the carcinogenic potential of insulin, thus, the value of including this end point is debatable. Moreover, X10 is not recommended as positive control, due to lack of proliferative effects. Typical CP markers vary greatly in quality, BrdU seemingly most reliable.

Emergency department safety assessment and follow-up evaluation 2: An implementation trial to improve suicide prevention

BackgroundEmergency departments (EDs) are important for preventing suicide. Historically, many patients with suicide risk are not detected during routine clinical care, and those who are often do not receive suicide-specific intervention. The original Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE 1) study examined the implementation of universal suicide risk screening and a multi-component ED-initiated suicide prevention intervention. PurposeThe ED-SAFE 2 aims to study the impact of using a continuous quality improvement approach (CQI) to improve suicide related care, with a focus on improving universal suicide risk screening in adult ED patients and evaluating implementation of a new brief intervention called the Safety Planning Intervention (SPI) into routine clinical practice. CQI is a quality management process that uses data and collaboration to drive incremental, iterative improvements. The SPI is a personalized approach that focuses on early identification of warning signs and execution of systematic steps to manage suicidal thoughts. ED-SAFE 2 will provide data on the effectiveness of CQI procedures in improving suicide-related care processes, as well as the impact of these improvements on reducing suicide-related outcomes. MethodsUsing a stepped wedge design, eight EDs collected data cross three study phases: Baseline (retrospective), Implementation (12 months), and Maintenance (12 months). Lean methods, a specific approach to pursuing CQI which focuses on increasing value and eliminating waste, were used to evaluate and improve suicide-related care. ConclusionsThe results will build upon the success of the ED-SAFE 1 and will have a broad public health impact through promoting better suicide-related care processes and improved suicide prevention.

Upscaling of radionuclide transport and retention in crystalline rocks exhibiting micro-scale heterogeneity of the rock matrix

In different in-situ diffusion experiments carried out in fractured crystalline rocks, sorbing radionuclides have shown a behaviour that strongly differs from what is predicted by homogeneous-based models. Their breakthrough curves are in fact often characterised by a fast first-arrival and these radionuclides can penetrate surprisingly long distances deep into the matrix. The heterogeneous structure of mineral distribution and porosity geometry had been offered as an explanation for these discrepancies. Here, we use reactive transport simulations to investigate the effect of the sparse distribution of sorption sites on the breakthrough curves of sorbing radionuclides. At small scale, the computed breakthrough curves significantly differ from those predicted using homogeneous models. For instance, the early part of these curves does not show any clear separation with the corresponding part of the curve of a non-sorbing tracer and a long transition zone is observed, with a very smooth slope of the tailing. Two different upscaling strategies, aimed at propagating the signal of heterogeneous retention over larger scales, are proposed and demonstrated against independent solutions computed at intermediate scales. The upscaling strategies are also used to show that at large scales (e.g. the scale of interest in a safety assessment study for a deep geological repository for nuclear waste) the signature of mineralogical heterogeneity is smoothed out and the heterogeneous breakthrough curve is well approximated by a homogeneous solution where the radionuclide distribution coefficient for the pure mineral phase is scaled by the mineral volume fraction. However, the spatial persistence of the heterogeneous signature is significant when the sorbing mineral is present in a low amount.

Recent Progress of Oridonin and Its Derivatives for the Treatment of Acute Myelogenous Leukemia.

First stage human clinical trial (CTR20150246) for HAO472, the L-alanine-(14-oridonin) ester trifluoroacetate, was conducted by a Chinese company, Hengrui Medicine Co. Ltd, to develop a new treatment for acute myelogenous leukemia. Two patents, WO2015180549A1 and CN201410047904.X, covered the development of the I-type crystal, stability experiment, conversion rate research, bioavailability experiment, safety assessment, and solubility study. HAO472 hewed out new avenues to explore the therapeutic properties of oridonin derivatives and develop promising treatment of cancer originated from naturally derived drug candidates. Herein, we sought to overview recent progress of the synthetic, physiological, and pharmacological investigations of oridonin and its derivatives, aiming to disclose the therapeutic potentials and broaden the platform for the discovery of new anticancer drugs.

