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Abstract: Background:Postpancreaticoduodenectomy (PD) hemorrhage (PPH) is a life-threatening complication after PD. The main objective of this study was to evaluate incidence and factors associated with late PPH as well as the management strategy and outcomes. Methods: Between May 2017 and March 2020, clinical data from 192 patients undergoing PD were collected prospectively in the CHIRPAN Database (NCT02871336) and retrospectively analyzed. In our institution, all patients scheduled for a PD are routinely admitted for monitoring and management in intensive/intermediate care unit (ICU/IMC). Results: The incidence of late PPH was 17% (32 of 192), whereas the 90-day mortality rate of late PPH was 19% (6 of 32). Late PPH was associated with 90-day mortality (P = 0.001). Using multivariate analysis, independent risk factors for late PPH were postoperative sepsis (P = 0.036), and on day 3, creatinine (P = 0.025), drain fluid amylase concentration (P = 0.023), lipase concentration (P < 0.001), and C-reactive protein (CRP) concentration (P < 0.001). We developed two predictive scores for PPH occurrence, the PANCRHEMO scores. Score 1 was associated with 68.8% sensitivity, 85.6% specificity, 48.8% predictive positive value, 93.2% negative predictive value, and an area under the receiver operating characteristic curves of 0.841. Score 2 was associated with 81.2% sensitivity, 76.9% specificity, 41.3% predictive positive value, 95.3% negative predictive value, and an area under the receiver operating characteristic curve of 0.859. Conclusions: Routine ICU/IMC monitoring might contribute to a better management of these complications. Some predicting factors such as postoperative sepsis and biological markers on day 3 should help physicians to determine patients requiring a prolonged ICU/IMC monitoring., Competing Interests: The author reports no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Introduction: Cannabis' effect on seizure activity is an emerging topic that remains without consensus and merits further investigation. We therefore performed a scoping review to identify the available evidence and knowledge gaps within the existing literature on cannabis product exposures as a potential cause of seizures in humans., Methods: A scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews guidelines. The PubMed and Scopus databases were searched over a 20-year period from the date of the database query (12/21/2020). Inclusion criteria were (1) English language original research articles, (2) inclusion of human subjects, and (3) either investigation of seizures as a part of recreational cannabinoid use OR of exogenous cannabinoids as a cause of seizures., Results: A total of 3104 unique articles were screened, of which 68 underwent full-text review, and 13 met inclusion/exclusion criteria. Ten of 11 studies evaluating acute cannabis exposures reported a higher seizure incidence than would be expected based on the prevalence of epilepsy in the general and pediatric populations (range 0.7-1.2% and 0.3-0.5% respectively). The remaining two studies demonstrated increased seizure frequency and/or seizure-related hospitalization in recreational cannabis users and those with cannabis use disorder., Conclusions: This scoping review demonstrates that a body of literature describing seizures in the setting of cannabis exposure exists, but it has several limitations. Ten identified studies showed a higher than expected incidence of seizures in populations exposed to cannabis products. Based on the Bradford Hill criteria, delta-9 tetrahydrocannabinol (THC) may be the causative xenobiotic for this phenomenon., (© 2022. American College of Medical Toxicology.)

The surface mixed layer of the world ocean regulates global climate by controlling heat and carbon exchange between the atmosphere and the oceanic interior 1-3 . The mixed layer also shapes marine ecosystems by hosting most of the ocean's primary production 4 and providing the conduit for oxygenation of deep oceanic layers. Despite these important climatic and life-supporting roles, possible changes in the mixed layer during an era of global climate change remain uncertain. Here we use oceanographic observations to show that from 1970 to 2018 the density contrast across the base of the mixed layer increased and that the mixed layer itself became deeper. Using a physically based definition of upper-ocean stability that follows different dynamical regimes across the global ocean, we find that the summertime density contrast increased by 8.9 ± 2.7 per cent per decade (10 -6 -10 -5 per second squared per decade, depending on region), more than six times greater than previous estimates. Whereas prior work has suggested that a thinner mixed layer should accompany a more stratified upper ocean 5-7 , we find instead that the summertime mixed layer deepened by 2.9 ± 0.5 per cent per decade, or several metres per decade (typically 5-10 metres per decade, depending on region). A detailed mechanistic interpretation is challenging, but the concurrent stratification and deepening of the mixed layer are related to an increase in stability associated with surface warming and high-latitude surface freshening 8,9 , accompanied by a wind-driven intensification of upper-ocean turbulence 10,11 . Our findings are based on a complex dataset with incomplete coverage of a vast area. Although our results are robust within a wide range of sensitivity analyses, important uncertainties remain, such as those related to sparse coverage in the early years of the 1970-2018 period. Nonetheless, our work calls for reconsideration of the drivers of ongoing shifts in marine primary production, and reveals stark changes in the world's upper ocean over the past five decades.

Purpose: KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL., Experimental Design: First, we searched for the most synergistic combination of KPT-8602 with dexamethasone, vincristine, or doxorubicin in vitro in both B-ALL and T-ALL cell lines using proliferation and apoptosis as a readout. Next, we validated this synergistic effect by treatment of clinically relevant B- and T-ALL patient-derived xenograft models in vivo . Finally, we performed RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the mechanism of synergy., Results: KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as in vivo in three patient-derived ALL xenografts. Compared with single-drug treatment, the drug combination caused increased apoptosis and led to histone depletion. Mechanistically, integration of ChIP-seq and RNA-seq data revealed that addition of KPT-8602 to dexamethasone enhanced the activity of the glucocorticoid receptor (NR3C1) and led to increased inhibition of E2F-mediated transcription. We observed strong inhibition of E2F target genes related to cell cycle, DNA replication, and transcriptional regulation., Conclusions: Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients., (©2020 American Association for Cancer Research.)