Unacceptable Variation Research Articles

Time–frequency ridge characterisation of sleep stage transitions: Towards improving electroencephalogram annotations using an advanced visualisation technique

Manual sleep stage scoring of polysomnography recordings is an expensive and time-consuming process, further complicated by inconsistent sleep stage agreement among sleep experts (clinicians and sleep technologists). Hence, development of automated sleep scoring algorithms are an emerging topic of interest. Automation typically mimics the clinical decision path by implementing a series of predefined rules, such as the American Academy of Sleep Medicine’s (AASM) scoring manual. Recently, data driven methods have emerged using machine or deep learning. Both manual and automated methods of scoring have known limitations; primarily, unacceptable variation in agreement between different scorers and algorithms. Within the literature, electroencephalogram (EEG) frequency is an important feature considered by both sleep experts and automated approaches for classifying sleep stages.This study presents a novel approach to sleep stage analysis, by developing a methodology to precisely determine the temporal location of sleep stage transitions. The current gold standard fails to identify such transitional changes, which leads to poor inter-scorer reliability. Therefore, development and implementation of such methodologies is a crucial, but overlooked, step in improving the consistency of scoring within sleep studies. In this work, EEG time–frequency ridge analysis was used to characterise the dominant frequency component of EEG signals in time, at the point of sleep stage transition. An in-depth analysis of N3 → N2 and N2 → N3 transitions in the 2018 PhysioNet challenge “You Snooze, You Win” and the Wisconsin Sleep Cohort (WSC) datasets (n = 994, n = 742; approximately 13,888 h of sleep data) showed consistent time–frequency patterns at the point of transition, from one sleep stage to another. This methodology allows simple and ‘interpretable’ features to be generated in future work, to precisely identify the temporal location of sleep stage transitions with the aim of improving inter-scorer reliability.

First Principles Variational Formulation and Analytical Solutions for Third Order Shear Deformable Beams with Simple Supports using Fourier Series Method

The Fourier series method for solving bending problems of third-order shear deformable beams (TSBD) is presented in this paper. The theory accounts for transverse shear deformation and is suitable for moderately thick beams. Transverse shear stress-free conditions are valid at the beam surfaces for TSDB. The field equations are two coupled ordinary differential equations in terms of two unknown displacement functions – transverse deflection w(x) and warping function For simply supported ends considered, the loading and unknown functions w(x) and are represented in Fourier series that satisfies the boundary conditions. The problem is reduced to a system of algebraic equations in terms of the Fourier coefficients wn and which is solved to obtain wn and Axial and transverse displacements fields, axial bending stress and transverse shear stress are then determined for the cases of point load at midspan, uniformly and linearly distributed loads over the span. The results are identical with previous results obtained by other scholars who used Ritz variational methods and other mathematical tools. For moderately thick beams under uniform load with l/h = 4, the results obtained for is 0.516% greater than the exact result by Timoshenko and Goodier while for thick beams under uniform load with l/h = 2, the result for is 1.96% greater than the exact result by Timoshenko and Goodier. Similar acceptable variation was obtained for for beams under linearly distributed load with the variations being less than 2% for l/h = 2. However, unacceptable variations of 68.37% were found for in thick beams under point load, for l/h = 2.0. The variation for however reduced to 12.513% for moderately thick beams under point load for l/h =4.

Repeatability of Scheimpflug-Placido camera in mild dry eye versus normal eyes according to the topographical position of the cornea.

We aimed to investigate the repeatability of various corneal measurements according to topographical location in the entire cornea measured by dual rotating Scheimpflug-Placido camera and to explore the differences in repeatability between patients with mild dry eye and those with normal eyes. In both the normal and dry eye groups, divided based on BUT or the height of the tear film, there were no statistically significant differences in the ratio of unacceptable variation (RUV) and ICC. The consistency of the examination of the anterior and posterior refractive values and corneal thickness according to the corneal location, measured three times repeatedly using the Galilei anterior segment camera, was high. There was no difference based on the height of the tear film or the tear film break-up time. However, caution is needed when interpreting the values of the anterior corneal refractive values, as there can be changes of more than 0.5D within 3mm of the central area.