Scientific Regulatory Policy Committee Points to Consider*: Nuisance Factors, Block Effects, and Batch Effects in Nonclinical Safety Assessment Studies

Detection of test article-related effects and the determination of the adversity of those changes are the primary goals of nonclinical safety assessment studies for drugs and chemicals in development. During these studies, variables that are not of primary interest to investigators may change and influence data interpretation. These variables, often referred to as "nuisance factors," may influence other groups of data and result in "block or batch effects" that complicate data interpretation. Definitions of the terms "nuisance factors," "block effects," and "batch effects," as they apply to nonclinical safety assessment studies, are reviewed. Multiple case examples of block and batch effects in safety assessment studies are provided, and the challenges these bring to pathology data interpretation are discussed. Methods to mitigate the occurrence of block and batch effects in safety assessment studies, including statistical blocking and utilization of study designs that minimize potential confounding variables, incorporation of adequate randomization, and use of an appropriate number of animals or repeated measurement of specific parameters for increased precision, are reviewed. [Box: see text].

Study of probabilistic safety assessment for a reprocessing plant

According to China’s nuclear power development plan, the demand for construction of more large-scale spent fuel reprocessing plant (RP) is increased. Nuclear safety is very important in the whole process of nuclear fuel cycle, and the safety supervision of RPs mainly draws lessons from the safety supervision of nuclear power plants (NPPs). The industry had come to realize that it could not eliminate all risks through its defense-in-depth principle and design basis accident methodologies. All nuclear power countries with advanced reprocessing industry such as the United Kingdom, France and Japan have carried out probabilistic safety assessment (PSA) research for RPs. This paper takes Chinese pilot RP as the research object. First, failure mode and effect analysis (FMEA) and master logic diagram (MLD) methodologies were adopted to identify initiating events (IEs), and then IEs were grouped. After that, fault tree (FT) analysis was performed to various accidents - red oil explosion, fire and criticality. Reliabilities of public systems - power and water and compressed air supply systems were modelled and analysed with GO methodology. And then, consequences of typical accidents were assessed. Finally, application of risk-informed technology in the reprocessing facility was investigated. In brief, PSA for a pilot RP was explored in this paper, and the results could be used as reference for Chinese commercial RP.

Capsule Based Aerosol Generation – test article conservation during the conduct of in vivo lead optimisation respiratory safety assessment studies

Capsule Based Aerosol Generation – test article conservation during the conduct of in vivo lead optimisation respiratory safety assessment studies

Modeling the Inactivation of Bacillus cereus in Tiger Nut Milk Treated with Cold Atmospheric Pressure Plasma

The impact of cold atmospheric pressure plasma treatment on the inactivation kinetics of Bacillus cereus ATCC 14579 and the resulting quality changes was investigated in tiger nut (Cyperus esculentus L.) milk (TNM). The effect of input power (39, 43, and 46 W) and treatment time (0 to 270 s) was fitted using the Weibull model to represent the microbial kinetic inactivation in the treated TNM. Inactivation efficacy increased with an increase in treatment time and input power. A 5.28-log reduction was achieved at 39 to 46 W without significant changes in titratable acidity, whereas no reduction in titratable acidity was observed in the pasteurized sample. The inactivation kinetics was adequately described by the Weibull model. Higher input power of 43 and 46 W and 120 s of treatment resulted in marked decreases in pH, flavonoid concentration, and antioxidant activity compared with those parameters in pasteurized TNM. Increases in total color difference and phenolic concentrations also were observed. The results indicate that these changes were caused by the immanent plasma reactive species. This study provides valuable inactivation kinetics information for food safety assessment studies of B. cereus vegetative cells in TNM.

Transport dynamic of strontium in groundwater: Safety Assessment study

One of the activities of the Safety Assessment is the evaluation of the impact of a nuclear facility on the environment. The radionuclide transport into groundwater is subjected to different phenomena (e.g. groundwater dynamic, surface stream dynamic, the interaction between surface water and groundwater, radionuclide interaction with environmental matrix, etc.) that influence the risk of contamination of water. The investigation of the source term is fundamental to understand its impact on radionuclide transport. In this paper, in situ surveys and modelling were coupled to investigate the dynamic of strontium in an Italian nuclear site. On-site measurements have identified low quantities of strontium in monitoring wells, and through the modelling, the possible migration pathway of this radionuclide was identified. For a primary safety evaluation purpose, a parametric detailed analysis was carried out to identify which hydrogeological parameters and which artificial structure present in the area could influence the dynamic of strontium in the investigated site. In particular, the effect of the Cavour artificial channel on the strontium migration and dilution was demonstrated. The coupling of monitoring activities, periodically performed in the area, and the modelling activities, focused on the detailed relationships between the Cavour artificial channel and the underground water flow, contributes to better evaluate the possible radiological risk for population and environment and to support future safety studies.

