Mature Data Research Articles

An improved ΔlogR model for evaluating organic matter abundance

Estimating the total organic carbon (TOC) content is crucial in shale reservoir evaluation. Among the available methods for TOC estimation from well logs, the ΔlogR technique is currently the only globally used model that is based on a rigorous petrophysical model. Literature reviews reveal that the overlay-coefficient between the porosity and the resistivity curves in the ΔlogR model has been the focus of many studies. However, the current methods of determining the overlay-coefficient based on the rock minerals or empirical parameters weaken its applicability and accuracy. In this study, we developed a V-ΔlogR model for the prediction of the total organic matter content. The V-ΔlogR model is comprised of three modifications to the ΔlogR model, i.e., replacing the fixed overlay-coefficient with a variable one, removing the maturity, and replacing the baselines with a single one. Among these, a critical improvement is treating the overlay-coefficient ( k ) as a variable and determining it from the measured TOC values or from well logs. The application of our improved model in the Songliao, Bohai Bay, and Sichuan basins indicates that the V-ΔlogR model can accurately predict the TOC of shale with large lithological and mature variations. Because it uses actual geological data to determine the overlay-coefficient in the model, the V-ΔlogR model offers more reliable results for test wells than other commonly used models (e.g., the modified Schomoker, multiple regression analysis, modified ΔlogR). The V-ΔlogR model eliminates the need for mineral and maturity data constraints and the overlay-coefficient can be determined using only the well logs, which significantly expands the applicability of the ΔlogR method. • An improved method (the V-ΔlogR model) predicts TOC content is proposed. • The method is based on sonic and the resistivity log, and a ratio of k between them. • A easily implemented method for predicting k using the log curves is presented. • The V-ΔlogR model expands the applicability of the ΔlogR method, and can be accurate in TOC predicting.

Glioma Radiation Therapy on a High Field 1.5 MR-Linac: Workflow and Initial Experience

The development of high-field strength MR-guided radiotherapy systems enables daily MR imaging, the opportunity for adaptive radiotherapy, and functional imaging acquisition. This study reports the workflow implementation, treatment times, and initial experience of glioma radiotherapy on the 1.5T MR-Linac (MRL).Selected glioma patients treated with concurrent chemoradiation (chemoRT) between October 2019 and August 2020 were identified from a prospective database. All patients were treated on the MRL with backup plans on conventional Linac if the MRL was unavailable. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow derived from a pre-beam T1-weighted MRI. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the Dice similarity coefficient (DSC) and relative FHR volumes, compared to the initial FLAIR contour at the first MRL fraction. Multi-parametric images were acquired on the MR-Linac during radiation treatment, including diffusion-weighted imaging (DWI), chemical exchange saturation transfer (CEST), magnetization transfer (MT), and blood oxygenation level dependent (BOLD) resting-state fMRI. The behavior of selected functional parameter values was investigated within the FHR at the imaged fractions.Ten high grade glioma patients completed chemoRT to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction was 37.3 minutes (range, 24-51 minutes), and 42.9 minutes if including post-beam research imaging. Three patients (30%) required re-planning between fractions 15 to 19 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30 day post-first fraction time points, 3, 3, and 4 patients had a FLAIR volume that changed by at least 20% relative to the first MRL fraction, respectively. Multi-parametric images including DWI, CEST, MT, and BOLD resting-state fMRI were successfully acquired on the MR-Linac. The median apparent diffusion coefficients (ADC) within the FHR and volumes of FLAIR were significantly correlated when the data from all patients and time points were pooled (r = 0.68, P < 10-3).We report the first clinical series of glioma patients treated with chemoRT on the MRL. The workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of multi-parametric imaging sequences was feasible on the MRL during routine treatment workflow. ADC parameter changes could be reliably tracked during chemoRT, and mature clinical outcomes data is anticipated to define the role of functional imaging in adaptive radiotherapy.C. Tseng: Advisory Board; Sanofi. H. Chen: Employee; North York General Hospital. J. Stewart: None. A. Lau: None. R. Chan: None. L.S. Lawrence: Student affiliated with University of Toronto; Sunnybrook Research Institute. M. Campbell: None. S.D. Myrehaug: Advisory Board; Novartis AG.H. Soliman: None. Z.A. Husain: Independent Contractor; RadOncQuestions LLC. Research Grant; Merck. Travel Expenses; Elekta; NIH Head and neck PULA task force. J. Detsky: None. P. Maralani: None. B.M. Keller: None. M.E. Ruschin: Patent/License Fees/Copyright; Elekta AB.A. Sahgal: Research Grant; Elekta.

