Predictors of Unmet Family Support Service Needs in Families of Children with Special Health Care Needs.

OBJECTIVES: This study describes rates of perceived and unmet need for family support services (care coordination, respite care, and family mental health care) among a national sample of children with special health care needs (CSHCN), distinguishing children with emotional, behavioral, or developmental problems (EBDPs) from children with primarily physical chronic conditions. It also examines if a child having EBDPs is associated with perceived and unmet family support service needs and investigates public versus private health insurance's moderating effect on this association. METHODS: Using data from the National Survey of Children with Special Health Care Needs (2005/2006 and 2009/2010), this cross-sectional study uses multi-level, fixed effects logistic regression. RESULTS: When compared to CSHCN with no EBDPs, parents of CSHCN with EBDPs report greater need for all family support services and greater rates of unmet need for all support services. This pattern of greater need for CSHCN with EBDPs versus those without is similar among those with public and private health insurance. Among CSHCN with family support needs, however, the pattern differs. For CSHCN with EBDPs, having public insurance is associated with lower probabilities of unmet needs compared to private insurance. For CSHCN without EBDPs, having public insurance has a mixed effect on probability of reporting unmet need. CONCLUSION: Having EBDPs and public insurance is associated with increased perceived need, but public insurance also confers particular benefit for children with EBDPs.

Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors.

The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, N-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (11b) is the most interesting compound, with IC50 values of 0.66; 1.46 and 3.67 µM. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for N-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (11d). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies.

Implementation of a Prophylactic Anticoagulation Guideline for Patients with Traumatic Brain Injury.

BACKGROUND: Patients with traumatic brain injury (TBI) are at an increased risk of developing complications from venous thromboembolisms (VTEs [blood clots]). Benchmarking by the American College of Surgeons Trauma Quality Improvement Program identified suboptimal use of prophylactic anticoagulation in patients with TBI. We hypothesized that institutional implementation of an anticoagulation protocol would improve clinical outcomes in such patients. METHODS: A new prophylactic anticoagulation protocol that incorporated education, weekly audits, and real-time adherence feedback was implemented in July 2015. The trauma registry identified patients with TBI before (PRE) and after (POST) implementation. Multivariable regression analysis with risk adjustment was used to compare use of prophylactic anticoagulation, VTE events, and mortality. RESULTS: A total of 681 patients with TBI (368 PRE, 313 POST) were identified. After implementation of the VTE protocol, more patients received anticoagulation (PRE: 39.4%, POST: 80.5%, p < 0.001), time to initiation was shorter (PRE: 140 hours, POST: 59 hours, p < 0.001), and there were fewer VTE events (PRE: 19 [5.2%], POST: 7 [2.2%], p = 0.047). Multivariable analysis showed that POST patients were more likely to receive anticoagulation (odds ratio [OR] = 10.8, 95% confidence interval [CI] = 6.9-16.7, p < 0.001) and less likely to develop VTE (OR = 0.33, 95% CI = 0.1-1.0, p = 0.05). CONCLUSION: Benchmarking can assist institutions to identity potential clinically relevant areas for quality improvement in real time. Combining education and multifaceted protocol implementation can help organizations to better focus limited quality resources and counteract barriers that have hindered adoption of best practices.

Trans-heteroclinic bifurcation: a novel type of catastrophic shift.

Global and local bifurcations are extremely important since they govern the transitions between different qualitative regimes in dynamical systems. These transitions or tipping points, which are ubiquitous in nature, can be smooth or catastrophic. Smooth transitions involve a continuous change in the steady state of the system until the bifurcation value is crossed, giving place to a second-order phase transition. Catastrophic transitions involve a discontinuity of the steady state at the bifurcation value, giving place to first-order phase transitions. Examples of catastrophic shifts can be found in ecosystems, climate, economic or social systems. Here we report a new type of global bifurcation responsible for a catastrophic shift. This bifurcation, identified in a family of quasi-species equations and named as trans-heteroclinic bifurcation, involves an exchange of stability between two distant and heteroclinically connected fixed points. Since the two fixed points interchange the stability without colliding, a catastrophic shift takes place. We provide an exhaustive description of this new bifurcation, also detailing the structure of the replication-mutation matrix of the quasi-species equation giving place to this bifurcation. A perturbation analysis is provided around the bifurcation value. At this value the heteroclinic connection is replaced by a line of fixed points in the quasi-species model. But it is shown that, if the replication-mutation matrix satisfies suitable conditions, then, under a small perturbation, the exchange of heteroclinic connections is preserved, except on a tiny range around the bifurcation value whose size is of the order of magnitude of the perturbation. The results presented here can help to understand better novel mechanisms behind catastrophic shifts and contribute to a finer identification of such transitions in theoretical models in evolutionary biology and other dynamical systems.