SC94 - Vacuum physiotherapy after first stage buccal mucosa graft (BMG) urethroplasty in proximal hypospadias: A feasibility, safety and protocol compliance assessment study

SC94 - Vacuum physiotherapy after first stage buccal mucosa graft (BMG) urethroplasty in proximal hypospadias: A feasibility, safety and protocol compliance assessment study

Screening and Intervention for Suicide Prevention: A Cost-Effectiveness Analysis of the ED-SAFE Interventions.

Suicide screening followed by an intervention may identify suicidal individuals and prevent recurring self-harm, but few cost-effectiveness studies have been conducted. This study sought to determine whether the increased costs of implementing screening and intervention in hospital emergency departments (EDs) are justified by improvements in patient outcomes (decreased attempts and deaths by suicide). The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) study recruited participants in eight U.S. EDs between August 2010 and November 2013. The eight sites sequentially implemented two interventions: universal screening added to treatment as usual and universal screening plus a telephone-based intervention delivered over 12 months post-ED visit. This study calculated incremental cost-effectiveness ratios and cost-effectiveness acceptability curves to evaluate screening and suicide outcome measures and costs for the two interventions relative to treatment as usual. Costs were calculated from the provider perspective (e.g., wage and salary data and rental costs for hospital space) per patient and per site. Average per-patient costs to a participating ED of universal screening plus intervention were $1,063 per month, approximately $500 more than universal screening added to treatment as usual. Universal screening plus intervention was more effective in preventing suicides compared with universal screening added to treatment as usual and treatment as usual alone. Although the choice of universal screening plus intervention depends on the value placed on the outcome by decision makers, results suggest that implementing such suicide prevention measures can lead to significant cost savings.

Higher Educational Attainment is Associated with Lower Risk of a Future Suicide Attempt Among Non-Hispanic Whites but not Non-Hispanic Blacks.

In a sample of patients presenting to the emergency department (ED), the current study was conducted with two aims: (1) to investigate the protective effects of educational attainment (i.e., completing college) on subsequent risk of suicide attempt/death among patients presenting to the ED and (2) to compare this effect between non-Hispanic Black and non-Hispanic White ED patients. The current study analyzed data from the Emergency Department Safety Assessment and Follow-Up Evaluation (ED-SAFE) study, a quasi-experimental, eight-center study of universal suicide screening and follow-up of ED patients presenting for suicidal ideation and behavior. Our sample included 937 non-Hispanic White and 211 non-Hispanic Blacks. The dependent variable was suicide attempt/death during the 52-week follow-up. The independent variable was completing college. Age, gender, lesbian/gay/bisexual status, psychiatric history, and previous suicide attempts at baseline were covariates. Race/ethnicity was the focal effect modifier. Logistic regression models were used to test the protective effects of educational attainment on suicide risk in the overall sample and by race/ethnicity. In the overall sample, educational attainment was not associated with suicide risk over the follow-up period. A significant interaction was found between race/ethnicity and educational attainment on suicide risk, suggesting a larger protective effect for non-Hispanic Whites compared with non-Hispanic Blacks. In race/ethnicity-specific models, completing college was associated with decreased future suicide risk for non-Hispanic Whites but not Blacks. Consistent with the Minorities' Diminished Return theory, educational attainment better protected non-Hispanic White than non-Hispanic Blacks against future suicide attempt/death. While Whites who have not completed college may be at an increased risk of suicide, risk of suicide seems to be independent of educational attainment for non-Hispanic Blacks.