Optical properties of advanced lithium disilicate.

A variety of firing protocols are available for the IPS e.max lithium disilicate (LD) and can be used for new, 'advanced' LD (ALD). However, the impact of firing protocols on the optical properties of ALD is still unknown. The aim of the present study was to evaluate the color difference (ΔE00), the translucency parameter (TP00) and the whiteness index for dentistry (WID) for both LD glass ceramics after the processes of firing/glazing. Fifty disk-shaped specimens, with a diameter of 10 mm and a thickness of 1.2 mm, were fabricated from IPS e.max CAD (LD; Ivoclar) and another 50 from CEREC Tessera™ (ALD; Dentsply Sirona). The specimens from each group were further divided into 5 subgroups (n = 10) according to the firing/glazing protocol applied: crystallization (c); one-step crystallization and glazing (cg); crystallization and refiring (c-r); two-step crystallization and glazing (c-g); or long-firing crystallization (lfc). The ΔE00, TP00 and WID were assessed. The statistical analysis of ΔE00 was performed using the one-way analysis of variance (ANOVA) and Tukey's post hoc test, while TP00 and WID were analyzed with the two-way ANOVA and Tukey's post hoc test at a statistical significance level of 0.05. The cg groups were designated as the reference. The ANOVA showed that the firing procedures had no effect on ΔE00, TP00 and WID in the case of LD. In addition, LD exhibited greater translucency and brightness as compared to ALD. For ALD, all color changes observed in relation to the reference firing protocol were clinically unacceptable. The ALD specimens which underwent 1 standard firing cycle showed higher TP00 and WID values than other ALD groups. The choice of the firing protocol has no impact on the color, TP00 or WID of LD. Additionally, LD presents higher WID values than ALD, irrespective of the firing protocol used. Alternative firing protocols result in clinically unacceptable color variations when compared to the manufacturer-recommended protocol for ALD. Advanced LD is more sensitive to different firing protocols with regard to its optical properties, which makes the workflow less predictable in comparison with LD.

Enhancing the Robustness of Rib-Groove Filling and Strain Homogeneity in the Isothermal Forging of Titanium Alloy Multi-Rib Components

Isothermal forging stands as an effective technology for the production of large-scale titanium alloy multi-rib components. However, challenges have persisted, including die underfilling and strain concentration due to the complex material flow and heterogeneous deformation within the forging die cavity. While approaches centered on optimized billet designs have mitigated these challenges, uncertainties in process parameters continue to introduce unacceptable variations in forming accuracy and stability. To tackle this issue, this study introduced a multi-objective robust optimization approach for billet design, accounting for the multi-rib eigenstructure and potential uncertainties. The approach includes finite element (FE) modeling for analyzing the die-filling and strain inhomogeneity within the multi-rib eigenstructure. Furthermore, it integrated image acquisition perception and feed back technologies (IAPF) for real-time monitoring of material flow and filling sequences within die rib-grooves, validating the accuracy of the FE modeling. By incorporating dimensional parameters of the billet and uncertainty factors, including friction, draft angle, forming temperature, speed, and deviations in billet and die, quantitative analyses on the rib-groove filling and strain inhomogeneity with fluctuation were conducted. Subsequently, a dual-response surface model was developed for statistical analysis of the cavity filling and strain homogeneity. Finally, the robust optimization was processed using a non-dominated sorting genetic algorithm II (NSGA-II) and validated using the IAPF technologies. The proposed approach enables robust design enhancements for rib-groove filling and strain homogeneity in titanium alloy multi-rib components.