Treatment Outcomes Following Proton Therapy for High Grade Spinal Cord Ependymoma in Children

There is limited information published on the outcome of children treated with radiation for high-grade ependymoma of the spinal cord. Thus, little evidence is available to inform decisions of target volume or prescription dose. Moreover, there is virtually no mature outcome data on proton therapy, despite theoretical advantages in normal tissue exposure. We therefore performed a bicentric retrospective study to better inform treatment of this rare tumor in children.Between 2008 and 2019, 14 consecutive pediatric patients with a non-metastatic grade II or III spinal ependymoma were treated with proton therapy at the University of Florida and Massachusetts General Hospital. The median age of the children at the time of radiation was 14 years old (range, 1.5-18 years). Five tumors arose within the cervical cord (C1-5, C1-2, C1-T1, C3-T1, C4-C6), 3 within the thoracic spine (C7-T4, T7-L1, T11-T12), and 6 within the lumbosacral spine (L3-L5, L3-L5, L4-S2, S2-S5, L2-L3, L2-L3). Six tumors were grade II histology and 8 were grade III. Prior to radiotherapy, 3 patients had undergone a subtotal resection while the other 11 had a gross total or near total resection. One patient received chemotherapy according to the International Society of Pediatric Oncology (SIOP) infant regimen and 1 patient received chemotherapy according to Children's Oncology Group (COG) ACNS0831. For radiation, the gross tumor volume (GTV) was defined by the gross disease and/or tumor bed at the time of radiation. The CTV was defined by the GTV + 5-10 mm. The CTV received 50.4 Gy (n = 8), 52.2 (n = 1), or 54 Gy (n = 5), with the latter undergoing boost to just the GTV following the initial 50.4 Gy to respect spinal cord tolerance. For the cohort, the median maximum point dose to the spinal cord was 52.4 Gy (range, 0-53.9 Gy). The median maximum dose to 0.1 cc of spinal cord was 51.3 Gy (range, 0-52.5 Gy). The median volume of cord receiving ≥50.4 Gy was 3.4 cc (range, 0-17.1 cc).With a median follow-up of 6.3 years (range, 1.5 - 14.8 years), no tumors have progressed and all patients are alive. Serious acute toxicity was limited to 1 case of grade 2 nausea. While most patients experienced neurologic sequela following surgery, only 1 patient developed additional neurologic deficits following radiation: An 18-year-old male who received 54 Gy following gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of chronic musculoskeletal toxicity attributable to surgery and radiation in survivors. No patients have developed cardiac, pulmonary, or other visceral organ complications, nor has any patient developed a second malignancy.These outcomes suggest that radiation to a dose of 50-54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with grade II/III spinal cord ependymoma. Proton therapy may reduce the late radiation effects and is not associated with unexpected spinal cord toxicity.

Long-Term Outcomes of a Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image-Guided Intensity-Modulated Radiotherapy for Localized High-Risk Prostate Adenocarcinoma

<h3>Purpose/Objective(s)</h3> In high-risk localized prostate cancer (HRLPC), the standard of care is dose-escalated radiation therapy (DERT) with long-term androgen deprivation therapy (LTADT). Unfortunately, outcomes are less than ideal. There is significant interest in improving outcomes by intensifying treatment for these patients using docetaxel (D). This phase I study was designed to find the maximum tolerable dose (MTD) of concurrent weekly D when combined with DERT to the prostate with long-term androgen deprivation therapy (LTADT) in HRLPC patients. Initial results reported demonstrated a MTD for docetaxel of 25 mg/m² with acceptable toxicities. Here we describe the long-term outcomes in these patients. <h3>Materials/Methods</h3> We enrolled 19 patients with HRLPC (≥1 of ≥cT2c, PSA ≥20ng/ml, or Gleason ≥8) on this phase 1 study. Patients received neoadjuvant combined androgen blockade for 2 months and then during radiation of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles with concurrent weekly D. No pelvic/nodal radiotherapy was given. D was administered in a standard dose-escalated scheme requiring ≥3 patients per cohort, starting at 10mg/m² and increasing to 30mg/m² in 5mg/m² increments. The GnRH agonist was continued for an additional 24 months. The primary objective of the study was to determine the MTD of D in combination with DERT and LTADT. Secondary end points included progression free survival (PFS), metastasis free survival (MFS) and overall survival (OS). Kaplan-Meier analysis was used to estimate the survival probabilities. <h3>Results</h3> MTD was found to be 25mg/m². There was no grade ≥3 toxicity at this or lower dose levels. At a median follow up of 10.5 years the median OS was not reached. 5-year and 10-year OS was found to be 89.5% and 68.4%, respectively. Median MFS was found to be 11.3 years with 5- and 10-year MFS of 84.2% and 57.9%. Median PFS was 9.0 years with 73.7% and 42.1% at 5 and 10 years, respectively. <h3>Conclusion</h3> In the setting of high-dose IMRT to the prostate with concurrent LTADT the MTD of concurrent weekly docetaxel is 25mg/m². This study showed a 5-year OS of 89.5% with a median OS not reached with > 10 years of follow-up. This mature data suggests that the addition of concurrent weekly docetaxel at 25mg/m² to high-dose IMRT to the prostate is safe and may provide cancer control rates similar to those recently reported for adjuvant full-dose D.

