Cystic Fibrosis Foundation Evidence-Based Guideline for the Management of CRMS/CFSPID.

A multidisciplinary committee developed evidence-based guidelines for the management of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID). A total of 24 patient, intervention, comparison, and outcome questions were generated based on surveys sent to people with CRMS/CFSPID and clinicians caring for these individuals, previous recommendations, and expert committee input. Four a priori working groups (genetic testing, monitoring, treatment, and psychosocial/communication issues) were used to provide structure to the committee. A systematic review of the evidence was conducted, and found numerous case series and cohort studies, but no randomized clinical trials. A total of 30 recommendations were graded using the US Preventive Services Task Force methodology. Recommendations that received ≥80% consensus among the entire committee were approved. The resulting recommendations were of moderate to low certainty for the majority of the statements because of the low quality of the evidence. Highlights of the recommendations include thorough evaluation with genetic sequencing, deletion/duplication analysis if <2 disease-causing variants were noted in newborn screening; repeat sweat testing until at least age 8 but limiting further laboratory testing, including microbiology, radiology, and pulmonary function testing; minimal use of medications, which when suggested, should lead to shared decision-making with families; and providing communication with emphasis on social determinants of health and shared decision-making to minimize barriers which may affect processing and understanding of this complex designation. Future research will be needed regarding medication use, antibiotic therapy, and the use of chest imaging for monitoring the development of lung disease.

Outcomes of follow-up care after an emergency department visit among pediatric asthmatics in the military health system.

BACKGROUND AND OBJECTIVES: Asthma exacerbations frequently trigger emergency department (ED) visits. Guidelines recommend timely follow-up after an ED visit for asthma, however, other studies have questioned the quality of follow-up care and their effect on subsequent ED utilization. We evaluated follow-up care on asthma outcomes in pediatric asthmatics enrolled in the Military Health System (MHS) after an ED visit for asthma. METHODS: This retrospective study utilized MHS data to evaluate 2-17-year-old persistent asthmatics with an ED visit for asthma between 2010-2012. Demographics, medication dispensing, and subsequent asthma related ED and hospital utilization were compared between those with or without a 28-day follow-up appointment. RESULTS: 10,460 of 88,837 persistent asthmatics met inclusion criteria for an asthma ED visit. 4,964 (47.5%) had ≥ 1 follow-up visit. In the 29-365 days after their ED visit, 21.1% of the follow-up cohort required an ED re-visit compared to 24.0% of the patients without follow-up. Follow-up care was associated with a reduction in ED re-visits (adjusted hazard ratio 0.86; 95% confidence interval 0.79, 0.93). Controller medications were dispensed to 76.0% of the follow-up cohort within 90 days of their ED visit compared to 49.7% in the group without follow-up. CONCLUSIONS: Despite universal access to healthcare, less than half of pediatric MHS asthma patients had follow-up within 28 days of an ED visit. Those with follow-up were more likely to fill a controller medication within 90 days post-ED visit, and less likely to have an asthma ED re-visit in the subsequent year.

A mathematical model for selective differentiation of neural progenitor cells on micropatterned polymer substrates.

The biological hypothesis that the astrocyte-secreted cytokine, interleukin-6 (IL6), stimulates differentiation of adult rat hippocampal progenitor cells (AHPCs) is considered from a mathematical perspective. The proposed mathematical model includes two different mechanisms for stimulation and is based on mass-action kinetics. Both biological mechanisms involve sequential binding, with one pathway solely utilizing surface receptors while the other pathway also involves soluble receptors. Choosing biologically-reasonable values for parameters, simulations of the mathematical model show good agreement with experimental results. A global sensitivity analysis is also conducted to determine both the most influential and non-influential parameters on cellular differentiation, providing additional insights into the biological mechanisms.

The evolutionary origins of gene regulation.

One way that organisms cope with constantly changing physical and biological conditions is by regulating the expression of genes and thereby altering protein production. Clearly, altering the protein production to match the environmental demands can be adaptive, but there may be evolutionary barriers to the transition from constitutive expression to regulated expression. In particular, down-regulating a gene when it is not needed means that there will necessarily be a delay in protein production when the protein is up-regulated in the future. We develop a model of simple gene regulation in response to randomly changing environmental conditions. We calculate the long-term behavior of gene expression and determine the fitness consequences of changes in the gene regulation. We then embed this model into a population genetic framework in order to determine the conditions that allow populations to evolve environment-specific transcription rates. The population genetic model follows the evolutionary transition from constitutive expression to regulated expression. There are three distinct possible evolutionary outcomes. The gene may be stuck in the always on position, the gene may first evolve to an intermediate constitutive expression level and then evolve regulation, or regulation can evolve directly from the ancestral state in a smooth fashion. Regulation is most likely to evolve when the costs of mis-expression are low and the transcript decay rate is high. This suggests that genes that have less severe reductions in fitness when mis-expressed are more likely to initially evolve regulation.

Gene expression dynamics in randomly varying environments.

A simple model of gene regulation in response to stochastically changing environmental conditions is developed and analyzed. The model consists of a differential equation driven by a continuous time 2-state Markov process. The density function of the resulting process converges to a beta distribution. We show that the moments converge to their stationary values exponentially in time. Simulations of a two-stage process where protein production depends on mRNA concentrations are also presented demonstrating that protein concentration tracks the environment whenever the rate of protein turnover is larger than the rate of environmental change. Single-celled organisms are therefore expected to have relatively high mRNA and protein turnover rates for genes that respond to environmental fluctuations.

A mathematical model for the onset of avascular tumor growth in response to the loss of p53 function.

We present a mathematical model for the formation of an avascular tumor based on the loss by gene mutation of the tumor suppressor function of p53. The wild type p53 protein regulates apoptosis, cell expression of growth factor and matrix metalloproteinase, which are regulatory functions that many mutant p53 proteins do not possess. The focus is on a description of cell movement as the transport of cell population density rather than as the movement of individual cells. In contrast to earlier works on solid tumor growth, a model is proposed for the initiation of tumor growth. The central idea, taken from the mathematical theory of dynamical systems, is to view the loss of p53 function in a few cells as a small instability in a rest state for an appropriate system of differential equations describing cell movement. This instability is shown (numerically) to lead to a second, spatially inhomogeneous, solution that can be thought of as a solid tumor whose growth is nutrient diffusion limited. In this formulation, one is led to a system of nine partial differential equations. We show computationally that there can be tumor states that coexist with benign states and that are highly unstable in the sense that a slight increase in tumor size results in the tumor occupying the sample region while a slight decrease in tumor size results in its ultimate disappearance.