The Australian Dementia Network Registry: A Nationwide Clinical Quality Registry to monitor and improve dementia diagnosis and care

AbstractBackgroundMany Australians live with dementia, yet limited evidence suggests there are unacceptable variations in clinical care. Until now there had been no systematic collection of high‐quality clinical data that benchmarks practice and helps drive improvements.MethodThe Australian Dementia Network (ADNeT) Registry, a clinical quality registry designed to close this gap, recruits sites involved in dementia diagnosis, such as memory clinics, and collects a minimum dataset from clinicians at the time of diagnosis of either dementia or mild cognitive impairment (MCI). The Registry later sends information to patients (and/or caregivers), including on how to withdraw if preferred, and collects co‐designed patient and/or caregiver outcome and experience measures by survey. The Registry oversees data analysis, generates clinical quality indicators (CQIs), and facilitates timely access for providers to this data.ResultCommencing in 2020, ADNeT Registry has so far collected data from 55 clinics, representing all Australian states, including from regional and rural areas, and public and private providers. Data on the 2250 participants to date, 1552 (69%) with dementia and 698 (31%) with MCI, indicates a median time from referral to diagnosis of 126 days. For dementia and MCI, respectively, mean ages (SD) at diagnosis are 78.7(8.7) and 76.8 (8.8) years, and mean MMSE scores are 20.7(5.3) and 26.1 (2.8). The most common dementia subtype diagnosed is Alzheimer’s Disease (76%), whilst the CQIs showing most substantial variation nationally are for cholinesterase prescription and appointment wait‐times. The Registry has an 11% opt‐out rate, receives 48% of patient/caregiver surveys sent, has published three site and one annual report, and continues to grow.ConclusionThe ADNeT Registry’s early experience is that a clinical quality registry for dementia in Australia is feasible to implement and provides value to participating clinicians. We anticipate that, over time, feedback to clinicians and benchmarking of their data compared to their colleagues’ will drive improvements in diagnostic practices and care. Additional Registry attributes, such as facility to enable research study participation, and expansion of dataset to enable uptake and outcome monitoring of new diagnostics and therapeutics, has made it attractive to governmental, regulatory, professional, consumer and pharmaceutical bodies.

Dose Escalation in Esophageal Cancer: Comparing Pre-Accrual and On-Trial Target Volume Delineation in the UK SCOPE2 Trial

The ongoing UK SCOPE2 trial evaluates radiotherapy (RT) dose escalation and PET-guided systemic therapy in esophageal cancer, and has an accompanying RT trials quality assurance (RTTQA) program, evolved through the preceding SCOPE trials. We compare pre-accrual with on-trial individual case review (ICR) target volume delineation (TVD). Prior to recruitment, centers were required to undertake TVD exercises using 3D/4D DICOM datasets with relevant clinical details and a RT planning guidance document (RPGD) provided. Contours were then compared against the RTTQA team-defined gold standard. Exceptions were those who had satisfied QA requirements for a previous esophageal RT trial (NeoSCOPE). For ICRs, prospective reviews (prior RT start, PRs) were undertaken for each center's first submission, plus high-dose cases submitted pending formal safety review. Additional PRs were undertaken at the RTTQA team's discretion. Timely retrospective reviews (within 2 weeks of RT start, TRR) were also undertaken for a random 10% sample. TVDs were assessed for compliance using predefined criteria and the RPGD. Resubmission was requested at reviewer's discretion, usually due to unacceptable variation (UV) from protocol. Clarification was sought before contour approval/resubmission request if appropriate. Review outcomes were then evaluated. PTV6000 was new to SCOPE2, along with a greater emphasis on use of 4DCT than in prior SCOPE trials. A total of 85 pre-accrual cases from 33 UK centers were reviewed, of which 20 (24%) were resubmissions, and 50 (59%) were accepted. 99 TVD UVs were observed in 49 cases, most commonly in CTVB (42/99, 42%), which included editing for normal structures and elective lymph node regions, followed by ITV (4D cases only, 14/52, 27%) and PTV6000 (13/99, 13%). 121 ICRs from 31 UK centers were available for review. 87 (72%) were PRs and 34 (28%) TRRs. 43 (36%) completed the relevant SCOPE2 exercise. 19 (16%) were resubmissions, and 82 (68%) were accepted. 72 UVs were observed in 45 ICRs; again, most commonly in CTVB (34/72, 48%), PTV6000 (high dose arm only, 11/46, 24%) and ITV (4D only, 5/26, 19%). Of the 45 cases where a UV was recorded, 16 (36%) had completed the relevant SCOPE2 pre-accrual. Comparing area of UV on SCOPE2 pre-accrual cases and ICRs, 3 (19%) contours contained the same (2 = CTVB, 1 = PTV6000), 5 (31%) contained different and 8 (50%) had no UVs at pre-accrual. The rate of UV was significantly lower for ICR than for pre-accrual submissions (0.60 and 1.16 respectively, p = 0.001). Significantly fewer UVs in ICR compared with pre-accrual supports a robust, educational RTTQA program through national collaboration and evolving trial series. CTVB, along with newer volumes of ITV and PTV6000, were recurring UV domains and should inform RPGD development and RTTQA for ongoing recruitment and future trials.