APBI Using Brachytherapy in the Presence of Breast Augmentation: 320 Women

Breast augmentation has been one of the most common surgical procedures in the US for the past 20 years with an average of 320,000 cases per year. Many of these women are being diagnosed with breast cancer as they age. The reported rate of capsular contracture with whole breast irradiation is 55%, resulting in many mastectomies for early-stage disease. Brachytherapy has the advantage of limited radiation exposure to the implant. We report mature data on 320 women treated between 2001 and 2021.This retrospective review includes patients from 2 institutions with 71 months mean follow-up. 64% had saline and 36% silicone implants, with 83% subpectoral and 17% prepectoral. Median age is 54 years (22-82). 269 interstitial (median 17 catheters), 43 SAVI, 8 balloons. Stage Tis = 26%, T1N0 = 52%, T2N0 = 8%, N1 = 14%. Surgical margins negative 85%, close 14%, and positive 0.6%.The mean PTV = 74cc, DHI for interstitial and single entry is 7(% and 58%, and median V90 = 96%. Ten had IBTR (3.1%), 4 TRMM and 6 elsewhere. 3 had nodal recurrence only. Cosmesis at 2 and 5 years: Excellent/Good 100%, 97.5% Mod-severe fibrosis 5%. Capsular contracture 4% before treatment and 3.4% after brachytherapy.Brachytherapy APBI in the presence of breast augmentation offers excellent tumor control with markedly reduced rates of capsular contracture or complications.

341 Meta-analysis of the Performance Responses of Replacement Heifers and Beef Cows to Monensin

Abstract Performance benefits of monensin have been extensively studied in finishing and stocker cattle, but considerably less published work is available evaluating response to monensin supplementation in cow-calf production systems. Feed additives are more difficult to study in cow-calf production systems due to unstable diet characteristics and cow physiological state throughout the production cycle. This meta-analysis investigated the impacts of monensin on performance of extensively raised beef cow-calf and developing replacement heifers. The replacement heifer analysis was conducted with a maximum of 48 treatment means in 18 experiments. The mature cow analysis included 21 publications and 26 mean comparisons. The metaphor package (version 2.4-0; Viechtbauer, 2010) for R (version 4.0.3; www.r-project.org) was used to determine the overall effect size of monensin compared to a negative control. Each study’s n, means, and SEM or P-value was used to calculate the mean difference and estimate of within study variance for responses of interest. For replacement heifers, average daily gain (+0.03 ± 0.008 kg/d), feed efficiency (+0.013 ± 0.008 gain:feed), and percentage cycling before the breeding season (+15.9 ± 5.13%) were increased (P &amp;lt; 0.01), while dry matter intake (-4.3%) and age at puberty (-8.9 ± 1.48 d) were decreased (P &amp;lt; 0.01). Six studies reporting ad libitum forage intake for mature cows showed that monensin decreased (P = 0.008) DMI by 0.85 ± 0.322 kg/day. Six studies showed monesin increased (P = 0.01) milk yield 0.39 ± 0.15 kg/day by mature cows in early lactation. There were no differences in artificial insemination pregnancy nor total pregnancy for either the heifer or mature cow data sets. This analysis also indicates potential for use of monensin in beef cow production systems, but further research is needed to elucidate the effects on DMI and milk production in beef cows.

