Dynamic modeling of geological carbon storage in an oil reservoir, Bredasdorp Basin, South Africa.

Geological carbon storage provides an efficient technology for the large-scale reduction of atmospheric carbon, and the drive for net-zero emissions may necessitate the future usage of oil reservoirs for CO2 projects (without oil production), hence, dynamic modeling of an oil reservoir for CO2 storage in the Bredasdorp basin, South Africa, was therefore conducted. Injection into the reservoir was for 20 years (2030-2050), and 100 years (2050-2150) to study the CO2-brine-oil interactions, with sensitivities carried out on reservoir boundary conditions. The closed boundary scenario experienced pressure buildup with a target injection rate of 0.5 Mt/year, and a cutback on injection rate progressively until 2050 to not exceed the fracture pressure of the reservoir. The CO2 plume migration was not rapid due to the reduced volume of CO2 injected and the confining pressure. The system was gravity dominated, and gravity stability was not attained at the end of the simulation as fluid interfaces were not yet flat. The open boundary reservoir did not experience a pressure buildup because all boundaries were open, the target injection rate was achieved, and it was a viscous-dominated system. In both cases, the dissolution of CO2 in oil and brine was active, and there was a growing increase of CO2 fraction dissolved in water and oil, a decline in gaseous mobile CO2 phase between 2050 and 2150, and active trapping mechanisms were structural trapping, dissolution in oil and water, and residual trapping. The study showed that boundary condition was very crucial to the success of the project, with direct impacts on injection rate and pressure. This pioneering study has opened a vista on the injection of CO2 into an oil reservoir, and CO2-brine-oil interactions, with sensitivities carried out on reservoir boundary conditions in a closed and an open hydrocarbon system in South Africa.

Head-to-head comparison of FOLFIRINOX versus gemcitabine plus nab-paclitaxel in advanced pancreatic cancer: a target trial emulation using real-world data.

PURPOSE: To emulate a hypothetical target trial assessing the effect of initiating 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) versus gemcitabine plus nab-paclitaxel (GN) within 8 weeks of diagnosis on overall survival. METHODS: An observational cohort study was conducted using population-level data from Alberta, Canada. Individuals diagnosed with advanced pancreatic cancer between April 2015 and December 2019 were identified through the provincial cancer registry and followed until March 2021. Records were linked to other administrative databases containing information on relevant variables. Individuals were excluded if they did not have adequate hemoglobin, platelet, white blood cell, and serum creatinine measures or if they received prior therapy. The observational analog of the per-protocol effect was estimated using inverse probability weighted Kaplan-Meier curves with bootstrapped 95% confidence intervals. RESULTS: Four hundred seven individuals were eligible. The weighted median overall survival was 8.3 months (95% CI, 5.7-11.9) for FOLFIRINOX and 5.1 months (95% CI: 4.3 to 5.8) for GN. The adjusted difference in median overall survival was 3.2 months (95% CI, 1.1-7.4) and the mortality hazard ratio was 0.78 (95% CI, 0.61-0.97). CONCLUSIONS: Our estimates favored the initiation of FOLFIRINOX over GN with respect to overall survival.

Indirect Treatment Comparison of Daratumumab, Pomalidomide, and Dexamethasone Versus Standard of Care in Patients with Difficult-to-Treat Relapsed/Refractory Multiple Myeloma.