A-245 Reagent Lot Variation—When should I be Concerned?

Abstract Background Reagent lot variation is often considered a major source of concern for infectious disease serology testing. Regular review of quality control testing data for specific assays confirms that, when using traditional statistical methods, such as using small datasets to establish mean/SD and then applying Westgard rules, reagent lot variation is the most common cause of variation observed. To investigate every incident is time consuming, costly and likely unnecessary in the majority of cases. But how do we create an alternative to monitoring QC data that accepts normal reagent lot variation yet highlight unacceptable variation? Applying the results from two assays using the same multimarker QC sample to traditional and an alternative QC monitoring method such as QConnect highlights when we should be concerned with lot variation and when the variation is normal. Methods QC testing data from 14 lots of the multimarker QC “Optitrol Blue” over a three year period tested on two assays—Abbott ARCHITECT Anti-HCV (n = 54 102) and Abbott ARCHITECT HIV AgAb Combo (n = 62 682) were reviewed for lot variation using traditional and alternative QC monitoring methods. Results Numerous examples of lot variation were identified from the two assays over the three-year period. Applying traditional QC methods resulted in frequent recalculation of mean/SD to accommodate the lot variation, effectively making the lot variation part of the routine, negating its importance, and making the clinical significance of reagent lot variation difficult to ascertain. Using an alternative QC monitoring method such as QConnect, which incorporated normal lot in calculations to create a constant acceptance range, removed the uncertainty and highlighted instances where variation was outside ‘normal’, triggering further investigation by using meaningful QC ranges. A clear example was observed where two similar looking Levey-Jennings charts (one for ARCHITECT HCV and one for ARCHITECT HIV) demonstrated reagent lot variation that was detected as an outlier whereas Traditional methods identified all reagent lots as being outliers. Conclusion In infectious disease serology testing, reagent lot variation is frequent, normal, and rarely a cause for concern. However, it is difficult to determine how much variation is acceptable when using traditional QC methods, because most lot changes are flagged as “rejections”. QC processes that incorporate normal reagent lot variation, derived from historical data, allows for rapid identification of unacceptable variation, saving money and time (particularly when all reagent lot variation identified as outliers need unnecessary investigation), while reducing risk of poor results.

Drop-on-Demand Inkjet Drop Control With One-Step Look Ahead Estimation of Model Parameters

Applications of drop-on-demand inkjet printing in dosage-matter manufacturing and scalable patterning are attributed to its capacity for producing consistent dosages with high placement accuracy. In practice, with the same drop jetting profile, drop volume and drop jetting velocity are affected by variations in ink properties and environmental conditions. Open-loop calibrations are time-consuming and contribute to frequent line stoppage or unacceptable product variations. In this work, a two-input two-output stochastic drop volume and jetting velocity model is derived based on ink jetting calibration data. A control algorithm using drop-image-based one-step look ahead estimation of process model parameters is developed to regulate drop volume and jetting velocity. Boundedness and convergence of the parameter estimation error and stability of the closed-loop system are provided. Experimental results demonstrate a significant reduction to within 1% relative error in the drop volume and jetting velocity using the proposed control algorithm.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma: Lessons Learned

Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.

