Adjustment For Imbalances Research Articles

Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer

BackgroundMAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. MethodsIPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. ResultsImprovements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. ConclusionsIPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. Trial registrationNCT03748641 (MAGNITUDE)

The ecor as global special purpose money: towards a green international monetary system to finance sustainable and just transformation

AbstractCountries from the Global South face significant challenges to finance sustainable and just transformation. These challenges primarily stem from the hierarchical character of the current international monetary system, which requires Global South countries to obtain US dollars to finance imports of green goods, services, and technologies that they cannot (yet) produce, but require for the sustainable transformation. To overcome this hurdle, we propose the foundation of a green international monetary system with a Green World Central Bank (GWCB) at its centre. The GWCB would be allowed to create its own unit of account, which in our model we refer to as the “ecor”. The ecor would be a global special purpose money similar to Keynes’ ‘bancor’. Ecors would be created by the GWCB in the act of lending, and credited to the GWCB accounts of countries to finance imports needed to combat the climate crisis and advance the process of sustainable and just transformation in their societies and economies. Ecors transferred by deficit countries to surplus countries would only be able to be used within the system, leading to an expansionary adjustment of international imbalances. In this way, the amount of ecors would adjust elastically to the real demands for sustainable change and would not be limited by reserves or by funding conditions from private finance. This would create an international monetary system capable of responding appropriately and flexibly to ease the financing needs of countries around the world, thus enabling them, to effectively address the climate crisis on a globally just basis.

Separating the wheat from the chaff: How to measure hospital quality in routine data?

To measure hospital quality based on routine data available in many health care systems including the United States, Germany, the United Kingdom, Scandinavia, and Switzerland. We use the Swiss Medical Statistics of Hospitals, an administrative hospital dataset of all inpatient stays in acute care hospitals in Switzerland for the years 2017-2019. We study hospital quality based on quality indicators used by leading agencies in five countries (the United States, the United Kingdom, Germany, Austria, and Switzerland) for two high-volume elective procedures: inguinal hernia repair and hip replacement surgery. We assess how least absolute shrinkage and selection operator (LASSO), a supervised machine learning technique for variable selection, and Mundlak corrections that account for unobserved heterogeneity between hospitals can be used to improve risk adjustment and correct for imbalances in patient risks across hospitals. The Swiss Federal Statistical Office collects annual data on all acute care inpatient stays including basic socio-demographic patient attributes and case-level diagnosis and procedure codes. We find that LASSO-selected and Mundlak-corrected hospital random effects logit models outperform common practice logistic regression models used for risk adjustment. Besides the more favorable statistical properties, they have superior in- and out-of-sample explanatory power. Moreover, we find that Mundlak-corrected logits and the more complex LASSO-selected models identify the same hospitals as high or low-quality offering public health authorities a valuable alternative to standard logistic regression models. Our analysis shows that hospitals vary considerably in the quality they provide to patients. We find that routine hospital data can be used to measure clinically relevant quality indicators that help patients make informed hospital choices.

Parental factors predicting social deviance and psychological outcomes in offspring: Evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC).

Objective: The objective of the present study was to examine whether exposure to prenatal psychoactive substances is associated with psychological outcomes and deviant behaviour. Methods: This was a secondary analysis of 7,769 mother-child dyads in the Avon Longitudinal Study of Parents and Children (ALSPAC) who were followed until the children were aged approximately 12 years. Parental characteristics and maternal use of various substances were collected in pregnancy and entered as predictors of psychological outcomes in childhood and deviant behaviours in early adolescence. The psychological outcomes were IQ, social cognition, working memory and inhibition, while the deviant behaviours were threatening others, truancy and cruelty to animals. Weighted logistic regression models were used to predict deviant behaviours and weighted linear regression for the psychological outcomes. Results: High prenatal alcohol exposure predicted truancy and cruelty to animals. Tobacco exposure predicted lower IQ, a greater social communication deficit, lower working memory, truancy and threatening others. Illicit drugs predicted a higher social communication deficit and truancy. All prenatal substance exposures remained significant after adjustment for peer influences and covariate imbalance. Conclusion: Alcohol, tobacco and illicit drugs were associated with deviant behaviours in early adolescence and these behaviours were preceded by psychological deficits in childhood. The present study supports the guideline that no amount of alcohol is safe to consume in pregnancy and that tobacco and illicit drugs should be avoided.

