DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development

Fox in the Trap: Thwarting Masqueraders via Automated Decoy Document Deployment

Organizations face a persistent challenge detecting malicious insiders as well as outside attackers who compromise legitimate credentials and then masquerade as insiders. No matter how good an organization’s perimeter defenses are, eventually they will be compromised or betrayed from the inside. Monitored decoy documents (honey files with enticing names and content) are a promising approach to aid in the detection of malicious masqueraders and insiders. In this paper, we present a new technique for decoy document distribution that can be used to improve the scalability of insider detection. We develop a placement application that automates the deployment of decoy documents and we report on two user studies to evaluate its effectiveness. The first study indicates that our automated decoy distribution tool is capable of strategically placing decoy files in a way that offers comparable security to optimal manual deployment. In the second user study, we measure the frequency that normal users access decoy documents on their own systems and show that decoy files do not significantly interfere with normal user tasks

Developing a Curriculum for the Nuisance Wildlife Control Industry in New York

The nuisance wildlife control industry continues to expand in New York State. Each year during the past 5 years, approximately 1,200-1 ,400 private Nuisance Wildlife Control Operators (NWCOs) were given authority to handle wildlife conflicts by the New York State Department of Environmental Conservation (DEC). These NWCOs were required to complete a trapper education course, and a personal interview or exam prior to obtaining a permit. The education and experience requirements for NWCOs varied by region in New York. The goals of this project were to: (1) develop a core curriculum for individuals who desired to handle nuisance wildlife and charge a fee for service, (2) standardize license requirements across the state, (3) enhance professionalism and training of individuals involved in the NWCO industry, and (4) develop a test bank of questions for administration of an examination. Existing educational programs from throughout the United States were reviewed for content and suitability in New York State. A core educational manual was developed by staff with Cornell University and a DEC review team. The curriculum will be piloted during 2003 in conjunction with legislative changes that mandate training for NWCOs in New York State

Prevalence and Prognostic Significance of Long QT Interval among Patients with Chest Pain: Selecting an Optimum QT Rate Correction Formula

Background: Little is known about the prevalence and prognostic significance of long QT interval among patients with chest pain during the acute phase of suspected cardiovascular injury. Objectives: Our aim was to investigate the prevalence and prognostic significance of long QT interval among patients presenting to the emergency department (ED) with chest pain using an optimum QT rate correction formula. Methods: We performed secondary analysis on data obtained from the IMMEDIATE AIM trial (N, 145). Data included 24-hour 12-lead Holter electrocardiographic recordings that were stored for offline computer analysis. The QT interval was measured automatically and rate corrected using seven QTc formulas including subject specific correction. The formula with the closer to zero absolute mean QTc/RR correlation was considered the most accurate. Results: Linear and logarithmic subject specific QT rate correction outperformed other QTc formulas and resulted in the closest to zero absolute mean QTc/RR correlations (mean ± SD: 0.003 ± 0.002 and 0.017 ± 0.016, respectively). These two formulas produced adequate correction in 100% of study participants. Other formulas (Bazett’s, Fridericia’s, Framingham\u27s, and study specific) resulted in inadequate correction in 47.6 to 95.2% of study participants. Using the optimum QTc formula, linear subject specific, the prevalence of long QTc interval was 14.5%. The QTc interval did not predict mortality or hospital admission at short and long term follow-up. Only the QT/RR slope predicted mortality at 7 year follow-up (odds ratio, 2.01; 95% CI, 1.02–3.96; p \u3c 0.05). Conclusions: Adequate QT rate correction can only be performed using subject specific correction. Long QT interval is not uncommon among patients presenting to the ED with chest pain