Development and preliminary validation of a modified EUCAST yeast broth microdilution MIC method with Tween 20-supplemented medium for rezafungin.

Rezafungin is a novel, once-weekly echinocandin. EUCAST rezafungin MIC testing has been associated with a good separation of WT and target gene mutant isolates in single-centre studies, but an unacceptable inter-laboratory MIC variation has prevented EUCAST breakpoint setting. This has been attributed to non-specific binding to surfaces across microtitre plates, pipettes, reservoirs, etc. used, as previously encountered for some antibiotics. To investigate use of a surfactant to mitigate non-specific binding of rezafungin in EUCAST E.Def 7.3 MIC testing. Surfactants including Tween 20 (T20), Tween 80 (T80) and Triton X-100 (TX100) were evaluated for stand-alone or synergistic antifungal activity via checkerboard assays in combination with rezafungin. Subsequent T20 studies defined an optimized assay concentration, validated in up to four microtitre plate types for WT and fks mutant Candida strains (seven species total) and the six-strain EUCAST Candida quality control (QC) panel. Lastly, T20 inter-manufacturer variability, thermostability and best handling practices were investigated. T20 and T80 performed equivalently, with characteristics slightly preferable to TX100. Due to existing use in EUCAST mould susceptibility testing, T20 was pursued. An optimized concentration of 0.002% T20 normalized rezafungin MIC values across plate types for all Candida spp. evaluated, maintained differentiation of WT versus fks mutants and generated robust QC ranges. Additionally, T20 performance was consistent across manufacturers and temperatures. T20 can be reliably transferred utilizing a syringe, wide-orifice pipette tip and/or by mass. Supplementation of RPMI (Roswell Park Memorial Institute) 1640 medium with 0.002% T20 generated a highly reproducible EUCAST yeast MIC methodology for rezafungin.

Association between radiotherapy protocol variations and outcome in the CONVERT trial

BackgroundRadiotherapy quality assurance (QA) is integral to radiotherapy delivery. Here we report comprehensive contouring, dosimetry, and treatment delivery QA, describe protocol compliance, and detail the impact of protocol variations on acute grade ≥3 toxicity, progression free survival (PFS), and overall survival (OS) in the phase III CONVERT trial. Materials/MethodsRadiotherapy planning data from one hundred randomly selected patients were requested. Members of the CONVERT Trial Management Group (TMG) recontoured the heart, lung, and spinal cord organs at risk (OAR) according to the trial guideline. The existing radiotherapy plan were re-applied to the new structures and the new dosimetric data were recollected. Compliance with radiotherapy QA components were recorded and radiotherapy QA components were pooled into protocol variations: acceptable, acceptable variation, and unacceptable variation. Univariable analysis with a Cox proportional hazards model established the relationship between protocol variations and patient outcome. ResultsNinety-three cases were submitted for retrospective radiotherapy QA review. Demographics of the radiotherapy QA cohort (n=93) matched the non-QA (n=450) cohort. 97.8% of gross tumour volume (GTV) contours were protocol compliant. OAR contours were non-compliant in 79.6% instances of the heart, 37.6% lung, and 75.3% spinal cord. Of the non-compliant heart contours, 86.5% and 2.7% had contours caudal and cranial to the protocol-defined heart borders. 10.8% did not include the pericardial sac and 2.7% did not include the anterior aspect of the pericardium. Eleven (11.8%) submissions exceeded protocol-defined dosimetric heart constraints; six of which were only noted on the application of protocol-compliant contours. Unacceptable variations were not associated with an increase in grade 3 toxicity (p=0.808), PFS (p=0.232), or OS (p=0.743). ConclusionNon-protocol compliant heart contours were associated with increased dose delivered to the heart OAR, with 11.8 % of submitted heart structures exceeding protocol-defined constraints. In this QA cohort of patients with small cell lung cancer, unacceptable variations were not associated with acute grade ≥3 toxicity, PFS, or OS. Radiotherapy QA remains the cornerstone of high-quality radiotherapy delivery and should be embedded into clinical trial and non-clinical trial practice; clinical trials should report standardised radiotherapy QA parameters alongside trial outcomes.