Effects of pancreatic enzyme replacement therapy (PERT) on overall survival (OS) in patients (pts) with advanced pancreatic ductal adenocarcinoma (APDAC) and evidence of pancreatic enzyme insufficiency (PEI): A single institution, retrospective, cohort study.

e16254 Background: Weight loss (WL)/cachexia is common in APDAC and associated with multiple adverse pt outcomes. Current NCCN guidelines recommend PERT in PDAC patients with PEI. However, little evidence exists regarding PERT use and clinical outcomes in PDAC, especially APDAC. We present here data on impact of PERT use from our institution. Methods: Study pts were identified from the Virginia Mason PDAC database (01-2010-12/2019). Eligibility criteria included: 1) No upfront resection, 2) no prior PDAC therapy, 3) FE 1 < 200 µg/g or documented evidence of PEI at diagnosis, 4) treatment at least to initial restaging event (8 wks), and 5) data regarding PERT use/dosage available. Pts were stratified by PERT/non-PERT usage. PERT use was defined by prescription for >50% of time from initial Rx to 1st restage using recommended dosing per package insert. Pts on PERT for < 50% of time during this time frame and/or prescribed less than recommended dose were excluded from analysis. Results: 505 total pts were study eligible, PERT 197(39%), non-PERT 308(61%). WL (80 vs 65%, p< 0.001) and cachexia (74 v 54%, p<0.001) were more common in PERT pts. ECOG PS 2 (4 vs 9%, p=0.02) and non-metastatic disease (51 vs 40%, p=0.02) more common in non-PERT pts. Other pt characteristics (age, sex, diabetes at dx, serum albumin, NLR, BMI distribution, % obese) were similar in both groups. OS after adjustment for PS and stage was 15.7 mo (95% CI 13.6-18.3 mo) among PERT users vs. !2.6 mo non-PERT users (95% CI 11.0 -13.7 mo, p=0.02, adjusted hazard ratio 0.81 (95% CI 0.67-0.99). Pts receiving PERT also tended to have a higher therapeutic response rate by both Ca 19.9 and CT: but without statistical significance (p=0.10, 0.09, respectively). Regarding nutrition, PERT vs. non-PERT pts at 8 weeks experienced less WL (-0.4 vs. -1.5 kg, p=0.03) and less change in BMI (-0.3 vs -1.6, p=0.02). This was true even in cachectic pts at dx (change in BMI + 0.1 vs -1.7, p=0.01). Additional analyses of impact of PERT on QOL are ongoing, including in a subset of patients who underwent serial PG-SGA scoring. Conclusions: In this pt cohort, APDAC pts prescribed PERT per recommended dosing had a statistically significant improvement in median OS vs. those not prescribed PERT. This remained true in multivariate analysis after adjustment for population imbalances. PERT use was also associated with a statistically significant reduction in weight loss and change in BMI at 8 weeks, even in those patients defined as cachectic at diagnosis. Further investigation into a) impact of PERT on quality of life, b) mechanisms producing the above observations, c) confirmatory observations in independent datasets, and d) additional therapeutic interventions designed to mitigate weight loss/cachexia in PDAC are needed.

A sequential therapy with sorafenib followed by regorafenib against single-line atezolizumab and bevacizumab in advanced hepatocellular carcinoma (HCC): Indirect treatment comparisons (ITC) using the RESORCE study.

