Abstract: Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%] , − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.

Abstract: Background: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age, and a generally poor prognosis. The prognosis remains especially grim for those who are older, have secondary AML, or relapsed or refractory (R/R) disease, in which 5-year OS is 5-10%. Therefore, novel therapeutic approaches are needed. CD123(IL3Rα) is a cell surface target that is expressed on normal, committed hematopoietic progenitor cells, and a variety of hematological neoplasms, including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). UCART123 is genetically modified, allogeneic ("off-the-shelf"), anti-CD123 CAR T cell product candidate in which the TCR alpha constant gene is disrupted to reduce the risk of GvHD, and the CD52 gene is disrupted to permit the use of alemtuzumab for selective and prolonged host lymphodepletion. Also, the CAR is co-expressed with a suicide mechanism (RQR8), which can be activated by using rituximab. In vitro data have demonstrated that UCART123 efficiently targets primary AML cells, with minimal effect on normal progenitors. Also, in PDX mouse models of AML, UCART123 cells can eliminate tumor cells in vivo, prevent relapse, and improve survival; in a competitive BM/AML PDX model, UCART123 cells demonstrated preferential targeting of AML blasts (Guzman; Blood 2016). Methods: AMELI-01 is a phase 1, multi-center clinical trial of UCART123 that employs an mTPI design to evaluate the safety, tolerability and preliminary anti-leukemia activity of UCART123 in patients (pts) with R/R AML. Additional objectives include determination of the MTD; characterization of the expansion, trafficking and persistence of UCART123; assessment of cytokine, chemokine and CRP levels after UCART123 infusion; and assessment of immune cell depletion, reconstitution and immune response. Dose escalation will include up to 28 pts. The dose expansion portion follows a Simon 2-stage design and will enroll up to an additional 37 pts. Eligible pts must be ≤ 65 years of age with R/R AML, adequate organ function, a confirmed donor for potential back-up stem cell transplantation, and no ongoing & gt; G1 toxicity from prior treatment. Pts with APL, prior gene or cellular therapy, & gt; 1 allogeneic SCT, or those with a clinically relevant CNS disorder (including CNS leukemia) are not eligible. Pts receive a lymphodepletion (LD) regimen of either fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide plus alemtuzumab (FCA) starting on Day -5, followed by an infusion of UCART123 at one of 5 dose levels on Day 0. Pts are evaluated for the presence of dose-limiting toxicities (DLT) during a 28-day observation period, which extends to 42 days in the setting of marrow aplasia and/or persistent clinically significant cytopenias without residual AML. DL1 has cleared safety without DLT, and enrollment at the next dose levels are proceeding. ClinicalTrials.gov Identifier: NCT03190278 Monica L. Guzman, et al; Allogeneic TCRα/β Deficient CAR T-Cells Targeting CD123 Prolong Overall Survival of AML Patient-Derived Xenografts. Blood 2016; 128 (22): 765. doi: https://doi.org/10.1182/blood.V128.22.765.765 Disclosures Roboz: Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Shire: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Autolos: Consultancy; Incyte Corporation: Consultancy; Agios: Consultancy. Sallman:Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Guzman:SeqRx: Honoraria; Cellectis: Research Funding. Kantarjian:Delta Fly: Honoraria; Novartis: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Immunogen: Research Funding; Aptitute Health: Honoraria. Konopleva:Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Agios: Research Funding; Amgen: Consultancy; Sanofi: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Ablynx: Research Funding; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Calithera: Research Funding; Cellectis: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Esteva:Cellectis: Current Employment. Garton:Cellectis: Current Employment. Backhouse:Cellectis: Current Employment. Galetto:Cellectis: Current Employment. Brownstein:Cellectis: Current Employment. Pemmaraju:Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Pacylex Pharmaceuticals: Consultancy.

