Understanding Streaming in Dictyostelium discoideum: Theory versus Experiments

Recent experimental work involving Dictyostelium discoideum seems to contradict several theoretical models. Experiments suggest that localization of the release of the chemoattractant cyclic adenosine monophosphate to the uropod of the cell is important for stream formation during aggregation. Yet several mathematical models are able to reproduce streaming as the cells aggregate without taking into account localization of the chemoattractant. A careful analysis of the experiments and the theory suggests the two major features of the system which are important to stream formation are random cell motion and chemotaxis to regions of higher cell density. Random cell motion acts to reduce streaming, whereas chemotaxis to regions of higher cell density reinforces streaming. With this understanding, the experimental results can be explained in a manner consistent with the theoretical results. In all the experiments, alterations in the two main factors of random motion and chemotaxis to regions of higher cell density, not the localization of the release of the chemoattractant, can explain the results as they relate to streaming. Additionally, a comparison of results from a mathematical model that simulates cells which localize the chemoattractant and cells which do not shows little difference in the streaming patterns

Power Efficient Scheduling for Hard Real-Time Systems on a Multiprocessor Platform

International audienceAn online, real-time scheduler is proposed to minimize the power consumption of a task set during execution on a multiprocessor platform. The scheduler is capable of handling the spectrum of task types (periodic, sporadic, and aperiodic) as well as supporting mutually exclusive, shared resources. The solution presented is a user adjustable scheduler which ranges from producing an optimal schedule which requires the minimum power during the worst case execution scenario to producing a suboptimal schedule which aggressively minimizes power during the typical execution scenario

Real-Time Identification of Serious Infection in Geriatric Patients Using Clinical Information System Surveillance

To develop and characterize an automated syndromic surveillance mechanism for early identification of older emergency department (ED) patients with possible life-threatening infection. DESIGN : Prospective, consecutive-enrollment, single-site observational study. SETTING : A large university medical center with an annual ED census of 75,273. PARTICIPANTS : Patients aged 70 and older admitted to the ED and having two or more systemic inflammatory response syndrome (SIRS) criteria during their ED stay. MEASUREMENTS : A search algorithm was developed to screen the census of the ED through its clinical information system. A study coordinator confirmed all patients electronically identified as having a probable infectious explanation for their visit. RESULTS : Infection accounted for 28% of ED and 34% of final hospital diagnoses. Identification using the software tool alone carried a 1.63 relative risk of infection (95% confidence interval CI=1.09–2.44) compared with other ED patients sufficiently ill to require admission. Follow-up confirmation by a study coordinator increased the risk to 3.06 (95% CI=2.11–4.44). The sensitivity of the strategy overall was modest (14%), but patients identified were likely to have an infectious diagnosis (specificity=98%). The most common SIRS criterion triggering the electronic notification was the combination of tachycardia and tachypnea. CONCLUSION : A simple clinical informatics algorithm can detect infection in elderly patients in real time with high specificity. The utility of this tool for research and clinical care may be substantial.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66036/1/j.1532-5415.2008.02094.x.pd

Altering Murine Leukemia Virus Integration Through Disruption of the Integrase and BET Protein Family Interaction

We report alterations to the murine leukemia virus (MLV) integrase (IN) protein that successfully result in decreasing its integration frequency at transcription start sites and CpG islands, thereby reducing the potential for insertional activation. The host bromo and extraterminal (BET) proteins Brd2, 3 and 4 interact with the MLV IN protein primarily through the BET protein ET domain. Using solution NMR, protein interaction studies, and next generation sequencing, we showthat the C-terminal tail peptide region ofMLV IN is important for the interaction with BET proteins and that disruption of this interaction through truncation mutations affects the global targeting profile of MLV vectors. The use of the unstructured tails of gammaretroviral INs to direct association with complexes at active promoters parallels that used by histones and RNA polymerase II. Viruses bearingMLV IN C-terminal truncations can provide new avenues to improve the safety profile of gammaretroviral vectors for human gene therapy

An Analysis of Private School Closings

We add to the small literature on private school supply by exploring exits of K-12 private schools. We find that the closure of private schools is not an infrequent event, and use national survey data from the National Center for Education Statistics to study closures of private schools. We assume that the probability of an exit is a function of excess supply of private schools over the demand, as well as the school's characteristics such as age, size, and religious affiliation. Our empirical results generally support the implications of the model. Working Paper 07-0

The Epidemiology of Acute Organ System Dysfunction From Severe Sepsis Outside of the Intensive Care Unit

