New Era Begins: Mental Health Law Reform in Virginia

Amidst calls for mental health reform and a sense of urgency stemming from the tragic events at Virginia Tech, the 2008 session of the Virginia General Assembly convened. The legislative reaction was overwhelming: Legislators introduced a vast array of bills relating to mental health. By the end of the session, the General Assembly enacted the most sweeping revisions to Virginia\u27s mental health laws since the 1970s

Web‐based Weight Management Programs in an Integrated Health Care Setting: A Randomized, Controlled Trial

Objective : To assess the efficacy of a Web‐based tailored behavioral weight management program compared with Web‐based information‐only weight management materials. Research Methods and Procedures : Participants, 2862 eligible overweight and obese (BMI = 27 to 40 kg/m 2 ) members from four regions of Kaiser Permanente's integrated health care delivery system, were randomized to receive either a tailored expert system or information‐only Web‐based weight management materials. Weight change and program satisfaction were assessed by self‐report through an Internet‐based survey at 3‐ and 6‐month follow‐up periods. Results : Significantly greater weight loss at follow‐up was found among participants assigned to the tailored expert system than among those assigned to the information‐only condition. Subjects in the tailored expert system lost a mean of 3 ± 0.3% of their baseline weight, whereas subjects in the information‐only condition lost a mean of 1.2 ± 0.4% ( p < 0.0004). Participants were also more likely to report that the tailored expert system was personally relevant, helpful, and easy to understand. Notably, 36% of enrollees were African‐American, with enrollment rates higher than the general proportion of African Americans in any of the study regions. Discussion : The results of this large, randomized control trial show the potential benefit of the Web‐based tailored expert system for weight management compared with a Web‐based information‐only weight management program.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93691/1/oby.2006.34.pd

A Study to Assess the Efficacy of Enasidenib and Risk-Adapted Addition of Azacitidine in Newly Diagnosed IDH2-Mutant AML

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n&nbsp;=&nbsp;45) or had a complex karyotype without TP53 mutation (cohort B; n&nbsp;=&nbsp;13) received entospletinib 400&nbsp;mg twice daily with decitabine 20&nbsp;mg/m2 on days 1-10 every 28&nbsp;days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2&nbsp;years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2&nbsp;months, respectively, and the median overall survival was 6.5 and 11.5&nbsp;months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need

Defective Interfering Viral Particles in Acute Dengue Infections

While much of the genetic variation in RNA viruses arises because of the error-prone nature of their RNA-dependent RNA polymerases, much larger changes may occur as a result of recombination. An extreme example of genetic change is found in defective interfering (DI) viral particles, where large sections of the genome of a parental virus have been deleted and the residual sub-genome fragment is replicated by complementation by co-infecting functional viruses. While most reports of DI particles have referred to studies in vitro, there is some evidence for the presence of DI particles in chronic viral infections in vivo. In this study, short fragments of dengue virus (DENV) RNA containing only key regulatory elements at the 3′ and 5′ ends of the genome were recovered from the sera of patients infected with any of the four DENV serotypes. Identical RNA fragments were detected in the supernatant from cultures of Aedes mosquito cells that were infected by the addition of sera from dengue patients, suggesting that the sub-genomic RNA might be transmitted between human and mosquito hosts in defective interfering (DI) viral particles. In vitro transcribed sub-genomic RNA corresponding to that detected in vivo could be packaged in virus like particles in the presence of wild type virus and transmitted for at least three passages in cell culture. DENV preparations enriched for these putative DI particles reduced the yield of wild type dengue virus following co-infections of C6–36 cells. This is the first report of DI particles in an acute arboviral infection in nature. The internal genomic deletions described here are the most extensive defects observed in DENV and may be part of a much broader disease attenuating process that is mediated by defective viruses

Evolution of Blind Beetles in Isolated Aquifers: A Test of Alternative Modes of Speciation

Evidence is growing that not only allopatric but also sympatric speciation can be important in the evolution of species. Sympatric speciation has most convincingly been demonstrated in laboratory experiments with bacteria, but field-based evidence is limited to a few cases. The recently discovered plethora of subterranean diving beetle species in isolated aquifers in the arid interior of Australia offers a unique opportunity to evaluate alternative modes of speciation. This naturally replicated evolutionary experiment started 10-5 million years ago, when climate change forced the surface species to occupy geographically isolated subterranean aquifers. Using phylogenetic analysis, we determine the frequency of aquifers containing closely related sister species. By comparing observed frequencies with predictions from different statistical models, we show that it is very unlikely that the high number of sympatrically occurring sister species can be explained by a combination of allopatric evolution and repeated colonisations alone. Thus, diversification has occurred within the aquifers and likely involved sympatric, parapatric and/or microallopatric speciation

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485

KMT2A partial tandem duplication occurs in approximately 5–10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1–10 and vorinostat 400 milligrams daily on days 5–10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506)