OAB-053: Clinical outcomes of relapsed/refractory multiple myeloma patients after BCMA-targeted CAR T therapy

OAB-053: Clinical outcomes of relapsed/refractory multiple myeloma patients after BCMA-targeted CAR T therapy

Daratumumab for post-ASCT maintenance treatment of myeloma.

Daratumumab, a potent CD38-directed monoclonal antibody, has veritably transformed the treatment landscape of multiple myeloma. 1 Nooka AK Kaufman JL Hofmeister CC et al. Daratumumab in multiple myeloma. Cancer. 2019; 125: 2364-2382 Crossref PubMed Scopus (58) Google Scholar CASSIOPEIA, a two-part, phase 3 trial, has brought daratumumab to the forefront of efforts aimed at improving outcome for transplant-eligible patients. 2 Moreau P Attal M Hulin C et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019; 394: 29-38 Summary Full Text Full Text PDF PubMed Scopus (346) Google Scholar Part 1 randomly assigned 1085 patients with newly diagnosed multiple myeloma to receive four pre-autologous stem-cell transplantation (ASCT) induction and two post-transplant consolidation cycles of bortezomib, thalidomide, and dexamethasone (VTd) alone, or in combination with daratumumab (D-VTd). D-VTd showed considerable improvement in depth of response and progression-free survival, leading to its regulatory approval. 2 Moreau P Attal M Hulin C et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019; 394: 29-38 Summary Full Text Full Text PDF PubMed Scopus (346) Google Scholar An improved overall survival with D-VTd became apparent with longer follow-up. 3 Moreau P Hulin C Perrot A et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021; (published online Sept 13.)https://doi.org/10.1016/S1470-2045(21)00428-9 Google Scholar A more contemporary regimen, D-VRd, involving lenalidomide, is awaiting mature data. 4 Voorhees PM Kaufman JL Laubach J et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020; 136: 936-945 Crossref PubMed Scopus (169) Google Scholar Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trialDaratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. Full-Text PDF

Current State and Development of Green Bonds Market in the Latin America and the Caribbean

The green bonds market has had a growth in recent years within its different sectors and regions. Specifically, up to 2020, the Latin America and the Caribbean (LAC) region has issued USD 26 billion. Some authors have studied the factors influencing financing through green bonds. However, a research gap is identified in the analysis of the regions that contribute to the issuance of this type of bond, specifically for LAC. This is the first study to examine the variables such as issue amount, number and type of issuers, currency, and maturity data in the region using a dataset of issuing performed between 2014–2020. We find the typical sizes of the issues, the search for a premium in the issue, the perception of complexity, the issuance of guides, and tax incentives as the main factors affecting this market. Finally, the study presents the potential for further research.

Bicentric Treatment Outcomes After Proton Therapy for Nonmyxopapillary High-Grade Spinal Cord Ependymoma in Children

Few studies report outcomes in children treated with radiation for nonmyxopapillary ependymoma of the spinal cord, and little evidence exists to inform decisions regarding target volume and prescription dose. Moreover, virtually no mature outcome data exist on proton therapy for this tumor. We describe our combined institutional experience treating pediatric classical/anaplastic ependymoma of the spinal cord with proton therapy. Between 2008 and 2019, 14 pediatric patients with nonmetastatic nonmyxopapillary grade II (n=6) and grade III (n=8) spinal ependymoma received proton therapy. The median age at radiation was 14 years (range, 1.5-18 years). Five tumors arose within the cervical cord, 3 within the thoracic cord, and 6 within the lumbosacral cord. Before radiation therapy, 3 patients underwent subtotal resection, and 11 underwent gross-total or near total resection. Two patients received chemotherapy. For radiation, the clinical target volume received 50.4 Gy (n=8), 52.2 (n=1), or 54 Gy (n=5), with the latter receiving a boost to the gross tumor volume after the initial 50.4 Gy, modified to respect spinal cord tolerance. With a median follow-up of 6.3 years (range, 1.5-14.8 years), no tumors progressed. Although most patients experienced neurologic sequela after surgery, only 1 developed additional neurologic deficits after radiation: An 18-year-old male who received 54 Gy after gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of musculoskeletal toxicity attributable to surgery and radiation. At analysis, no patient had developed cardiac, pulmonary, or other visceral organ complications or a second malignancy. Radiation to a total dose of 50 to 54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with nonmyxopapillary spinal cord ependymoma. Proton therapy may reduce late radiation effects and is not associated with unexpected spinal cord toxicity.