537 Background: Our objective was to explore ITC of sequential therapy with sorafenib followed by regorafenib (sorego) against atezolizumab+bevacizumab (atezobev) in HCC. Naïvely comparing median Overall Survival (OS) from sorafenib initiation on sorego in the RESORCE trial with atezobev from IMbrave150 is biased by population imbalance and selection of patients who survived on sorafenib in RESORCE. We used unanchored Matching Adjusted Indirect Comparison (MAIC) and novel survivorship bias adjusted anchored ITC (SBITC) to overcome these limitations. Methods: Overall Survival (OS) from sorafenib initiation in RESORCE on sorego were compared with reconstructed Individual Patient Data (IPD) OS based on Kaplan-Meier curves from IMbrave150 on atezobev. In MAIC, the sorego arm of RESORCE was weighted on reported baseline characteristics to match the IMbrave150 atezobev arm. In SBITC, sorafenib IPD from IMbrave150 were sampled with replacement and added to the RESORCE BSC arm to correct for “survivorship bias”. Sample size was sufficient for follow-up prior to RESORCE randomisation to be within 5% of sorafenib follow-up in IMbrave150. Anchored Bucher ITC was used to compare to unadjusted IMbrave150 with bootstrapping to obtain standard errors. Hazard Ratios (HRs) were used to compare OS. Results: MAIC gave an OS HR of 0.75 (95% confidence interval 0.60, 0.93; p-value=0.007). Effective sample size (ESS) was reduced from 379 to 271.75. SBITC gave a HR of 0.63 (0.52, 0.76; p-value <0.001) requiring an average of 83 sorafenib patients to be added from IMbrave150. Conclusions: We proposed MAIC and SBITC to overcome biases in naïve comparisons of OS on sorego with atezobev in HCC. However, MAIC is limited to baseline characteristics in IMbrave150 and does not adjust for “survivorship bias”. SBITC depends on sample size from IMbrave150, and makes no adjustment for imbalance in baseline characteristics. Despite these limitations, our methods were consistent with naïve comparisons and suggested longer OS with sorego compared to atezobev in patients with HCC.

Validity of Machine Learning in Detecting Complicated Appendicitis in a Resource-Limited Setting: Findings from Vietnam.

Complicated appendicitis, a potentially life-threatening condition, is common. However, the diagnosis of this condition is mainly based on physician's experiences and advanced diagnostic equipment. This study built and validated machine learning models to facilitate the detection of complicated appendicitis. A retrospective cohort study was conducted based on medical charts of all patients undergoing a laparoscopic appendectomy at a city hospital during 2016-2020. The synthetic minority over-sampling technique (SMOTE) was used to adjust for the imbalance. Multiple classification approaches were used to train and validate models including support vector machine (SVM), decision tree (DT), K-nearest neighbor (KNN), logistic regression (LR), artificial neural network (ANN), and gradient boosting (GB). Among 1,950 patients included in the data analysis, there were 483 patients identified as having complicated appendicitis (24.8%). Based on data without SMOTE adjustment for imbalance, the accuracy levels and AUCs were high in all models using different parameters, ranging from 0.687 to 0.815. After adjusting for imbalance data using SMOTE, AUC and accuracy levels in the models using imbalance adjusted data were higher. Of these, the GB had all AUC and accuracy values of approximately 0.8 or more in both adjusted and unadjusted data. Machine learning approaches including SVM, DT, logistic, KNN, ANN, and GB have a high level of validity in classifying patients with complicated appendicitis and patients without complicated appendicitis. Among these, GB had the highest level of validity and should be used or further validated. Our study indicates the beneficial potentials of machine learning techniques in a clinical setting in general and in the diagnosis of complicated appendicitis in particular.

The Asymmetric Adjustment of Global Imbalances: Myth or Fact?

The Asymmetric Adjustment of Global Imbalances: Myth or Fact?