Radiotherapy Quality Assurance in SIOP Ependymoma II – Experiences from Germany, Austria and Switzerland

<h3>Objectives</h3> Radiotherapy (RT) for pediatric ependymoma remains challenging due to the young age of the patients and the close proximity of the tumour to critical structures. In Germany, Austria and Switzerland, a Radiotherapy Quality Assurance (RTQA) program was implemented within the SIOP Ependymoma II trial to ensure patient safety and protocol compliance. <h3>Methods</h3> Pre-trial site approvals and prospective plan reviews for patients in stratum 1 and 2 were performed. Plans were submitted by the treating centres to the reference centres Essen and Leipzig, who evaluated the plans regarding compliance to the study protocol and the German RTQA guideline. Results were categorized as per protocol, acceptable variation, justified unacceptable variation or unacceptable variation, respectively. Unacceptable variations required plan modification and re-review. <h3>Results</h3> Between May 2019 and December 2021, 33 patients (median age 5.1 years) from 8 institutions were reviewed. Thirty patients in stratum 1 received conformal RT. Within stratum 2, 3 patients received an additional stereotactic boost. The majority (n=31) of the patients were treated with protons. Of the 33 conformal RT plans, 4 (12%) were reviewed as per protocol, 14 (42%) as acceptable variation, 4 (12%) as justified unacceptable variation and 11 (33%) as unacceptable variation. Six of the unacceptable plans were re-submitted after modification. Four of them were approved after re-submission (acceptable variation=1, justified unacceptable variation=3), whereas 2 plans still had unacceptable variations. Reasons for rejecting plans were target volume delineation (44%), uniformity of target volume (33%) and dose to organs at risk (22%). All stereotactic boost plans were accepted (acceptable variation=1, justified unacceptable variation=2). <h3>Conclusion</h3> The high rate of rejected initial RT plans underlines the importance of a rigorous RTQA program. Improving the quality of RT plans potentially impacts favourably on outcome and long term side effects although requiring a high effort.

Durvalumab in Combination with Chemoradiotherapy (CRT) in Locally Advanced Cervical Cancer (LACC): Radiotherapy (RT) Delivery and Subgroup Analyses from CALLA