Biased Survival Predictions When Appraising Health Technologies in Heterogeneous Populations.

IntroductionTime-to-event data from clinical trials are routinely extrapolated using parametric models to estimate the cost effectiveness of novel therapies, but how this approach performs in the presence of heterogeneous populations remains unknown.MethodsWe performed a simulation study of seven scenarios with varying exponential distributions modelling treatment and prognostic effects across subgroup and complement populations, with follow-up typical of clinical trials used to appraise the cost effectiveness of therapies by agencies such as the UK National Institute for Health and Care Excellence (NICE). We compared established and emerging methods of estimating population life-years (LYs) using parametric models. We also proved analytically that an exponential model fitted to censored heterogeneous survival times sampled from two distinct exponential distributions will produce a biased estimate of the hazard rate and LYs.ResultsLYs are underestimated by the methods in the presence of heterogeneity, resulting in either under- or overestimation of the incremental benefit. In scenarios where the overestimation of benefit is likely, which is of interest to the healthcare provider, the method of taking the average LYs from all plausible models has the least bias. LY estimates from complete Kaplan–Meier curves have high variation, suggesting mature data may not be a reliable solution. We explore the effect of increasing trial sample size and accounting for detected treatment–subgroup interactions.ConclusionsThe bias associated with heterogeneous populations suggests that NICE may need to be more cautious when appraising therapies and to consider model averaging or the separate modelling of subgroups when heterogeneity is suspected or detected.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01082-x.

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development

ABSTRACT Introduction Immunotherapy through the blockade of PD1-PDL1 axis has shown to improve outcomes in advanced and early triple negative breast cancer (TNBC). To further enhance immune-stimulation, and ultimately improve patient outcomes, a wide variety of next-generation immunotherapies (NGIO) is being developed for this disease. Areas covered In the present article, we discuss the immune landscape of TNBC and recapitulate the rationale and available clinical evidence of NGIO under early phase development for TNBC, highlighting challenges and opportunities in this emerging field of research. Expert opinion Multiple immunotherapeutic strategies beyond PD-(L)1 blockade have been tested for TNBC, including the targeting of further inhibitory checkpoints, the agonism of costimulatory molecules, the intratumoral administration of immunotherapies and cancer vaccines. Most of these strategies have demonstrated to be safe in early clinical trials, with some exhibiting early signs of antitumor activity. To optimally harness the potential of NGIO, a refined patient selection based on emerging immune biomarkers will be required, through an adaptation of immunotherapeutic strategies based on patient and tumor characteristics. More mature data from ongoing clinical trials, added to the progressively increasing knowledge on breast cancer immune landscape, will hopefully clarify the role of NGIO for the treatment of TNBC.

In Vitro Biomechanics of Human Cadaveric Cervical Spines With Mature Fusion.

This study sought to compare index and adjacent-level biomechanics of cadaveric specimens with mature fusion versus normal spines in intact and acutely fused conditions. Eight human cadaveric cervical spines with mature fusion across 1 to 3 levels were studied. Intervertebral angular range of motion (ROM) was determined at fused and adjacent levels during pure moments inducing flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Mature fusion data were compared to data from normal spine specimens tested intact and then with a 1-level anterior plate/graft (fresh fixation). Bone qualities were compared using dual-energy x-ray absorptiometry. Mean bone mineral density was significantly greater in mature fusion spines (0.632 ± 0.239 g/cm2) than in normal spines (0.489 ± 0.195 g/cm2) (P < .001). Mean ROM for levels with mature fusion was 42% (FE), 42% (LB), and 29% (AR) of the mean same-level ROM in freshly fixated specimens (P ≤ .045). The mean adjacent-level ROM in spines with mature fusion was less than in normal spines (matched levels) in all directions, with the greatest difference 1 level below fusion (FE: -38%, P < .001; LB: -42%, P < .001; AR: -49%, P = .001), followed by 1 level above fusion (FE: -23%, P = .04; LB: -22%, P = .07; AR: -28%, P = .02) and 2 levels above fusion (FE: -20%, P = .08; LB: -18%, P = .11; AR: -31%, P = .009). Mature fusion reduced the magnitude of coupled LB during AR at C6-7 and C7-T1 (P ≤ .03). Cervical spine segments with mature fusion have higher bone mass, are less flexible than freshly fixed spines, and have reduced mobility at adjacent levels.