Gravity Wave Morphology During the 2018 Sudden Stratospheric Warming Simulated by a Whole Neutral Atmosphere General Circulation Model

AbstractAtmospheric gravity waves (GWs) during the February 2018 sudden stratospheric warming (SSW) event are simulated using the T639L340 whole neutral atmosphere general circulation model. Their characteristic morphology around the drastically evolving polar vortex is revealed by three‐dimensional (3D) visualization and ray‐tracing analyses. The 3D morphology of simulated GWs is described for the three key days that represent the pre‐SSW conditions, the mature stage for the vortex splitting, and the late SSW. The combination of strong winds along the polar vortex edge and underneath the tropospheric winds with similar wind directions consist of the deep waveguide for the upward‐propagating GWs, forming GW hot spots in the middle atmosphere. The GW hot spots associated with the development of the SSW are limited to North America and Greenland, and they include the typical upward‐propagating orographic GWs with relatively long vertical wavelengths. Different types of characteristic GW signatures are also recognized around the Canadian sub‐vortex (CV). GWs having short vertical wavelengths form near the surface and obliquely propagate over long distances along the CV winds. The non‐orographic GWs with short vertical wavelengths form in the middle stratosphere through the spontaneous adjustment of flow imbalance around the CV. Those GWs cyclonically ascend into the mesosphere along CV winds.

Global natural projections.

The paper contributes to the debate on natural interest rates and potential growth rates. We build a model-based projection of the world’s most significant economies/areas to improve understanding of their change over the long run and the factors behind their decline. We use a general equilibrium overlapping generation model to understand the simultaneous role of demographics, technology, and globalization. The novelty of the model lies in the way it constructs a human capital index based on UN population projections and an estimated increasing returns production function for major economies worldwide. We find that the decline in interest rates is well explained through labor market dynamics and the increasing obsolescence of capital goods. We also find that a reduced share of labor income has caused movement in the opposite direction, leading to an increase in natural interest rates, which runs counter to the empirical evidence. Moreover, the dynamics of economic integration predict an endogenous adjustment of global imbalances over the long run, with an increasing weight of the Chinese economy and, consequently, a phase of weakness in United States growth between 2030 and 2040. The model is also used to perform shock scenario analysis. We find that demographic decline can adversely affect the growth dynamics for European countries, while a change in the dynamics of globalization can have serious consequences, especially for the United States, with significant benefits for European countries and China.

Ensemble method using real images, metadata and synthetic images for control of class imbalance in classification.

Binary classification and anomaly detection face the problem of class imbalance in data sets. The contribution of this paper is to provide an ensemble model that improves image binary classification by reducing the class imbalance between the minority and majority classes in a data set. The ensemble model is a classifier of real images, synthetic images, and metadata associated with the real images. First, we apply a generative model to synthesize images of the minority class from the real image data set. Secondly, we train the ensemble model jointly with synthesized images of the minority class, real images, and metadata. Finally, we evaluate the model performance using a sensitivity metric to observe the difference in classification resulting from the adjustment of class imbalance. Improving the imbalance of the minority class by adding half the size of the majority class we observe an improvement in the classifier’s sensitivity by 12% and 24% for the benchmark pre-trained models of RESNET50 and DENSENet121 respectively.

Intracranial Pressure Monitoring in Patients With Severe Traumatic Brain Injury: Extension of the Recommendations and the Effect on Outcome by Propensity Score Matching.

Intracranial pressure (ICP) monitoring is recommended for patients with traumatic brain injury (TBI) with a Glasgow Coma Scale (GCS) <9 on admission and revealing space-occupying lesions or swelling on computed tomography. However, previous studies that have evaluated its effect on outcome have shown conflicting results. To study the effect of ICP monitoring on outcome after adjustment of patient's characteristics imbalance and determine the potential benefit on patients with higher GCS that deteriorates early or in the absence of computed tomography results suggesting high ICP. We searched for adult patients with TBI admitted between 1996 and 2020 with a GCS <9 on admission or deterioration from higher scores within 24 hours after TBI. Patients were divided into groups if they fulfilled strict (Brain Trauma Foundation guidelines) or extended criteria (patients who worsened after admission or without space-occupying lesions) for ICP monitoring. Propensity score analyses based on nearest neighbor matching was performed. After matching, we analyzed data from 454 patients and 184 patients who fulfilled strict criteria or extended criteria for ICP monitoring, respectively. A decreased on in-hospital mortality was detected in monitored patients following strict and extended criteria . Those patients with a higher baseline risk of poor outcome showed higher odds of favorable outcome if they were monitored. ICP monitoring in patients with severe TBI within 24 hours after injury following strict and extended criteria was associated with a decreased in-hospital mortality. The identification of patients with a higher risk of an unfavorable outcome might be useful to better select cases that would benefit more from ICP monitoring.