<h3>Purpose/Objective(s)</h3> Concurrent platinum-based CRT has been standard of care in LACC for 20+ years. Simultaneously, RT techniques/technology have advanced, providing opportunity for improved treatment outcomes. In LACC, global standardization is critical to enhance RT quality and brachytherapy (BT) utilization. CALLA was the first global, placebo-controlled, Phase 3 study evaluating durvalumab (D), in combination with and following CRT, in LACC . We examine RT technological approaches, quality assurance measures, and related RT-based findings from CALLA. <h3>Materials/Methods</h3> Newly diagnosed, untreated patients (pts) with high-risk LACC (FIGO 2009 IB2–IIB node positive, IIIA–IVA any node status) were randomized 1:1 to D (1500 mg IV) or placebo (P) Q4W (total ≤24 doses), in combination with and following CRT. CRT comprised concurrent weekly IV platinum agent with external beam radiotherapy (EBRT) and BT. Detailed EBRT/BT protocol guidelines were included to ensure regional alignment. Prior to site qualification, a feasibility questionnaire and credentialing process confirmed compliance. A global RT subcommittee reviewed RT quality/compliance and created a scoring system to identify plan variations and potential clinical significance. RT quality was evaluated for each pt, including detailed review of contouring, EBRT plan dose/metrics, BT utilization/quality, RT completion, and treatment plan dose/quality variations. <h3>Results</h3> A total of 770 women (105 sites,15 countries; 44% Hispanic, 39% Asian) were randomized. The primary endpoint of PFS was not met (hazard ratio [95% CI] for D+CRT vs P+CRT: 0.84 [0.65–1.08]; <i>P</i>=0.174). PFS at 12 and 24 months for D+CRT vs P+CRT were 76.0% vs 73.3% and 65.9% vs 62.1%, respectively. EBRT and BT were completed per protocol in 96.4% and 94.3% of pts for D+CRT and 98.4% and 95.3% for P+CRT. RT was delivered in ≤59 days in 72.2% and 72.5% for D+CRT and P+CRT, respectively. Intensity-modulated RT was used for 86.8% (D+CRT) and 88.1% (P+CRT) of pts. A majority of pts received volume-directed BT (59.7% D+CRT, 63.3% P+CRT), and 87.4% and 88.1% of BT was high-dose rate. In both arms, median RT dose delivered was 5400 cGy and median equivalent dose was 8387.0 cGy (median BT dose/fraction 700 cGy, 4 fractions) (RT doses omit Japan). Clinically significant unacceptable variations in RT delivery were low; <25% of unacceptable variations were clinically significant. PFS by RT subgroups were generally aligned with the ITT population. <h3>Conclusion</h3> CALLA integrated an exceptional quality assurance/control strategy to ensure global protocol compliance, showing high-quality RT delivery is achievable with high compliance. Although D+CRT did not significantly improve PFS vs P+CRT, CALLA illustrates the importance of strong multidisciplinary collaboration for optimal CRT delivery in high-risk LACC. Funding: AstraZeneca

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial

PurposeTo report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. MethodsThree credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. ResultsFifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. ConclusionsClear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Repeated Drop-Weight Impact Testing of Fibrous Concrete: State-Of-The-Art Literature Review, Analysis of Results Variation and Test Improvement Suggestions.

The ACI 544-2R introduced a qualitative test to compare the impact resistance of fibrous concretes under repeated falling-mass impact loads, which is considered to be a low-cost, quick solution for material-scale impact tests owing to the simplified apparatus, test setup and procedure, where none of the usual sophisticated sensors and data acquisition systems are required. However, previous studies showed that the test results are highly scattered with noticeably unacceptable variations, which encouraged researchers to try to use statistical tools to analyze the scattering of results and suggest modifications to reduce this unfavorable disadvantage. The current article introduces a state-of-the-art literature review on the previous and recent research on repeated impact testing of different types of fibrous concrete using the ACI 544-2R test, while focusing on the scattering of results and highlighting the adopted statistical distributions to analyze this scattering. The influence of different mixture parameters on the variation of the cracking and failure impact results is also investigated based on data from the literature. Finally, the article highlights and discusses the literature suggestions to modify the test specimen, apparatus and procedure to reduce the scattering of results in the ACI 544-2R repeated impact test. The conducted analyses showed that material parameters such as binder, aggregate and water contents in addition to the maximum size of aggregate have no effect on the variation of test results, while increasing the fiber content was found to have some positive influence on decreasing this variation. The survey conducted in this study also showed that the test can be modified to lower the unfavorable variations of impact and failure results.