Comparisons among four different upscaling strategies for cultivar genetic parameters in rainfed spring wheat phenology simulations with the DSSAT-CERES-Wheat model

Cropping system models are widely used to assess the impacts of and adaptation practices to climate change on agricultural production. However, crop growth simulations at large scales have often lacked consideration of variation in crop cultivars, which were represented by different sets of genetic coefficients in crops models. In this study, taking the phenology of spring wheat (Triticum aestivum L.) as an example, we compared four different strategies for upscaling genetic parameters in phenology simulations at large scales with two experimental datasets. The first dataset was from field experiments comprising 40 different spring wheat cultivars at Altay (2014) and Yangling (2015–2017) station; the second dataset was historical (2010–2014) observed phenology records from 57 national agro-meteorological observation stations in China. The four strategies were the representative cultivar estimated at a single site (SSPs), the representative cultivar estimated at the 57 sites (NRPs), the various representative cultivars estimated at different agro-ecological zones (RRPs), and the virtual cultivars generated from the posterior distributions (VCPs). The posterior distributions aforesaid were established based on the calibrated parameter values of the 40 different spring wheat cultivars planted in Yangling. Then, 1000 sets of VCPs were randomly sampled from the posterior distributions. The results indicated that both the SSPs and NRPs strategy obtained large errors and uncertainties in spring wheat phenology simulations in China since only one representative cultivar was used. The RRPs strategy achieved the second high and the highest accuracy in anthesis and maturity data simulations. The VCPs strategy obtained the highest accuracy in anthesis simulation but relative larger errors in maturity simulation. The VCPs strategy can be directly used in large-scale crop growth simulations without tedious process of calibration. Hence, this strategy is recommended in areas where observations are scarce and for model users who not good at model parameter estimation.

Long term results of a phase II trial of hypofractionated adjuvant radiotherapy for early-stage breast cancer with volumetric modulated arc therapy and simultaneous integrated boost

Purposeto report toxicity and cosmetic outcome with a median follow-up of 6 years of a phase II trial of hypofractionated radiotherapy with volumetric modulated arc therapy (VMAT) and simultaneous integrated boost (SIB) for early-stage breast cancer after conservative surgery. Materials and methodsFrom August 2010 to September 2014, patients requiring adjuvant radiotherapy for early-stage breast cancer were treated according to a phase I–II protocol with SIB to 40.5 and 48 Gy to the breast and the boost region, respectively, with VMAT technique. The primary endpoint evaluated the treatment feasibility regarding adherence to required dose constraints for target, heart and lungs. Acute and late toxicity, local and distant control were secondary endpoints. Results450 patients were included in the trial and analysed after a median follow-up of 6 years. Acute toxicity was already presented in a previous paper. Regarding late toxicity, 93% of patients had no skin alteration at five years, while 5.3% and 1.3% did record G1 and G2 residual toxicity, respectively. Cosmetic outcome was scored good or excellent in almost all cases (97.2%), fair only in 2.3% of patients. Residual tenderness in the irradiated breast was reported by 10% of patients. Cosmesis and breast pain improved during follow-up. Two cases of G2 pneumonitis and two cases of ischemic cardiopathy were registered during follow-up.Five cases presented local recurrence in the homolateral breast, four patients had a new primary cancer in the contralateral breast, while distant metastasis developed in 7 patients. ConclusionAfter more than six years, hypofractionated VMAT with SIB for adjuvant radiotherapy in early-stage breast cancer patients remains a safe and effective approach. Mature data on skin toxicity and cosmetic outcome are encouraging. However, longer follow-up is required to evaluate local control, cardiac toxicity and secondary carcinogenesis.

Cost Effectiveness of Durvalumab in Unresectable Stage III NSCLC: 4-Year Survival Update and Model Validation from a UK Healthcare Perspective.