INTRODUCTION: The phase 3 APOLLO study demonstrated significantly better progression-free survival (PFS) and clinical responses with daratumumab, pomalidomide, and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM). On the basis of these results and those from the phase 1b EQUULEUS trial, D-Pd was approved in this patient population. In the absence of head-to-head data comparing D-Pd with further standard of care (SOC) therapies, indirect treatment comparisons (ITCs) can provide important information to help optimize treatment selection. The objective of this study was to indirectly compare PFS improvement with D-Pd versus daratumumab, bortezomib, and dexamethasone (D-Vd) and D-Pd versus bortezomib and dexamethasone (Vd) in patients with RRMM. METHODS: Patient-level data were from APOLLO, EQUULEUS, and CASTOR. Three methods of adjusting imbalances in baseline characteristics including stabilized inverse probability of treatment weighting (sIPTW), cardinality matching (CM), and propensity score matching (PSM) were initially considered. CM offers mathematically guaranteed largest matched sample meeting pre-specified maximum standardized mean difference criteria for matching covariates. sIPTW and PSM were based on propensity scores derived from logistic regression. Feasibility assessment of the PSM method returned too low effective sample size to support a meaningful comparison. CM was chosen as the base case and sIPTW as a sensitivity analysis. RESULTS: After harmonized eligibility criteria were applied, 253, 104, and 122 patients from the D-Pd, D-Vd, and Vd cohorts, respectively, were included in the ITC analyses. Some imbalances in baseline characteristics were identified between D-Pd and D-Vd/Vd cohorts that remained after adjustment. PFS hazard ratios showed significant improvement for D-Pd over D-Vd and Vd for CM and sIPTW analyses. CONCLUSIONS: Results showed consistent PFS benefit for D-Pd versus D-Vd and Vd regardless of the adjustment technique used. These findings support the use of D-Pd versus D-Vd or Vd in patients with difficult-to-treat RRMM. TRIAL REGISTRATION: NCT03180736; NCT02136134, NCT01998971.

Keeping it real: implications of real-world treatment outcomes for first-line immunotherapy in metastatic non-small-cell lung cancer.

Tweetable abstract Recent RWD studies suggest that the performance of immunotherapy in NSCLC is not as good as that seen in RCTs. However, analyses using RWD (and their interpretation) require careful appraisal and quantification of possible sources of bias.

Assessment of Alectinib vs Ceritinib in ALK-Positive Non-Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data.

Importance: Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). Objective: To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. Design, Setting, and Participants: This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. Exposures: Initiation of alectinib or ceritinib therapy. Main Outcomes and Measures: The main outcome was OS. Results: In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. Conclusions and Relevance: Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.

Predictive accuracy of prenatal ultrasound findings for lower urinary tract obstruction: A systematic review and Bayesian meta-analysis.

BACKGROUND: Lower urinary tract obstruction (LUTO) is a rare but critical fetal diagnosis. Different ultrasound markers have been reported with varying sensitivity and specificity. AIMS: The objective of this systematic review and meta-analysis was to identify the diagnostic accuracy of ultrasound markers for LUTO. MATERIALS AND METHODS: We performed a systematic literature review of studies reporting on fetuses with hydronephrosis or a prenatally suspected and/or postnatally confirmed diagnosis of LUTO. Bayesian bivariate random effects meta-analytic models were fitted, and we calculated posterior means and 95% credible intervals for the pooled diagnostic odds ratio (DOR). RESULTS: A total of 36,189 studies were identified; 636 studies were available for full text review and a total of 42 studies were included in the Bayesian meta-analysis. Among the ultrasound signs assessed, megacystis (DOR 49.15, [15.28, 177.44]), bilateral hydroureteronephrosis (DOR 41.33, [13.36,164.83]), bladder thickening (DOR 13.73, [1.23, 115.20]), bilateral hydronephrosis (DOR 8.36 [3.17, 21.91]), male sex (DOR 8.08 [3.05, 22.82]), oligo- or anhydramnios (DOR 7.75 [4.23, 14.46]), and urinoma (DOR 7.47 [1.14, 33.18]) were found to be predictive of LUTO (Table 1). The predictive sensitivities and specificities however are low and wide study heterogeneity existed. DISCUSSION: Classically, LUTO is suspected in the presence of prenatally detected megacystis with a dilated posterior urethra (i.e., the keyhole sign), and bilateral hydroureteronephrosis. However, keyhole sign has been found to have modest diagnostic performance in predicting the presence of LUTO in the literature which we confirmed in our analysis. The surprisingly low specificity may be influenced by several factors, including the degree of obstruction, and the diligence of the sonographer at searching for and documenting it during the scan. As a result, providers should consider this when establishing the differential for a fetus with hydronephrosis as the presence or absence of keyhole sign does not reliably rule in or rule out LUTO. CONCLUSIONS: Megacystis, bilateral hydroureteronephrosis and bladder wall thickening are the most accurate predictors of LUTO. Given the significant consequences of a missed LUTO diagnosis, clinicians providing counselling for prenatal hydronephrosis should maintain a low threshold for considering LUTO as part of the differential diagnosis.

