A biomechanical model for the transendothelial migration of cancer cells

We propose a biomechanical model for the extravasation of a tumor cell (TC) through the endothelium of a blood vessel. Based on prior in vitro observations, we assume that the TC extends a protrusion between adjacent endothelial cells (ECs) that adheres to the basement membrane via focal adhesions. As the protrusion grows in size and branches out, the actomyosin contraction along the stress fibers inside the protrusion pulls the relatively rigid nucleus through the endothelial opening. We model the chemo-mechanics of the stress fibers and the focal adhesions by following the kinetics of the active myosin motors and high-affinity integrins, subject to mechanical feedback. This is incorporated into a finite-element simulation of the extravasation process, with the contractile force pulling the nucleus of the tumor cell against elastic resistance of the ECs. To account for the interaction between the TC nucleus and the endothelium, we consider two scenarios: solid-solid contact and lubrication by cytosol. The former gives a lower bound for the required contractile force to realize transmigration, while the latter provides a more realistic representation of the process. Using physiologically reasonable 1 parameters, our model shows that the stress-fiber and focal-adhesion ensemble can produce a contractile force on the order of 70 nN, which is sufficient to deform the ECs and enable transmigration. Furthermore, we use an atomic force microscope to measure the resistant force on a human bladder cancer cell that is pushed through an endothelium cultured in vitro. The magnitude of the required force turns out to be in the range of 70-100 nN, comparable to the model predictions

Closing the loop in child TB contact management: completion of TB preventive therapy outcomes in western Kenya

SETTING: Children especially those \u3c 5 years of age exposed to pulmonary tuberculosis (TB) are at a high risk of severe TB disease and death. Isoniazid preventive therapy (IPT) has been shown to decrease disease progression by up to 90%. Kenya, a high TB burden country experiences numerous operational challenges that limit implementation of TB preventive services. IPT completion in child contacts is not routinely reported in Kenya. OBJECTIVE: This study aims to review the child contact management (CCM) cascade and present IPT outcomes across 10 clinics in western Kenya. DESIGN: A retrospective chart review of programmatic data of a TB Reach-funded active, clinic-based CCM strategy. RESULTS: Of 553 child contacts screened, 231 (42%) were reported symptomatic. 74 (13%) of the child contacts were diagnosed with active TB disease. Of those eligible for IPT, 427 (90%) initiated IPT according to TB REACH project data while 249 (58%) were recorded in the IPT register with 49 (11%) recorded as a transfer to other facilities. Of the 249 recorded in the IPT register, 205 (82%) were documented to complete therapy (48% of project initiation children). CONCLUSION: Our evaluation shows gaps in the routine CCM care cascade related to completeness of documentation that require further programmatic monitoring and evaluation to improve CCM outcomes

The relationship between a microfinance-based healthcare delivery platform, health insurance coverage, health screenings, and disease management in rural Western Kenya

BACKGROUND: Structural barriers often prevent rural Kenyans from receiving healthcare and diagnostic testing. The Bridging Income Generation through grouP Integrated Care (BIGPIC) Family intervention facilitates microfinance groups, provides health screenings and treatment, and delivers education about health insurance coverage to address some of these barriers. This study evaluated the association between participation in BIGPIC microfinance groups and health screening/disease management outcomes. METHODS: From November 2018 to March 2019, we interviewed a sample of 300 members of two rural communities in Western Kenya, 100 of whom were BIGPIC microfinance members. We queried participants about their experiences with health screening and disease management for HIV, diabetes, hypertension, tuberculosis, and cervical cancer. We used log-binomial regression models to estimate the association between microfinance membership and each health outcome, adjusting for key covariates. RESULTS: Microfinance members were more likely to be screened for most of the health conditions we queried, including those provided by BIGPIC [e.g. diabetes: aPR (95% CI): 3.46 (2.60, 4.60)] and those not provided [e.g. cervical cancer: aPR (95% CI): 2.43 (1.21, 4.86)]. Microfinance membership was not significantly associated with health insurance uptake and disease management outcomes. CONCLUSIONS: In rural Kenya, a microfinance program integrated with healthcare delivery may be effective at increasing health screening. Interventions designed to thoughtfully and sustainably address structural barriers to healthcare will be critical to improving the health of those living in low-resource settings

Performance Analysis of Mobile Agents for Filtering Data Streams on Wireless Networks

Wireless networks are an ideal environment for mobile agents, since their mobility allows them to move across an unreliable link to reside on a wired host, next to or closer to the resources that they need to use. Furthermore, client-specific data transformations can be moved across the wireless link and run on a wired gateway server, reducing bandwidth demands. In this paper we examine the tradeoffs faced when deciding whether to use mobile agents in a data-filtering application where numerous wireless clients filter information from a large data stream arriving across the wired network. We develop an analytical model and use parameters from filtering experiments conducted during a U.S. Navy Fleet Battle Experiment (FBE) to explore the model\u27s implications

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency with a Small-Molecule Activator

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency

Should Endovascular Repair Be Reimbursed for Low Risk Abdominal Aortic Aneurysm Patients? Evidence from Ontario, Canada

Background. This paper presents unpublished clinical and economic data associated with open surgical repair (OSR) in low risk (LR) patients and how it compares with EVAR and OSR in high risk (HR) patients with an AAA > 5.5 cm. Design. Data from a 1-year prospective observational study was used to compare EVAR in HR patients versus OSR in HR and LR patients. Results. Between 2003 and 2005, 140 patients were treated with EVAR and 195 with OSR (HR: 52; LR: 143). The 1-year mortality rate with EVAR was statistically lower than HR OSR patients and comparable to LR OSR patients. One-year health-related quality of life was lower in the EVAR patients compared to OSR patients. EVAR was cost-effective compared to OSR HR but not when compared to OSR LR patients. Conclusions. Despite a similar clinical effectiveness, these results suggest that, at the current price, EVAR is more expensive than open repair for low risk patients