The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m 2 daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m 2 orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.(Blood.

ObjectivesTo evaluate the association between experience in the management of acute pulmonary embolism, reflected by hospital case volume, and mortality.DesignMultinational population based cohort study using data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry between 1 January 2001 and 31 August 2018.Setting353 hospitals in 16 countries.Participants39 257 consecutive patients with confirmed diagnosis of acute symptomatic pulmonary embolism.Main outcome measurePulmonary embolism related mortality within 30 days after diagnosis of the condition.ResultsPatients with acute symptomatic pulmonary embolism admitted to high volume hospitals (>40 pulmonary embolisms per year) had a higher burden of comorbidities. A significant inverse association was seen between annual hospital volume and pulmonary embolism related mortality. Admission to hospitals in the highest quarter (that is, >40 pulmonary embolisms per year) was associated with a 44% reduction in the adjusted odds of pulmonary embolism related mortality at 30 days compared with admission to hospitals in the lowest quarter (<15 pulmonary embolisms per year; adjusted risk 1.3% v 2.3%; adjusted odds ratio 0.56 (95% confidence interval 0.33 to 0.95); P=0.03). Results were consistent in all sensitivity analyses. All cause mortality at 30 days was not significantly reduced between the two quarters (adjusted odds ratio 0.78 (0.50 to 1.22); P=0.28). Survivors showed little change in the odds of recurrent venous thromboembolism (odds ratio 0.76 (0.49 to 1.19)) or major bleeding (1.07 (0.77 to 1.47)) between the low and high volume hospitals.ConclusionsIn patients with acute symptomatic pulmonary embolism, admission to high volume hospitals was associated with significant reductions in adjusted pulmonary embolism related mortality at 30 days. These findings could have implications for management strategies.

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Key PointsQuestionDoes an active search for pulmonary embolism (PE) improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD)?FindingsThis multicenter randomized clinical trial included 746 patients who required hospitalization for exacerbation of COPD and were randomized to receive usual care plus an active strategy for diagnosing PE or usual care alone. The primary outcome (a composite of nonfatal symptomatic venous thromboembolism, readmission for COPD, or death within 90 days after randomization) occurred in 29.7% of patients in the intervention group vs 29.2% in the control group, a difference that was not statistically significant.MeaningAmong patients hospitalized for an exacerbation of COPD, addition of an active diagnostic strategy for PE to usual care compared with usual care alone did not improve a composite set of health outcomes.

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The Late Miocene and Pliocene Quillagua depocenter lake system existed in a forearc basin on the west side of the Andes Mountains in northern Chile, alternating between standing-water and salar conditions. Quaternary incision of the Loa River Canyon resulted in bypass of the prior depositional surface and drainage of groundwater from the abandoned depocenter. Systematic regional geological mapping, 32 new chronological constraints on the strata in the basin, outcrop-scale facies analyses, and geophysical data underpin a revised evaluation of the controls on the lake system. The progressive stages, ages, and causes of the Quaternary destruction of the lake system are reconstructed based on mapped distributions of superficial fluvial sediments, chronological studies of terrace deposits, and landform analysis. The lake system occurred at the junction of small catchments draining the slowly rising western Andean foothills and the large paleo-Loa River catchment draining the Andean volcanic arc, during a time span of intense caldera activity. Small magnitude climate variability affected both the hyperarid low elevation sectors and arid upper sectors of the catchments. By 10 Ma, the regional climate was extremely arid, limiting water and sediment to small amounts, and during the Late Miocene and Pliocene, there was no surface-water outlet to the Pacific. Hydrological variations from 9 to 2.6 Ma led to sediment accumulation in variable lake environments, alternating with long hiatuses. Minor deformation within the Quillagua depocenter shifted the topographic axis and groundwater outlets. Simultaneous headward erosion from the Pacific shore captured the Loa River, which triggered large-magnitude incision that persists today. The progression of surface water environmental change was accompanied by changing composition and amount of surface and groundwater, which determined deposition of primary evaporite minerals, extensive diagenesis, and eventually, complex patterns of dissolution expressed as karst.

Introduction Some previous studies have suggested a high prevalence of pulmonary embolism (PE) during exacerbations of chronic obstructive pulmonary disease (ECOPD). The SLICE trial aims to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE (vs usual care) in patients hospitalized because of ECOPD. Methods SLICE is a phase III, prospective, international, multicenter, randomized, open‐label, and parallel‐group trial. A total of 746 patients hospitalized because of ECOPD will be randomized in a 1:1 fashion to receive either an active strategy for the diagnosis and anticoagulant treatment of PE or usual care (ie, standard care without any diagnostic test for diagnosing PE). The primary outcome is a composite of all‐cause death, non‐fatal (recurrent) venous thromboembolism (VTE), or readmission for ECOPD within 90 days after enrollment. Secondary outcomes are (a) death from any cause within 90 days after enrollment, (b) non‐fatal (recurrent) VTE within 90 days after enrollment, (c) readmission within 90 days after enrollment, and (d) length of hospital stay. Results Enrollment started in September 2014 and is expected to proceed until 2020. Median age of the first 443 patients was 71 years (interquartile range, 64‐78), and 26% were female. Conclusions This multicenter trial will determine the value of detecting PEs in patients with ECOPD. This has implications for COPD patient morbidity and mortality. Trial registration number: NCT02238639.

Abstract Background The association between the use of inferior vena cava filters (IVCFs) and outcomes among patients with cancer-associated thromboembolism (CT) and contraindications to anticoagulation remains unclear. Methods In this prospective cohort study of patients with CT from the Registro Informatizado de la Enfermedad TromboEmbólica Registry, we assessed the association between IVCF insertion due to contraindication to anticoagulation and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, recurrent thromboembolism, and major bleeding rates through 30 days after initiation of treatment. We used propensity score matching to adjust for the likelihood of receiving a filter. For outcomes assessment, we implemented generalized estimating equation methods to incorporate the matched-pairs design, and adjusted for covariates that remained unbalanced after matching. Results Of the 17,005 patients with CT, 270 underwent IVCF placement because of contraindication to anticoagulation. Of those, 247 were successfully matched with 247 patients treated without a filter. Propensity score-matched pairs showed a nonsignificantly lower risk of all-cause death (12.2% vs. 17.0%; p = 0.13), and a significantly lower risk of PE-related mortality (0.8% vs. 4.0%; p = 0.04) for patients receiving IVCFs compared with those who did not. While there was no significant difference in the rate of major bleeding (6.1% vs. 5.7%; p = 0.85), risk-adjusted recurrent rates were higher for patients who received IVCFs compared with those who did not (7.3% vs. 3.2%; p = 0.05). Conclusion In patients with CT and a contraindication to anticoagulation, IVCF insertion was associated with a lower risk of PE-related death, and a higher risk of recurrences.