The Landscape of Emerging Randomized Clinical Trial Evidence for COVID-19 Disease Stages: A Systematic Review of Global Trial Registries.

PURPOSE: A multitude of randomized controlled trials (RCTs) have emerged in response to the novel coronavirus disease (COVID-19) pandemic. Understanding the distribution of trials among various settings is important to guide future research priorities and efforts. The purpose of this review was to describe the emerging evidence base of COVID-19 RCTs by stages of disease progression, from pre-exposure to hospitalization. METHODS: We collated trial data across international registries: ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Registry; Chinese Clinical Trial Registry; Clinical Research Information Service; EU Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; German Clinical Trials Register (up to 7 October 2020). Active COVID-19 RCTs in international registries were eligible for inclusion. We extracted trial status, intervention(s), control, sample size, and clinical context to generate descriptive frequencies, network diagram illustrations, and statistical analyses including odds ratios and the Mann-Whitney U-test. RESULTS: Our search identified 11503 clinical trials registered for COVID-19 and identified 2388 RCTs. After excluding 45 suspended RCTs and 480 trials with unclear or unreported disease stages, 1863 active RCTs were included and categorized into four broad disease stages: pre-exposure (n=107); post-exposure (n=208); outpatient treatment (n=266); hospitalization, including the intensive care unit (n=1376). Across all disease stages, most trials had two arms (n=1500/1863, 80.52%), most often included (hydroxy)chloroquine (n=271/1863, 14.55%) and were US-based (n=408/1863, 21.90%). US-based trials had lower odds of including (hydroxy)chloroquine than trials in other countries (OR: 0.63, 95% CI: 0.45-0.90) and similar odds of having two arms compared to other geographic regions (OR: 1.05, 95% CI: 0.80-1.38). CONCLUSION: There is a marked difference in the number of trials across settings, with limited studies on non-hospitalized persons. Focus on pre- and post-exposure, and outpatients, is worthwhile as a means of reducing infections and lessening the health, social, and economic burden of COVID-19.

Impact of Maximum Allowable Cost on CO2 Storage Capacity in Saline Formations.

Injecting CO2 into deep saline formations represents an important component of many greenhouse-gas-reduction strategies for the future. A number of authors have posed concern over the thousands of injection wells likely to be needed. However, a more important criterion than the number of wells is whether the total cost of storing the CO2 is market-bearable. Previous studies have sought to determine the number of injection wells required to achieve a specified storage target. Here an alternative methodology is presented whereby we specify a maximum allowable cost (MAC) per ton of CO2 stored, a priori, and determine the corresponding potential operational storage capacity. The methodology takes advantage of an analytical solution for pressure build-up during CO2 injection into a cylindrical saline formation, accounting for two-phase flow, brine evaporation, and salt precipitation around the injection well. The methodology is applied to 375 saline formations from the U.K. Continental Shelf. Parameter uncertainty is propagated using Monte Carlo simulation with 10 000 realizations for each formation. The results show that MAC affects both the magnitude and spatial distribution of potential operational storage capacity on a national scale. Different storage prospects can appear more or less attractive depending on the MAC scenario considered. It is also shown that, under high well-injection rate scenarios with relatively low cost, there is adequate operational storage capacity for the equivalent of 40 years of U.K. CO2 emissions.