Oligorecurrent nodal prostate cancer: Radiotherapy quality assurance of the randomized PEACE V-STORM phase II trial

PurposeAim of this study is to report the results of the radiotherapy quality assurance program of the PEACE V-STORM randomized phase II trial for pelvic nodal oligorecurrent prostate cancer (PCa). Material and methodsA benchmark case (BC) consisting of a postoperative case with 2 nodal recurrences was used for both stereotactic body radiotherapy (SBRT, 30 Gy/3 fx) and whole pelvic radiotherapy (WPRT, 45 Gy/25 fx + SIB boost to 65 Gy). ResultsBC of 24 centers were analyzed. The overall grading for delineation variation of the 1st BC was rated as ‘UV’ (Unacceptable Variation) or ‘AV’ (Acceptable Variation) for 1 and 7 centers for SBRT (33%), and 3 and 8 centers for WPRT (46%), respectively. An inadequate upper limit of the WPRT CTV (n = 2), a missing delineation of the prostate bed (n = 1), and a missing nodal target volume (n = 1 for SBRT and WPRT) constituted the observed ‘UV’. With the 2nd BC (n = 11), the overall delineation review showed 2 and 8 ‘AV’ for SBRT and WPRT, respectively, with no ‘UV’. For the plan review of the 2nd BC, all treatment plans were per protocol for WPRT. SBRT plans showed variability in dose normalization (Median D90% = 30.1 Gy, range 22.9–33.2 Gy and 30.6 Gy, range 26.8–34.2 Gy for nodes 1 and 2 respectively). ConclusionsUp to 46% of protocol deviations were observed in delineation of WPRT for nodal oligorecurrent PCa, while dosimetric results of SBRT showed the greatest disparities between centers. Repeated BC resulted in an improved adherence to the protocol, translating in an overall acceptable contouring and planning compliance rate among participating centers.

Physical Modelling of Nitrogen Variation in Continuously Cast Blooms Resulting from Atmospheric Exposure of Steel in Tundish during Initial Stages of Teeming

Exposure of liquid steel to air, consequent re-oxidation as well as nitrogen absorption are common in steelmaking and produce unacceptable variations in product chemistry. The phenomena, during continuous casting of the lead or first heat, have been investigated in a full-scale water model of a two-strand, bloom casting shroud-tundish system. Physical modelling results supported by industrial scale measurements have demonstrated that exposure of liquid steel to tundish atmosphere during initial period of ladle teeming and consequent nitrogen absorption, manifest over substantial period, influencing predominantly the first three blooms.

Evidence-based selection of reference genes for RT-qPCR assays in periodontal research.

ObjectiveTo underline the necessity of adequate reference genes for real‐time quantitative polymerase chain reaction (RT‐qPCR) and evaluate a novel tool for condition‐specific reference gene selection.BackgroundRT‐qPCR is a commonly used experimental technique that allows for highly sensitive analysis of gene transcription. Moreover, the use of internal reference genes as a means for relative quantification has rendered RT‐qPCR a straightforward method for a variety of sciences, including dentistry. However, the expressional stability of internal reference genes must be evaluated for every assay in order to account for possible quantification bias.Materials and MethodsHerein, we used the software tool RefGenes to identify putatively stable reference genes with the help of microarray datasets and evaluated them. Additionally, we propose an evidence‐based workflow for adequate normalization of thusly identified genes. Human gingival fibroblasts (HGF‐hTert), human acute leukemia‐derived monocytes (THP‐1), and telomerase immortalized gingival keratinocytes (TIGKs) were subjected to set‐ups simulating various glycemic conditions and lipopolysaccharide challenges. Five common housekeeping genes (HKGs) and five genes from RefGenes were selected as targets and RT‐qPCR was performed subsequently. Then, normalization algorithms Bestkeeper, Normfinder, and geNorm were used for further analysis of the putative reference gene stability.ResultsRefGenes‐derived targets exhibited the highest stability values in THP‐1 and TIGK cell lines. Moreover, unacceptable standard variations were observed for some common HKG like β‐actin. However, common HKG exhibited good stability values in HGF‐hTert cells.ConclusionThe results indicate that microarray‐based preselection of putative reference genes is a valuable refinement for RT‐qPCR studies. Accordingly, the present study proposes a straightforward workflow for evidence‐based preselection and validation of internal reference genes.