BackgroundIn the phase III PACIFIC study, durvalumab improved survival versus placebo in patients with unresectable stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed after platinum-based concurrent chemoradiotherapy. The appraisal by the UK’s National Institute for Health and Care Excellence (NICE) included a cost-effectiveness analysis based on an early data readout from PACIFIC [March 2018 data cut-off (DCO); median follow-up duration 25.2 months; range 0.2–43.1]. Uncertainties regarding long-term survival outcomes with durvalumab led to some challenges in estimating the cost effectiveness of this therapy.ObjectiveHere, we validate the survival extrapolations used in the original company base-case analysis by benchmarking them against updated survival data from the 4-year follow-up analysis of PACIFIC (i.e. approximately 4 years after the last patient was randomised; March 2020 DCO; median follow-up duration 34.2 months; range 0.2–64.9). Moreover, we update the original analysis with these more mature survival data to examine the consistency of key economic outputs with the original analysis.MethodsThe original analysis used a semi-Markov (state-transition) approach and was based on patients whose tumours expressed programmed cell death-ligand 1 on ≥ 1% of cells (to reflect the European licence for durvalumab). We benchmarked the survival extrapolations used in the original company base-case analysis against survival data from the 4-year follow-up of PACIFIC and updated the cost-effectiveness analysis with these more mature survival data. Early deaths avoided by the adoption of durvalumab into the UK Cancer Drugs Fund (CDF) in March 2019 were estimated using the 4-year follow-up survival data and an assumed uptake of 125 patients/year (lower estimate) and 367 patients/year (higher estimate).ResultsThe original company base-case analysis had a good visual fit with the observed overall survival (OS) distribution for the durvalumab arm and accurately predicted the 48-month OS rate (predicted 55%; observed 55%); by comparison, the fit was less precise for the placebo arm, for which the analysis underestimated the 48-month OS rate (predicted 32%; observed 38%). In the updated company base-case analysis, durvalumab yielded 2.51 incremental quality-adjusted life-years (QALYs) (− 0.43 vs. the original company base-case analysis), corresponding to an incremental cost-effectiveness ratio of £22,665/QALY (+£3298 vs. the original analysis), which falls within the upper bound of NICE’s willingness-to-pay threshold (£30,000/QALY gained). We estimate that between 31 and 91 early patient deaths may have been avoided by the adoption of durvalumab into the CDF.ConclusionsThese findings reinforce the patient benefit observed with durvalumab in unresectable stage III NSCLC, support the routine use and cost effectiveness of this therapy, and demonstrate how appropriate modelling can inform the early adoption of therapies by payers to achieve patient benefit.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-021-00301-7.

Otolith "spawning zones" across multiple Atlantic cod populations: Do they accurately record maturity and spawning?

Specific changes identified in the otolith macrostructure of Northeast Arctic cod as "spawning zones" are presumed to represent spawning events, but recent experimental studies have challenged this relationship. Because these zones are not routinely recorded outside of Norway, otoliths from multiple Atlantic cod populations with different life history and environmental traits were first examined to see if spawning zones could be identified as a general characteristic of cod. Then, a large archival collection of cod otoliths was used to investigate temporal changes in the occurrence of spawning zones and test for correlations between maturity at age derived from otolith spawning zones and gonad maturity stages. This study shows that spawning zones likely are a universal trait of Atlantic cod and not limited to certain environments or migratory behaviors as previously proposed. Maturity at age derived from spawning zone data showed trends consistent with those from gonad examinations. However, spawning zones appear to form with a one- or two-year lag with sexual maturity, which is suspected to reflect a stabilizing of energy partitioning after the first spawning events. Our results illustrate the potential for use of spawning zones, for example in species or populations with limited available maturity data, and highlights the need for addressing the physiological processes behind their formation.

The association between physical fitness, sports club participation and body mass index on health-related quality of life in primary school children from a socioeconomically deprived area of England

We examined associations between physical fitness components, body mass index (BMI) and sports club participation on health-related quality of life (HRQoL) in 8- to 11-year-old children from a socioeconomically deprived region of England. From May-October 2019, 432 children completed the HRQoL questionnaire Kidscreen-27 and Leisure Time Physical Activity Survey, and a physical fitness testing battery of 20 m shuttle run test (20mSRT), handgrip strength (Handgrip), standing broad jump (Broad Jump), and sit-and-reach. Height, body mass, BMI and somatic maturity data were collected. Comparisons with reference populations were undertaken using a quintile framework. Linear and quantile regression assessed associations between physical fitness components and HRQoL variables. Using English Indices of Multiple Deprivation, 90% of children were from the most deprived quintile and 39% were overweight or obese. More children scored poorly on the Physical Wellbeing (40%) and Psychological Wellbeing (45%) HRQoL domains than the reference population (31%). Physical fitness scores were generally classed as ‘low’-’very low’ (42–58%). 20mSRT and Broad Jump performance explained an additional 10.7% of variance in Physical Wellbeing after adjusting for BMI z-score, sex and age (total R2 21.2%). Quantile regression identified a subset of children who rated Physical Wellbeing as high regardless of 20mSRT performance. Sports club participation was associated with better 20mSRT and Broad Jump performance, and all domains of HRQoL. Our data indicate that some physical fitness components and sports club participation are positively associated with HRQoL of children from socioeconomically deprived areas, irrespective of BMI z-score. Interventions to improve HRQoL should consider both aspects.