Abstract 1300: Novel thyrointegrin αvβ3 antagonist in the treatment of glioblastoma multiforme

Abstract Background: The proliferative and pro-angiogenic actions mediated by L-thyroxine, pro-inflammatory and all known growth factors in glioblastoma multiforme (GBM) are initiated at cell surface thyrointegrin αvβ3 receptors for thyroid hormone on the extracellular domain of integrin αvβ3. Thyrointegrin αvβ3 receptors are over-expressed on cancer and rapidly dividing blood vessel cells, but quiescent on normal cells. A macromolecule Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) acts with high affinity (Ki 3.1 nM) and specificity for the thyrointegrin αvβ3 receptors without any significant nuclear translocation. Methods: In the present studies, three primary human GBM cells and U87 glioma cell line were implanted orthotopically or subcutaneously (s.c.) into nude mice that were treated daily for up to 21 days with P-bi-TAT at different doses. Additionally, preclinical Pharmacokinetic and Safety assessments were carried out in multiple species. Results: Pharmacokinetic profiles indicated once-a-day dosing, and safety assessment studies demonstrated high safety and tolerability at 100-fold over the anticipated human equivalent dose. Fluorescence labeled P-bi-TAT administered s.c. demonstrated high biodistribution to GBM tumor in the brain that was comparable to peripherally implanted tumor. P-bi-TAT administered daily for 10-21 days s.c. at 0.3-10 mg/kg resulted in a dose-dependent suppression of GBM tumor growth and viability monitored with IVIS imaging (p <0.001). Histopathological analysis of tumors revealed 95% loss of the vascularity of treated tumors at 10 days (p <0.001) along with extensive cellular necrosis and apoptosis, without intratumoral hemorrhage. GBM tumors had a 97% volume loss and maximal loss of GBM cell viability during a subsequent 22 days off-treatment period (p < 0.001). Genomic micro-array studies with human primary GBM revealed that over 30 pathways relevant to the progression of GBM are modulated by P-bi-TAT. Conclusions: P-bi-TAT is a promising lead clinical candidate effective in the treatment of human GBM. Citation Format: Shaker A. Mousa, Thangirala Sudha, Kavitha Godugu, Mehdi Rajabi, Stewart Sell, Paul J. Davis. Novel thyrointegrin αvβ3 antagonist in the treatment of glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1300.

Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products.

CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD-2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism-based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ-12,918 inhibited lens cholesterol biosynthesis (LCB). A 2-day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5-LO inhibitors. Thereafter, this 2-day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl-CoA desaturase-1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH-6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1month.

The IWGT in vitro Mammalian Cell Gene Mutation (MCGM) assays working group—Introductory remarks & consensus statements

Assays for gene mutations in cultured mammalian cells, i.e., Mammalian Cell Gene Mutation (MCGM) assays, are widely used in genetic toxicology laboratories worldwide; over the past four decades they have been commonly employed in safety assessment studies, and studies designed to address hypothesis-driven research questions. Despite many advances in the fields of cellular and molecular biology over the past four decades, the MCGM assays commonly used for regulatory evaluations continue to be those developed in the 1970s, including assays that enumerate induced mutations at the hprt or tk loci of several commonly used cell lines. Consequently, the Steering Committee of the 7th International Workshops on Genotoxicity Testing (IWGT) convened a working group (WG) to critically assess the state-of-the-science in regards to the current and emerging tools for the detection of mutagens using cultured mammalian cells. The WG was divided into four sub-groups that evaluated the state-of- the-science with respect to the: (1) in vitro Pig-a gene mutation assay, (2) in vitro assays based on cells from transgenic rodents, (3) technologies and innovations to improve MCGM assays using TK6 cells, and (4) novel and emerging technologies and approaches for detection and enumeration of gene mutations in mammalian cells. Each of these sub-groups critically reviewed the scientific literature, along with other unpublished data, to develop consensus statements on the status of the test systems in their respective focus areas. These reviews, with their associated consensus statements, are presented in the accompanying works by Bemis and Heflich., White et al., Honma et al., and Evans et al. The MCGM assay WG, in consultation with the entire IWGT, formulated consensus statements regarding the overall utility of MCGM assays for identification and assessment of mutagenic hazard.

A Comprehensive Preclinical Evaluation of Intravenous Etoposide Lipid Emulsion.