Risk of selection bias assessment in the NINDS rt-PA stroke study

ObjectivesThe NINDS rt-PA Stroke Study is frequently cited in support of alteplase for acute ischemic stroke within 3 h of symptom onset. Multiple post-hoc reanalyses of this trial have been published to adjust for a baseline imbalance in stroke severity. We performed a risk of selection bias assessment and reanalyzed trial data to determine if the etiology of this baseline imbalance was more likely due to random chance or randomization errors.MethodsA risk of selection bias assessment was conducted using signaling questions from the Cochrane Risk of Bias 2 (ROB 2) tool. Four sensitivity analyses were conducted on the trial data based on the randomization process: assessment of imbalances in allocation in unique strata; adherence to a pre-specified restriction on randomization between time strata at each randomization center; assessment of differences in baseline computed tomography (CT) results in unique strata; and comparison of baseline characteristics between allocation groups within each time strata. A multivariable logistic regression model was used to compare reported treatment effects with revised treatment effects after adjustment of baseline imbalances identified in the sensitivity analyses.ResultsBased on criteria from the ROB 2 tool, the risk of bias arising from the randomization process was high. Sensitivity analyses found 11 of 16 unique strata deviated from the expected 1:1 allocation ratio. Three randomization centers violated an apriori rule regarding a maximum difference in allocation between the time strata. Three unique strata had imbalances in baseline CT results that prognostically favored alteplase. Four imbalances in baseline characteristics were identified in the 91–180-min time stratum that all prognostically favored alteplase and were consistent with a larger alteplase treatment effect size compared to the 0–90-min time stratum. After adjustments for baseline imbalances, all reported treatment effects were reduced. Three out of seven originally positive reported results were revised to non-significant.ConclusionThis risk of selection bias assessment revealed a high risk of selection bias in the NINDS rt-PA Stroke Study. Sensitivity analyses conducted based on the randomization process supported this assessment. Baseline imbalances in the trial were more likely due to randomization errors than random chance. Adjusted analyses accounting for baseline imbalances revealed a reduction in reported treatment effects supporting the presence of selection bias in the trial. Treatment decisions and guideline recommendations based on the original treatment effect reported in the NINDS rt-PA Stroke Study should be done cautiously.

Endovascular treatment for acute basilar artery occlusion due to different stroke etiologies of large artery atherosclerosis and cardioembolism.