Variable-frequency-train stimulation of skeletal muscle after spinal cord injury

Skeletal muscle, after spinal cord injury (SCI), becomes highly susceptible to fatigue. Variable-frequency trains (VFTs) enhance force in fatigued human skeletal muscle of able-bodied (AB) individuals. VFTs do this by taking advantage of the catch-like property of skeletal muscle. However, mechanisms responsible for fatigue in AB and SCI subjects may not be the same, and the efficacy of VFT stimulation after SCI is unknown. Accordingly, we tested the hypothesis that VFT stimulation would augment torque-time integral in SCI subjects. The quadriceps femoris muscle was stimulated with constant frequency trains (CFTs) (six 200 s square wave pulses separated by 70 ms) or VFTs (a train identical to the CFT, except that the first two pulses were separated by 5 ms) in SCI and AB subjects. After 180 contractions (50% duty cycle), isometric peak torque decreased 44, 56, and 67 percent, in the AB (n = 10), acute SCI (n = 10), and chronic SCI (n = 12) groups, respectively. In fatigued muscle, VFTs enhanced the torque-time integral by 18 percent in AB subjects and 6 percent in chronic SCI patients, and had no effect in acute SCI patients when compared to the corresponding CFT. The much faster rise times in SCI subjects (~80 ms vs. 120 ms in AB subjects) probably contributed to the inability of VFTs to enhance torque-time integrals in SCI patients. The results suggest that the use of VFT stimulation in patients with SCI may not be as efficacious as it is in AB persons

Customised and Noncustomised Birth Weight Centiles and Prediction of Stillbirth and Infant Mortality and Morbidity: A Cohort Study of 979,912 Term Singleton Pregnancies in Scotland.

BACKGROUND: There is limited evidence to support the use of customised centile charts to identify those at risk of stillbirth and infant death at term. We sought to determine birth weight thresholds at which mortality and morbidity increased and the predictive ability of noncustomised (accounting for gestational age and sex) and partially customised centiles (additionally accounting for maternal height and parity) to identify fetuses at risk. METHODS: This is a population-based linkage study of 979,912 term singleton pregnancies in Scotland, United Kingdom, between 1992 and 2010. The main exposures were noncustomised and partially customised birth weight centiles. The primary outcomes were infant death, stillbirth, overall mortality (infant and stillbirth), Apgar score <7 at 5 min, and admission to the neonatal unit. Optimal thresholds that predicted outcomes for both non- and partially customised birth weight centiles were calculated. Prediction of mortality between non- and partially customised birth weight centiles was compared using area under the receiver operator characteristic curve (AUROC) and net reclassification index (NRI). FINDINGS: Birth weight ≤25th centile was associated with higher risk for all mortality and morbidity outcomes. For stillbirth, low Apgar score, and neonatal unit admission, risk also increased from the 85th centile. Similar patterns and magnitude of associations were observed for both non- and partially customised birth weight centiles. Partially customised birth weight centiles did not improve the discrimination of mortality (AUROC 0.61 [95%CI 0.60, 0.62]) compared with noncustomised birth weight centiles (AUROC 0.62 [95%CI 0.60, 0.63]) and slightly underperformed in reclassifying pregnancies to different risk categories for both fatal and non-fatal adverse outcomes (NRI -0.027 [95% CI -0.039, -0.016], p < 0.001). We were unable to fully customise centile charts because we lacked data on maternal weight and ethnicity. Additional analyses in an independent UK cohort (n = 10,515) suggested that lack of data on ethnicity in this population (in which national statistics show 98% are white British) and maternal weight would have misclassified ~15% of the large-for-gestation fetuses. CONCLUSIONS: At term, birth weight remains strongly associated with the risk of stillbirth and infant death and neonatal morbidity. Partial customisation does not improve prediction performance. Consideration of early term delivery or closer surveillance for those with a predicted birth weight ≤25th or ≥85th centile may reduce adverse outcomes. Replication of the analysis with fully customised centiles accounting for ethnicity is warranted.SI is funded by a UK Medical Research Council skills development fellowship (MR/N015177/1). DAL works in a Unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_12013/5); she is a National Institute of Health Research (NIHR) Senior Investigator (NF-SI-0611-10196). This work is also supported by the NIHR through the University of Bristol NIHR Biomedical Research Centre (BRC) and the University of Cambridge BRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB

Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation

A Multicenter Phase 2 Study Incorporating High-Dose Rituximab into the CODOX-M/IVAC Regimen for Untreated Burkitt’s Lymphoma (BL): Examination of Correlative Serum and CSF Rituximab Levels

Background: Two-year survival rates for adult BL remain Methods: Twenty-five BL patients were enrolled. Patients had low-risk (LR) or high-risk (HR) disease; LR patients received 3 CODOX-M cycles, while HR had 4 alternating CODOX-M/IVAC cycles (Mead et al. Blood 2009). Rituximab (500mg/m2) was given x 2 doses each cycle. Correlative analyses of paired serum and CSF Rituximab levels were obtained for cycles 1+3 at 24+72 hours. Results: There were 20 HR and 5 LR patients and median age was 44 years (range, 23-70). 3 HR and 1 LR patient were HIV+, while 15% of HR patients had CNS disease. Additionally, 35% of HR patients had bulk \u3e10 cm and 40% had bone marrow involvement. Myelosuppression and mucositis appeared comparable with prior CODOX-M/IVAC data. The overall remission rate after 2 cycles was 100% with 67% complete remission. At 34-month median follow-up, 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS: both 100%; HR 2-year PFS and OS: both 82%). Further, the 2-year PFS and OS for HR, HIV-negative patients were 91% and 91%, respectively (disease-specific survival 100%). Two patients died from progressive disease (both HIV+ HR). The median serum and CSF rituximab levels for these patients were compared with patients without relapse (Table 1). Interestingly, cycle 1, 24-hour serum Rituximab levels were significantly higher among patients without relapse compared with the two patients who relapsed/died (P=0.042). Cycle 3, 24-hour Rituximab levels were of borderline significance (P=0.06). Conclusions: The integration of Rituximab into CODOX-M/IVAC was associated with excellent survival rates, especially for HIV-negative BL. Further investigation of the predictive value of serum Rituximab levels is warranted

Gestational age at delivery and special educational need: retrospective cohort study of 407,503 schoolchildren

&lt;STRONG&gt;Background&lt;/STRONG&gt; Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation. &lt;STRONG&gt;Methods and Findings&lt;/STRONG&gt; We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37–39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12–1.20; 33–36 wk adjusted OR 1.53, 95% CI 1.43–1.63; 28–32 wk adjusted OR 2.66, 95% CI 2.38–2.97; 24–27 wk adjusted OR 6.92, 95% CI 5.58–8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37–39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (&lt;37 wk), which accounted for only 3.6% of cases. &lt;STRONG&gt;Conclusions&lt;/STRONG&gt; Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery

Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients.

Summary pointsMain concepts- The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach defines quality of evidence as confidence in effect estimates; this conceptualization can readily be applied to bodies of evidence estimating the risk of future of events (that is, prognosis) in broadly defined populations- In the field of prognosis, a body of observational evidence (including single arms of randomized controlled trials) begins as high quality evidence- The five domains GRADE considers in rating down confidence in estimates of treatment effect—that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias—as well as the GRADE criteria for rating up quality, also apply to estimates of the risk of future of events from a body of prognostic studies- Applying these concepts to systematic reviews of prognostic studies provides a useful approach to determine confidence in estimates of overall prognosis in broad populationsLay summary- The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to rating confidence in the results of research studies was initially developed for therapeutic questions- The GRADE approach considers study design (randomized trials versus non-randomized designs), risk of bias, inconsistency, imprecision, indirectness, and publication bias; size and trend in the effect are also considered- Observational studies looking at patients’ prognosis may provide robust estimates of the likelihood of undesirable or desirable outcomes in both treated and untreated patients- Patients will often find this information helpful in understanding the likely course of their disease, in planning their future, and in engaging in shared decision making with their healthcare providers- In a previous article, we examined factors that affect confidence in estimates of baseline risk (the risk of bad outcomes in untreated patients), providing examples of how this might influence the confidence in estimates of absolute treatment effect- This paper provides guidance for the use of the GRADE approach to determine confidence in estimates of future events in systematic reviews of prognostic studies in broad categories of patient