The genomic landscape of juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome

Prevalence and Predictors of Prescription Sleep Aid Use among Individuals with DSM-5 Insomnia: The Role of Hyperarousal

STUDY OBJECTIVES: Despite mounting evidence for the overuse of prescription sleep aids (PSA), reliable data on PSA use among insomniacs are unavailable. Current studies focus on trends in PSA use at the general population level, and thus do not distinguish between transient sleep disturbance and insomnia disorder. Therefore, we prospectively examined the prevalence and predictors of baseline and chronic PSA use in a well-defined sample of individuals with insomnia. METHODS: We analyzed longitudinal data from an urban, community-based cohort of 649 adults (48.1 ± 11.6 y; 69.3% female) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-based insomnia disorder. Participants completed standardized measures of sleep disturbance, daytime alertness, depression, and anxiety at baseline and follow-up 1 y later. They also reported whether and with what frequency they used PSA at both time points. RESULTS: Approximately 19% of the sample used PSA at baseline, the majority (69.4%) of whom continued use 1 y later. Anxiety and daytime alertness were the only independent predictors of both acute and chronic PSA use. An increase of 1 standard deviation (SD) in alertness was associated with a 33% increase in the odds of chronic PSA use (χ(2) = 4.98; odds ratio [OR] = 1.33; 95% confidence interval [CI]: 1.04-1.72; P \u3c 0.05), and a 1-SD increase in anxiety was associated with a 41% increase (χ(2) = 6.95; OR = 1.41; 95% CI: 1.09-1.82; P \u3c 0.05). Chronic PSA users did not report any significant improvements in sleep from baseline to follow-up relative to nonusers. CONCLUSIONS: Hyperarousal, as indexed by daytime alertness and anxiety, is a strong determinant of PSA use among individuals with insomnia. These findings are consistent with emerging data showing that insomnia is not just a nocturnal sleep disorder, but one characterized by 24-h arousal. Though current research targets sleep disturbance, this study highlights the role of the arousal system in pharmacological treatment seeking

Improving Daytime Functioning, Work Performance, and Quality of Life in Postmenopausal Women with Insomnia: Comparing Cognitive Behavioral Therapy for Insomnia, Sleep Restriction Therapy, and Sleep Hygiene Education

Study Objectives: Insomnia is a chief complaint among postmenopausal women, and insomnia impairs daytime functioning and reduces quality of life. Recent evidence supports the efficacy of cognitive behavioral therapy for insomnia (CBTI) for menopausal insomnia, but it remains unclear whether treating insomnia improves daytime function in this population. This study evaluated whether CBTI improves daytime fatigue, energy, self-reported sleepiness, work productivity, and quality of life in postmenopausal women with insomnia, and whether sleep restriction therapy (SRT)—a single component of CBTI—is equally efficacious. Methods: Single-site, randomized control trial. One hundred fifty postmenopausal women (56.44 ± 5.64 years) with perimenopausal or postmenopausal onset or exacerbation of chronic insomnia were randomized to 3 treatment conditions: sleep hygiene education control (SHE), SRT, and CBTI. Blinded assessments were performed at pretreatment, posttreatment, and 6-month follow-up. Results: CBTI and SRT produced moderate-to-large improvements in fatigue, energy, sleepiness, and work function at posttreatment and 6 months later. The CBTI group reported better quality of life as indicated by substantial improvements in emotional wellbeing and resiliency to physical and emotional problems, whereas the SRT and SHE groups only showed improvements in resiliency to physical problems. Pain complaints decreased as sleep improved b were not associated with specific treatment conditions. Similarly, insomnia remitters reported fewer daytime and nighttime hot flashes, although reductions were not associated with any specific treatment. Conclusions: CBTI and SRT are efficacious options for postmenopausal women with chronic insomnia. Both interventions improve daytime function, quality of life, and work performance, although CBTI produces superior results including the added benefit of improved emotional health

Long-term Efficacy of the Sleep to Prevent Evolving Affective Disorders (SPREAD) Trial as an Internet-based Treatment for Insomnia

Introduction: A growing body of evidence supports the acute benefits of internet-based interventions for insomnia; however, the durability of the acute treatment gains from internet-based interventions has not been adequately examined. This randomized controlled-trial compared the efficacy of digital Cognitive Behavioral Therapy for Insomnia to an online attention control at post-treatment and at 12-month follow-up. Methods: 1383 subjects diagnosed with Insomnia based on DSM-5 criteria were randomized into 2 conditions: digital Cognitive behavioral Therapy for Insomnia (dCBT-I; N=946) through Sleepio or online Sleep Education control (N=440). After attrition, the final sample was 358 in the dCBT-I group and 300 in the Sleep Education group. The dCBT-I group received 6 online weekly CBT-I sessions while the control group received 6 weekly informational sleep hygiene emails. The Insomnia Severity Scale (ISI) was used as the outcome measure at three time points: pre-treatment, post-treatment and 12-month follow-up. Results: Compared to the control group, those in the dCBT-I group showed a two-fold reduction in insomnia severity (dCBT-I: -8.11 ± 0.45 SE; control: -3.87 ± 0.39 SE) at post-treatment. Importantly, these improvements were sustained at 12-month follow-up (dCBT-I: -9.96 ± 0.30 SE, control: -4.44 ± 0.26 SE). Similarly, remission T post-treatment (operationalized as ISI \u3c 8) was also significantly higher in the dCBT-I group (53.9%) compared to the control group (14.0%), χ2 (1) =111.5, p \u3c .0001. The remission rate was also sustained at 12-month follow-up (dCBT-I: 46.6%, control: 17.1%). Conclusion: This study provides evidence for the long-term efficacy of dCBT-I, and supports further examination of dCBT-I as an easily accessible and low-cost alternative to face-to-face CBT-I