Stroke etiology may affect the prognosis of acute basilar artery occlusion (BAO). This study aimed to estimate the efficacy and safety of endovascular treatment (EVT) in BAO strokes due to the underlying stroke etiologies of large artery atherosclerosis (LAA) and cardioembolism (CE). Patients with LAA and CE subtypes from the registry EVT for Acute Basilar Artery Occlusion Study (BASILAR) were selected for this analysis. We estimated the EVT treatment effect relative to standard medical treatment (SMT) in these patients by using a propensity score approach with inverse probability of treatment weighted estimation. Outcomes included 90-day favorable functional outcomes (modified Rankin scale (mRS) 0-3), functional independence (mRS 0-2), all-cause mortality, and symptomatic intracranial hemorrhage (sICH). A total of 744 patients were included in the final analysis. After weighting with inverse probability of treatment estimation, the patients who, based on their characteristics, were treated with EVT rather than SMT, demonstrated higher rates of favorable functional outcomes in both the LAA (29.2% vs 11.7%, adjusted OR with 95% CI: 4.34 [2.15-8.78], p < 0.001) and the CE subtype (36.0% vs 8.1%, adjusted OR with 95% CI: 9.14 [1.96-42.55], p = 0.005). A similar finding was also observed for functional independence. EVT patients also demonstrated lower rates of mortality than SMT. Among EVT patients, no significant difference was observed in mortality or sICH between LAA and CE groups, but LAA patients had lower rates of favorable functional outcome and functional independence (29.2% vs 37% and 24.2% vs 32.9%, respectively), where the latter remained significant after adjustment for imbalances in baseline data (p = 0.04). In acute BAO strokes, both LAA and CE patients who, based on their characteristics, were treated with EVT rather than SMT, demonstrated better outcomes. Among EVT patients, LAA and CE subtypes displayed important baseline and treatment differences, and LAA patients were less likely to achieve functional independence at 3 months, but mortality and sICH were similar between LAA or CE subtypes. These results need to be confirmed in future clinical trials.

Paying attention for adjacent areas: Learning discriminative features for large-scale 3D scene segmentation

Despite recent improvements in analyzing large-scale 3D point clouds, several problems still exist: (a) segmentation models suffer from intra-class inconsistency and inter-class indistinction; (b) the existing methods ignore the inherent long-tailed class distribution of real-world 3D data. These problems result in unsatisfactory semantic segmentation predictions, especially in object adjacent areas. To handle these problems, this paper proposes a novel Adjacent areas Refinement Network (ARNet). Specifically, an Adjacent areas Refinement (AR) module is designed, which consists of two parallel attention blocks. Besides, our proposed attention blocks can process a large number of points (N∼105) with a slight increase in the computational complexity and time cost. Additionally, to deal with the inherent long-tailed class distribution in real-world 3D data, imbalance adjustment loss and occupancy regression loss are introduced. Based on this, the proposed network can handle the classification of both majority and minority classes, which is essential in distinguishing the ambiguous parts in large-scale 3D scenes. The proposed AR module and the loss functions can be easily integrated into the cutting-edge backbone networks, contributing to better performance in modeling semantic inter-dependencies and significantly improving the accuracy of the state-of-the-art semantic segmentation methods on indoor and outdoor scenes.

Comparative Safety and Efficacy of Remdesivir Versus Remdesivir Plus Convalescent Plasma Therapy (CPT) and the Effect of Timing of Initiation of Remdesivir in COVID-19 Patients: An Observational Study From North East India.

IntroductionAs per the COVID-19 treatment guidelines of India, remdesivir and convalescent plasma therapy (CPT) are indicated in moderate and severe patients. In this study, we have evaluated the comparative safety and efficacy of remdesivir versus remdesivir CPT combination and effect of early versus late initiation of remdesivir.Materials and methodsA hospital-based observational study was conducted among hospitalized moderate and severe COVID-19 patients treated with either remdesivir and/or CPT as per national guidelines. Response to therapy was evaluated in terms of mortality, mechanical ventilation requirement, ICU requirement, and safety.Results and observationsA total of 95 moderate and severe COVID-19 patients on remdesivir (n=35) or remdesivir + CPT combination (n=60) were included. Both the remdesivir and remdesivir + CPT groups were comparable in terms of baseline characteristics, however, proportion of patients with baseline serum creatinine >1.5 was higher in the remdesivir group. No difference was seen between both the groups in terms of mortality, mechanical ventilation requirement, ICU requirement, and safety parameters in the overall moderate and severe COVID-19 populations and when each of these severity categories (moderate and severe) were analyzed separately. Early initiation (<9 days from symptom onset) of remdesivir was associated with better treatment outcome in terms of mortality and requirement of ICU. Post-therapy shortness of breath and LFTs (liver function tests) elevation was more in the late initiation of remdesivir group, which may be due to the lack of efficacy and subsequent disease progression or a direct effect of the drug. The beneficial effect of remdesivir was maintained even after adjustment for important prognostic factors and baseline imbalances (age, sex, disease severity, CPT use, and serum creatinine level).ConclusionsEarly initiation of remdesivir was associated with clinical benefit in terms of mortality and mechanical ventilation requirement. However, addition of convalescent plasma therapy as an additional therapeutic modality to remdesivir was not found to be beneficial.

