42 research outputs found
Progress report no. 1
Statement of responsibility on title-page reads: Editors: I.A. Forbes, M.J. Driscoll, D.D. Lanning, I. Kaplan, N.C. Rasmussen; Contributors: S.A. Ali, S.T. Brewer, D.K. Choi, F.M. Clikeman, W.R. Corcoran, M.J. Driscoll, I.A. Forbes, C.W. Forsberg, S.L. Ho, C.S. Kang, I. Kaplan, J.L. Klucar, D.D. Lanning, T.C. Leung, E.L. McFarland P.G. Mertens, N.R. Ortiz, A. Pant, N.A. Passman, N.C. Rasmussen, M.K. Sheaffer, D.A. Shupe, G.E. Sullivan, A.T. Supple, J.W. Synan, C.P. Tzanos, W.J. Westlake"MIT-4105-3."Includes bibliographical referencesProgress report; June 30, 1970U.S. Atomic Energy Commission contracts: AT(30-1)410
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (nâ=â143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (nâ=â152), or no hydrocortisone (nâ=â108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (nâ=â137), shock-dependent (nâ=â146), and no (nâ=â101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Data-driven competitive facilitative tree interactions and their implications on nature-based solutions
Spatio-temporal data are more ubiquitous and richer than even before and the availability of such data poses great challenges in data analytics. Ecological facilitation, the positive effect of density of individuals on the individual's survival across a stress gradient, is a complex phenomenon. A large number of tree individuals coupled with soil moisture, temperature, and water stress data across a long temporal period were followed. Data-driven analysis in the absence of hypothesis was performed. Information theoretic analysis of multiple statistical models was employed in order to quantify the best data-driven index of vegetation density and spatial scale of interactions. Sequentially, tree survival was quantified as a function of the size of the individual, vegetation density, and time at the optimal spatial interaction scale. Land surface temperature and soil moisture were also statistically explained by tree size, density, and time. Results indicated that in space both facilitation and competition co-exist in the same ecosystem and the sign and magnitude of this depend on the spatial scale. Overall, within the optimal data-driven spatial scale, tree survival was best explained by the interaction between density and year, sifting overall from facilitation to competition through time. However, small sized trees were always facilitated by increased densities, while large sized trees had either negative or no density effects. Tree size was more important predictor than density in survival and this has implications for nature-based solutions: maintaining large tree individuals or planting species that can become large-sized can safeguard against tree-less areas by promoting survival at long time periods through harsh environmental conditions. Large trees had also a significant effect in moderating land surface temperature and this effect was higher than the one of vegetation density on temperature
Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations
Purpose
To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics.
Patients and Methods
One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS).
Results
There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO.
Conclusion
Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of patients with acute myeloid leukemia (AML) and are associated with adverse prognosis. The important role played by FLT3 in the survival and proliferation of blasts, and its overexpression in most patients with AML, make FLT3 an attractive therapeutic target. We undertook a phase 2 trial of the FLT3-selective tyrosine kinase inhibitor lestaurtinib (CEP701) used as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. Lestaurtinib was administered orally for 8 weeks, initially at a dose of 60 mg twice daily, escalating to 80 mg twice daily, and was generally well tolerated. Clinical activity, manifest as transient reductions in bone marrow and peripheral-blood blasts or longer periods of transfusion independence, was seen in 3 (60%) of 5 patients with mutated FLT3 and 5 (23%) of 22 evaluable wild-type FLT3 patients. Laboratory data demonstrated that clinical responses occurred where the presence of sustained FLT3-inhibitory drug levels were combined with in vitro cytotoxic sensitivity of blasts to lestaurtinib. Further evaluation of this compound, in combination with cytotoxic chemotherapy or other targeted agents, is warranted in both FLT3 mutant and wild-type patients