BACKGROUND: Severe sepsis is a common, costly, and complex problem, the epidemiology of which has only been well studied in the intensive care unit (ICU). However, nearly half of all patients with severe sepsis are cared for outside the ICU. OBJECTIVE: To determine rates of infection and organ sys- tem dysfunction in patients with severe sepsis admitted to non-ICU services. DESIGN: Retrospective cohort study. SETTING: A large, tertiary, academic medical center in the United States. PATIENTS: Adult patients initially admitted to non-ICU medical services from 2009 through 2010. MEASUREMENTS: All International Classification of Dis- eases, 9th Revision, Clinical Modification diagnosis codes were screened for severe sepsis. Three hospitalists reviewed a sample of medical records evaluating the char- acteristics of severe sepsis. The International Consensus Conference (ICC) for sepsis defines severe sepsis as an infection leading to acute organ dysfunction.1,2 Severe sepsis afflicts over 1 million patients each year in Medicare alone, and is substantially more common among older Americans than acute myocardial infarction.3–5 Recently, the Agency for Healthcare Research and Quality identified severe sepsis as the single most expensive cause of hospitalization in the United States.6 The incidence of severe sepsis continues to rise.4,5 Severe sepsis is often mischaracterized as a diagno- sis cared for primarily in the intensive care unit (ICU). Yet, studies indicate that only 32% to 50% of patients with severe sepsis require ICU care, leaving *Address for correspondence and reprint requests: Jeffrey M. Rohde, MD, Department of Internal Medicine, University of Michigan Medical School, 3119 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-5376; Telephone: 734-647-1599; Fax: 734-233-9343; E-mail: [email protected] Additional Supporting Information may be found in the online version of this article. Received: July 15, 2012; Revised: December 16, 2012; Accepted: December 26, 2012 2013SocietyofHospitalMedicine DOI10.1002/jhm.2012 Published online in Wiley Online Library (Wileyonlinelibrary.com). RESULTS: Of 23,288 hospitalizations, 14% screened posi- tive for severe sepsis. A sample of 111 cases was manually reviewed, identifying 64 cases of severe sepsis. The mean age of patients with severe sepsis was 63 years, and 39% were immunosuppressed prior to presentation. The most common site of infection was the urinary tract (41%). The most common organ system dysfunctions were cardiovas- cular (hypotension) and renal dysfunction occurring in 66% and 64% of patients, respectively. An increase in the num- ber of organ systems affected was associated with an increase in mortality and eventual ICU utilization. Severe sepsis was documented by the treating clinicians in 47% of cases. CONCLUSIONS: Severe sepsis was commonly found and poorly documented on the wards at our medical center. The epidemiology and organ dysfunctions among patients with severe sepsis appear to be different from previously described ICU severe sepsis populations.This work was supported in part by the US National Insti- tutes of Health–K08, HL091249 (TJI) and the University of Michigan Specialist–Hospitalist Allied Research Program (SHARP). This work was also supported in part by VA Ann Arbor Healthcare System, Geriatric Research Education and Clinical Center (GRECC).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102728/1/Rohde 13 JHM epi acute organ dysfxn sepsis outside ICU.pdf11

Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling

Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target. However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common. It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment. In this study, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo. These results were validated in ex vivo patient-derived AML cells. Our findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL

Estimation of colorectal adenoma recurrence with dependent censoring

<p>Abstract</p> <p>Background</p> <p>Due to early colonoscopy for some participants, interval-censored observations can be introduced into the data of a colorectal polyp prevention trial. The censoring could be dependent of risk of recurrence if the reasons of having early colonoscopy are associated with recurrence. This can complicate estimation of the recurrence rate.</p> <p>Methods</p> <p>We propose to use midpoint imputation to convert interval-censored data problems to right censored data problems. To adjust for potential dependent censoring, we use information from auxiliary variables to define risk groups to perform the weighted Kaplan-Meier estimation to the midpoint imputed data. The risk groups are defined using two risk scores derived from two working proportional hazards models with the auxiliary variables as the covariates. One is for the recurrence time and the other is for the censoring time. The method described here is explored by simulation and illustrated with an example from a colorectal polyp prevention trial.</p> <p>Results</p> <p>We first show that midpoint imputation under an assumption of independent censoring will produce an unbiased estimate of recurrence rate at the end of the trial, which is often the main interest of a colorectal polyp prevention trial, and then show in simulations that the weighted Kaplan-Meier method using the information from auxiliary variables based on the midpoint imputed data can improve efficiency in a situation with independent censoring and reduce bias in a situation with dependent censoring compared to the conventional methods, while estimating the recurrence rate at the end of the trial.</p> <p>Conclusion</p> <p>The research in this paper uses midpoint imputation to handle interval-censored observations and then uses the information from auxiliary variables to adjust for dependent censoring by incorporating them into the weighted Kaplan-Meier estimation. This approach can handle a situation with multiple auxiliary variables by deriving two risk scores from two working PH models. Although the idea of this approach might appear simple, the results do show that the weighted Kaplan-Meier approach can gain efficiency and reduce bias due to dependent censoring.</p