Abstract: Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME ( n  = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 ( P  = 7.5 × 10 −9 ) and 10p11.21 ( P  = 3.6 × 10 −8 ). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex ( P  = 9.5 × 10 −3 ). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes ( P  = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes ( P  = 0.0005) including NLGN1 and PTPRD . RNAi knockdown of Oatp30B , the Drosophila polypeptide with the highest homology to SLCO5A1 , causes over-reactive startling behaviour ( P  = 8.7 × 10 −3 ) and increased seizure-like events ( P  = 6.8 × 10 −7 ). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME ( P  = 1.60 × 10 −3 ). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Abstract: Abnormal EEG features are a hallmark of epilepsy, and abnormal frequency and network features are apparent in EEGs from people with idiopathic generalized epilepsy in both ictal and interictal states. Here, we characterize differences in the resting-state EEG of individuals with juvenile myoclonic epilepsy and assess factors influencing the heterogeneity of EEG features. We collected EEG data from 147 participants with juvenile myoclonic epilepsy through the Biology of Juvenile Myoclonic Epilepsy study. Ninety-five control EEGs were acquired from two independent studies [Chowdhury et al. (2014) and EU-AIMS Longitudinal European Autism Project]. We extracted frequency and functional network-based features from 10 to 20 s epochs of resting-state EEG, including relative power spectral density, peak alpha frequency, network topology measures and brain network ictogenicity: a computational measure of the propensity of networks to generate seizure dynamics. We tested for differences between epilepsy and control EEGs using univariate, multivariable and receiver operating curve analysis. In addition, we explored the heterogeneity of EEG features within and between cohorts by testing for associations with potentially influential factors such as age, sex, epoch length and time, as well as testing for associations with clinical phenotypes including anti-seizure medication, and seizure characteristics in the epilepsy cohort. P-values were corrected for multiple comparisons. Univariate analysis showed significant differences in power spectral density in delta (2–5 Hz) (P = 0.0007, hedges’ g = 0.55) and low-alpha (6–9 Hz) (P = 2.9 × 10−8, g = 0.80) frequency bands, peak alpha frequency (P = 0.000007, g = 0.66), functional network mean degree (P = 0.0006, g = 0.48) and brain network ictogenicity (P = 0.00006, g = 0.56) between epilepsy and controls. Since age (P = 0.009) and epoch length (P = 1.7 × 10−8) differed between the two groups and were potential confounders, we controlled for these covariates in multivariable analysis where disparities in EEG features between epilepsy and controls remained. Receiver operating curve analysis showed low-alpha power spectral density was optimal at distinguishing epilepsy from controls, with an area under the curve of 0.72. Lower average normalized clustering coefficient and shorter average normalized path length were associated with poorer seizure control in epilepsy patients. To conclude, individuals with juvenile myoclonic epilepsy have increased power of neural oscillatory activity at low-alpha frequencies, and increased brain network ictogenicity compared with controls, supporting evidence from studies in other epilepsies with considerable external validity. In addition, the impact of confounders on different frequency-based and network-based EEG features observed in this study highlights the need for careful consideration and control of these factors in future EEG research in idiopathic generalized epilepsy particularly for their use as biomarkers.

Abstract: Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.

Abstract: Aim This paper documents reconstructions of the vegetation patterns in Australia, Southeast Asia and the Pacific (SEAPAC region) in the mid‐Holocene and at the last glacial maximum (LGM). Methods Vegetation patterns were reconstructed from pollen data using an objective biomization scheme based on plant functional types. The biomization scheme was first tested using 535 modern pollen samples from 377 sites, and then applied unchanged to fossil pollen samples dating to 6000 ± 500 or 18,000 ± 1000 14 C yr bp . Results 1. Tests using surface pollen sample sites showed that the biomization scheme is capable of reproducing the modern broad‐scale patterns of vegetation distribution. The north–south gradient in temperature, reflected in transitions from cool evergreen needleleaf forest in the extreme south through temperate rain forest or wet sclerophyll forest (WSFW) and into tropical forests, is well reconstructed. The transitions from xerophytic through sclerophyll woodlands and open forests to closed‐canopy forests, which reflect the gradient in plant available moisture from the continental interior towards the coast, are reconstructed with less geographical precision but nevertheless the broad‐scale pattern emerges. 2. Differences between the modern and mid‐Holocene vegetation patterns in mainland Australia are comparatively small and reflect changes in moisture availability rather than temperature. In south‐eastern Australia some sites show a shift towards more moisture‐stressed vegetation in the mid‐Holocene with xerophytic woods/scrub and temperate sclerophyll woodland and shrubland at sites characterized today by WSFW or warm‐temperate rain forest (WTRF). However, sites in the Snowy Mountains, on the Southern Tablelands and east of the Great Dividing Range have more moisture‐demanding vegetation in the mid‐Holocene than today. South‐western Australia was slightly drier than today. The single site in north‐western Australia also shows conditions drier than today in the mid‐Holocene. Changes in the tropics are also comparatively small, but the presence of WTRF and tropical deciduous broadleaf forest and woodland in the mid‐Holocene, in sites occupied today by cool‐temperate rain forest, indicate warmer conditions. 3. Expansion of xerophytic vegetation in the south and tropical deciduous broadleaf forest and woodland in the north indicate drier conditions across mainland Australia at the LGM. None of these changes are informative about the degree of cooling. However the evidence from the tropics, showing lowering of the treeline and forest belts, indicates that conditions were between 1 and 9 °C (depending on elevation) colder. The encroachment of tropical deciduous broadleaf forest and woodland into lowland evergreen broadleaf forest implies greater aridity. Main conclusions This study provides the first continental‐scale reconstruction of mid‐Holocene and LGM vegetation patterns from Australia, Southeast Asia and the Pacific (SEAPAC region) using an objective biomization scheme. These data will provide a benchmark for evaluation of palaeoclimate simulations within the framework of the Palaeoclimate Modelling Intercomparison Project.