Abrupt transitions to tumor extinction: a phenotypic quasispecies model.

The dynamics of heterogeneous tumor cell populations competing with healthy cells is an important topic in cancer research with deep implications in biomedicine. Multitude of theoretical and computational models have addressed this issue, especially focusing on the nature of the transitions governing tumor clearance as some relevant model parameters are tuned. In this contribution, we analyze a mathematical model of unstable tumor progression using the quasispecies framework. Our aim is to define a minimal model incorporating the dynamics of competition between healthy cells and a heterogeneous population of cancer cell phenotypes involving changes in replication-related genes (i.e., proto-oncogenes and tumor suppressor genes), in genes responsible for genomic stability, and in house-keeping genes. Such mutations or loss of genes result into different phenotypes with increased proliferation rates and/or increased genomic instabilities. Despite bifurcations in the classical deterministic quasispecies model are typically given by smooth, continuous shifts (i.e., transcritical bifurcations), we here identify a novel type of bifurcation causing an abrupt transition to tumor extinction. Such a bifurcation, named as trans-heteroclinic, is characterized by the exchange of stability between two distant fixed points (that do not collide) involving tumor persistence and tumor clearance. The increase of mutation and/or the decrease of the replication rate of tumor cells involves this catastrophic shift of tumor cell populations. The transient times near bifurcation thresholds are also characterized, showing a power law dependence of exponent [Formula: see text] of the transients as mutation is changed near the bifurcation value. These results are discussed in the context of targeted cancer therapy as a possible therapeutic strategy to force a catastrophic shift by simultaneously delivering mutagenic and cytotoxic drugs inside tumor cells.

Indoor air pollution from solid fuels and peripheral blood DNA methylation: findings from a population study in Warsaw, Poland.

DNA methylation is a potential mechanism linking indoor air pollution to adverse health effects. Fetal and early-life environmental exposures have been associated with altered DNA methylation and play a critical role in progress of diseases in adulthood. We investigated whether exposure to indoor air pollution from solid fuels at different lifetime periods was associated with global DNA methylation and methylation at the IFG2/H19 imprinting control region (ICR) in a population-based sample of non-smoking women from Warsaw, Poland. Global methylation and IFG2/H19 ICR methylation were assessed in peripheral blood DNA from 42 non-smoking women with Luminometric Methylation Assay (LUMA) and quantitative pyrosequencing, respectively. Linear regression models were applied to estimate associations between indoor air pollution and DNA methylation in the blood. Compared to women without exposure, the levels of LUMA methylation for women who had ever exposed to both coal and wood were reduced 6.70% (95% CI: -13.36, -0.04). Using both coal and wood before age 20 was associated with 6.95% decreased LUMA methylation (95% CI: -13.79, -0.11). Further, the negative correlations were more significant with exposure to solid fuels for cooking before age 20. There were no clear associations between indoor solid fuels exposure before age 20 and through the lifetime and IFG2/H19 ICR methylation. Our study of non-smoking women supports the hypothesis that exposure to indoor air pollution from solid fuels, even early-life exposure, has the capacity to modify DNA methylation that can be detected in peripheral blood.

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations.

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Time-Motion Analysis of Four Automated Systems for the Detection of Chlamydia trachomatis and Neisseria gonorrhoeae by Nucleic Acid Amplification Testing.

Next-generation diagnostics for Chlamydia trachomatis and Neisseria gonorrhoeae are available on semi- or fully-automated platforms. These systems require less hands-on time than older platforms and are user friendly. Four automated systems, the ABBOTT m2000 system, Becton Dickinson Viper System with XTR Technology, Gen-Probe Tigris DTS system, and Roche cobas 4800 system, were evaluated for total run time, hands-on time, and walk-away time. All of the systems evaluated in this time-motion study were able to complete a diagnostic test run within an 8-h work shift, instrument setup and operation were straightforward and uncomplicated, and walk-away time ranged from approximately 90 to 270 min in a head-to-head comparison of each system. All of the automated systems provide technical staff with increased time to perform other tasks during the run, offer easy expansion of the diagnostic test menu, and have the ability to increase specimen throughput.