Evaluating transformation of marine kerogens from Rock-Eval measurements: B. Confirmation of a scaled thermal maturation path by natural samples

Kerogen transformation with thermal maturation is often assessed using open system Rock-Eval pyrolysis. The decrease in hydrogen index (HI, mg HC/g TOC) with increase in Tmax of kerogen can be viewed as a maturation path that describes kerogen transformation. However, natural heterogeneity causes the initial properties (i.e., HIinitial and Tmaxinitial) of immature kerogens to vary. This heterogeneity, as well as instrument variability, can lead to distinct maturation paths on the classical HI-Tmax plot, especially when comparing sulfur-lean (Type II) and sulfur-rich (Type II-S) marine kerogens. For these reasons, a scaled maturation path (HIrelative-ΔTmax) was previously formulated based on laboratory maturation data. The HIrelative-ΔTmax maturation path considers the HIinitial and Tmaxinitial of each kerogen, shows their relative change with thermal maturation, and reveals two distinct maturation paths for Type II and II-S kerogens.In this contribution, natural maturation data for Type II and II-S kerogens were compiled and used to test the applicability of the HIrelative-ΔTmax maturation path. The compilation is based on literature data for 16 datasets of natural thermal maturation, comprising eight different source rocks, including the Barnett, New Albany, Monterey, Ghareb (Ein Zeitim), Nordegg, Upper and Lower Eagle Ford, Bakken and Posidonia formations. As long as the immature HIinitial and Tmaxinitial can be adequately estimated, the data for most of these source rocks fall within the expected kerogen type on the HIrelative-ΔTmax plot, supporting the usefulness of the scaled maturation paths. Moreover, the scaled HIrelative-ΔTmax maturation paths minimize the impact of the heterogeneity of different kerogens and instrumental variability that can affect the measured Rock-Eval parameters. Hence, the HIrelative-ΔTmax scale is a tool to evaluate the transformation ratio of marine kerogens better.

Evaluating transformation of marine kerogens from Rock-Eval measurements: A. Derivation of a scaled thermal maturation path from laboratory maturation data

Identification of kerogen type in source rocks and quantification of its transformation to hydrocarbon products upon thermal maturation are vital for petroleum exploration. These elements can be evaluated using the open pyrolysis of the Rock-Eval. Despite the importance of sulfur-rich marine kerogens (Type II-S) in petroleum systems, the maturation path of only Types I, II and III kerogens were characterized by the Rock-Eval parameters, and a comparison of the maturation path (defined as the HI-Tmax relation) for Type II and II-S is needed.A comparison of the HI-Tmax relation between Type II and II-S kerogens is presented here by compiling literature data of laboratory thermal maturation for six well-known source rocks. The source rocks include the Toarcian Shale, Kimmeridge, Barnett and Woodford for Type II and the Ghareb and Monterey for Type II-S. When comparing the HI-Tmax relation among the different source rocks, the extent of kerogen transformation cannot be readily evaluated because of variations in the immature properties of kerogens. This variation is overcome by normalizing the HI and scaling the Tmax of mature samples to their immature values. These operations create a new thermal maturation scale defined here as HIrelative-ΔTmax. While the suggested scale minimizes the impact of the heterogeneity within each kerogen type, it generates two distinctive maturation paths for each of them. Although Type II-S kerogens have a lower Tmax at the onset of maturation, the maturation path needed for full transformation is longer than that for Type II kerogens. The two maturation paths are statistically analyzed to generate an empirical law for each of them. Thus, the extent of marine kerogen transformation can be estimated using the empirical law and the suggested HIrelative-ΔTmax thermal maturation scale. The longer maturation path of Type II-S is hypothesized to result from enhanced thermal stabilization of the residual kerogen, driven by the rearrangement of sulfur moieties.