The Impact of Trial Eligibility Criteria on Outcomes in a Nationwide Cohort of Newly Diagnosed DLBCL Patients Treated with R-CHOP

Background: Generalizability of results from clinical trials with narrow in-/exclusion criteria are a concern as significant deviations in efficacy or toxicity may occur when treatments are used in populations of elderly and more comorbid patients. The cost-effectiveness of novel therapies may also be less favorable if real-world treatment effects are inferior to clinical trial results. In diffuse large B-cell lymphoma (DLBCL), a recent US study showed that baseline organ function-based eligibility criteria had substantial impact on survival with ineligible patients being at higher risk of dying from progressive lymphoma (1).Aims: The present study explored the impact of commonly used in-/exclusion criteria in key completed and ongoing first line DLBCL trials on survival in a Danish population-based study of patients with de novo DLBCL.Patients and methods: DLBCL patients enrolled in the Danish Lymphoma Registry (LYFO) and treated with R-CHOP in the period 2008-19 were screened for completeness of data to match trial eligibility criteria. The key organ/hematology eligibility criteria of completed or ongoing all-comers DLBCL studies (REMoDL-B, Goya, Polarix and Hovon84) were collected (bilirubin, ALAT, creatinine, eGFR, leucocytes, neutrophils, thrombocytes and ECOG).First, high-level trial matching on disease risk group (Ann Arbor, bulky disease, international prognostic index (IPI)) and age-groups were performed so that patients assessed for trial eligibility had a relevant risk profile. Subsequently, patients were divided into eligible or ineligible based on selected in/exclusion criteria. For each trial, overall survival (OS) from treatment start were compared for eligible and ineligible patients using inverse probability of treatment weighted Kaplan-Meier and log-rank tests. Crude OS and OS adjusted for residual imbalances in IPI and age were estimated. When possible, the OS curves from standard arms of the original trials were superimposed on OS plots. For each trial, the Shapley value of each criterion was calculated, using the HRs as well as the 5y restricted loss of lifetimes (RLOLs). The Shapley value measures the average influence of each eligibility criterion on the estimated IPI- and age-adjusted HR/5y RLOL.Results: A total of 3,150 R-CHOP treated DLBCL patients without discordant low-grade lymphoma were identified in the surveyed period. A total of 1,666 patients (52.89% of surveyed population) were available for the REMoDL-B trial, 1,431 (45.43%) for Goya, 1,125 (35.71%) for Polarix, and 1,432 (45.46%) for Hovon84. The variations of numbers for each trial evaluation were explained by trial inclusion criteria and missing data in LYFO. Crude OS estimates for patients with and without all necessary information were similar (data not shown).OS curves for eligible and ineligible patients are shown in Figure 1 and, when possible, with superimposed trial results (Goya, REMoDL-B, Hovon84). Survival differences between trial eligible and ineligible patients were robust to further adjustment of imbalances in age and IPI.Associated crude and adjusted 2 and 5-year OS rates for trial eligible and ineligible are shown in Table 1. The largest numerical difference in 2-year crude OS between eligible and ineligible was observed in the REMoDL-B trial (ineligible had 26% lower 2-year OS rate). The largest numerical difference in 2-year OS adjusted for IPI and age between eligible and ineligible was observed for the Polarix trial (ineligible had 17% lower 2-year OS rate). The strongest drivers of OS differences between trial eligible and ineligible patients in terms of the tested eligibility criteria were thrombocyte count (HR-contribution calculated from Shapley values -0.11; -0.14) and ECOG (HR-contribution -0.09; -0.21). Liver function parameters (bilirubin and ALAT) had low impact on OS (HR-contribution 0.00; -0.05 and 0.00; 0.07).Conclusions: The present population-based study confirms that trial ineligible patients have worse survival even after adjustments in imbalances in age and disease risk category. Thus, trial eligibility criteria have substantial impact on generalizability of results to a wider unselected population. Interestingly, the trial eligible patients identified in the present study had very similar outcomes to R-CHOP treated patients in the original trials supporting the possible use of RWD as synthetic control arms. [Display omitted] DisclosuresMaurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jørgensen: Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Celgene: Consultancy. Larsen: BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Odense University Hospital, Denmark: Current Employment; Gilead: Consultancy. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Abbvie: Consultancy; Janssen: Consultancy. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months.