Etoposide is one of the principal chemotherapeutic agents used for the treatment of small cell lung cancer (SCLC). There are some disadvantages of currently available etoposide injections (EI) such as low LD50, necessary dilution before clinical application, thus, etoposide lipid emulsion (ELE) was developed and expected to have a comparable or better effect on SCLC. ELE was prepared through high-pressure homogenization method, and a series of evaluations such as encapsulation efficiency (EE%), in vitro release, stability studies, pharmacokinetics study, safety assessment and pharmacodynamic study were systematically performed. ELE had high EE% and good stability. Pharmacokinetics study revealed ELE had a longer T1/2 F compared with EI, which is in agreement with in vitro release in which ELE released slower than EI (EI released over 80% within 12h, while ELE released 50%). Safety tests showed there was no hematology or significant tendency of accumulated toxicity, and LD50 of ELE was higher than EI. Furthermore, percentage of tumor inhibition (TI%) of ELE was comparable with EI in the same dose. Unlike EI, ELE could further increase the dose, which endowed etoposide with a greater potential for cytotoxic agent. LE is a promising delivery system for etoposide.

Physico-chemical characteristics of graphite aerosols generated during postulated air ingress accident

Graphite is used as a structural material, neutron moderator and reflector in some designs of nuclear reactors. The core of a prismatic or pebble bed type High Temperature Reactor (HTR) is also comprised of graphite components. In addition to HTRs, it is also used as a structural material in the Molten Salt Breeder Reactor (MSBR). It’s response to postulated accidental condition is a critical aspect of probabilistic safety assessment studies for such futuristic reactor designs. Generation of graphite aerosol particles has been shown as a possible hazard in the case of an air ingress accident for HTRs. These aerosol particles act as a carrier for radioactive source term and their characteristics decide the impact of accident. This study aims to measure and interpret number and mass characteristics of graphite particles generated by exposing graphite to varying high temperature conditions. An exclusive sophisticated facility is developed, tuned and employed for measuring the aerosol characteristics at extreme temperature and concentration conditions. Apart from measuring number and mass size distributions of generated particles at different temperatures and flows, emission of CO and CO2 was also monitored. Particle concentration and CO gas concentration was found to be maximum at 700 °C, the transition temperature for the generation process. Evaporation-condensation and transport of unburnt carbon particles could be linked to the observed particles in nucleation and accumulation mode size ranges, respectively. Mechanism of particle generation and graphite particle transformation at different temperatures is also discussed.

Exemplification of AC2’s multidimensional capabilities to the application of large pools within the frame of the German EASY project

Realistic numerical predictions of dynamic, complex, multidimensional flow scenarios occurring in light water reactors are vital prerequisites for every reliable safety assessment study. System analysis codes employing only one-dimensional fluid-mechanics models may fail to realistically capture the complex flow conditions in large scale passive components of light water reactors.Even though today’s CFD codes are capable of accurately representing multidimensional flow behaviour, they require huge computational efforts to simulate long-term transients. The German thermal-hydraulic system code (THS) ATHLET (Analysis of Thermal-hydraulics of LEaks and Transients) part of the AC2 simulation environment, is being developed by GRS (Gesellschaft für Anlagen- und Reaktorsicherheit gGmbH) for the analysis of the whole spectrum of operational transients, design-basis accidents and beyond design-basis accidents anticipated for nuclear energy facilities. The code provides a wide range of specific models for several light water reactor designs of Generation II, III+ and IV. Currently, the code’s one-dimensional six-equation two-fluid model, is being extended towards a fully three-dimensional set of thermal-hydraulic conservation equations. Until now ATHLET’s ability to capture multidimensional flow behaviour has mainly been assessed for the flow mixing behaviour in the reactor pressure vessel. Within this work, ATHLET’s capabilities to capture the multidimensional flow behaviour will be assessed for the flow within large scale passive components of light water reactors.These analyses highlight the advantages of ATHLET’s newly developed 3D model for the simulation of large scale passive systems.

562 - Vacuum physiotherapy after first stage buccal mucosa graft (BMG) urethroplasty in proximal hypospadias: A feasibility, safety and protocol compliance assessment study

562 - Vacuum physiotherapy after first stage buccal mucosa graft (BMG) urethroplasty in proximal hypospadias: A feasibility, safety and protocol compliance assessment study