A pilot randomized clinical trial of cryopreserved versus liquid-stored platelet transfusion for bleeding in cardiac surgery: The cryopreserved versus liquid platelet-New Zealand pilot trial.

Platelets for transfusion have a shelf-life of 7 days, limiting availability and leading to wastage. Cryopreservation at -80°C extends shelf-life to at least 1 year, but safety and effectiveness are uncertain. This single centre blinded pilot trial enrolled adult cardiac surgery patients who were at high risk of platelet transfusion. If treating clinicians determined platelet transfusion was required, up to three units of either cryopreserved or liquid-stored platelets intraoperatively or during intensive care unit admission were administered. The primary outcome was protocol safety and feasibility. Over 13 months, 89 patients were randomized, 23 (25.8%) of whom received a platelet transfusion. There were no differences in median blood loss up to 48 h between study groups, or in the quantities of study platelets or other blood components transfused. The median platelet concentration on the day after surgery was lower in the cryopreserved platelet group (122 × 103 /μl vs. 157 × 103 /μl, median difference 39.5×103 /μl, p= 0.03). There were no differences in any of the recorded safety outcomes, and no adverse events were reported on any patient. Multivariable adjustment for imbalances in baseline patient characteristics did not find study group to be a predictor of 24-h blood loss, red cell transfusion or a composite bleeding outcome. This pilot randomized controlled trial demonstrated the feasibility of the protocol and adds to accumulating data supporting the safety of this intervention. Given the clear advantage of prolonged shelf-life, particularly for regional hospitals in New Zealand, a definitive non-inferiority phase III trial is warranted.

A Comparative Analysis of Dynamic Interactions between European and Indonesian Cocoa Markets during the 2008 Global Financial Crisis and the 2011 European Debt Crisis

This study empirically explores the dynamic interactions between the European and Indonesian cocoa markets during the 2008 global financial crisis (GFC) and the 2011 European debt crisis (EDC) using a battery of time series approaches of cointegration and multivariate Granger causality. The study documented a long-run equilibrium between the European and Indonesian cocoa markets, implying a reciprocal relationship. However, an inefficient adjustment transmission in the Indonesian cocoa prices was recorded throughout the study. The US currency constantly influenced Indonesian cocoa prices, while cocoa markets were independent of fluctuations in world oil prices. Overall, the study recorded a different level of the speed of adjustment of short-run imbalances to long-run equilibrium in the domestic cocoa market across economic crises.

An indirect treatment comparison of the efficacy of semaglutide 1.0mg versus dulaglutide 3.0 and 4.5mg.

AimTo compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes.Materials and MethodsA Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD‐11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD‐11 were conducted to explore the impact of adjustment for cross‐trial imbalances in baseline characteristics.ResultsSemaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of −0.24%‐points (95% confidence interval [CI] −0.43, −0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of −0.07%‐points (95% CI −0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of −2.65 kg (95% CI −3.57, −1.73) and −1.95 kg (95% CI −2.87, −1.03), respectively. Sensitivity analyses supported the primary analysis findings.ConclusionsThis indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon‐like peptide‐1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.