Specialized managed care for children with cystic fibrosis: Resource use patterns and rate design for a high cost Medicaid population

Objective. This research study had two goals: (1) to describe resource consumption patterns for Medi-Cal children with cystic fibrosis, and (2) to explore the feasibility from a rate design perspective of developing specialized managed care plans for such a special needs population.^ Background. Children with special health care needs (CSHN) comprise about 2% of the California Medicaid pediatric population. CSHN have rare but serious health problems, such as cystic fibrosis. Medicaid programs, including Medi-Cal, are enrolling more and more beneficiaries in managed care to control costs. CSHN, however, do not fit the wellness model underlying most managed care plans. Child health advocates believe that both efficiency and quality will suffer if CSHN are removed from regionalized special care centers and scattered among general purpose plans. They believe that CSHN should be "carved out" from enrollment in general plans. One alternative is the Specialized Managed Care Plan, tailored for CSHN.^ Methods. The study population consisted of children under age 21 with CF who were eligible for Medi-Cal and California Children's Services program (CCS) during 1991. Health Care Financing Administration (HCFA) Medicaid Tape-to-Tape data were analyzed as part of a California Children's Hospital Association (CCHA) project.^ Results. Mean Medi-Cal expenditures per month enrolled were $2,302 for 457 CF children, compared to about \$1,270 for all 47,000 CCS special needs children and roughly $60 for almost 2.6 million ``regular needs'' children. For CF children, inpatient care (80\%) and outpatient drugs (9\%) were the major cost drivers, with {\it all\/} outpatient visits comprising only 2\% of expenditures. About one-third of CF children were eligible due to AFDC (Aid to Families with Dependent Children). Age group explained about 17\% of all expenditure variation. Regression analysis was used to select the best capitation rate structure (rate cells by age and eligibility group). Sensitivity analysis estimated moderate financial risk for a statewide plan (360 enrollees), but severe risk for single county implementation due to small numbers of children.^ Conclusions. Study results support the carve out of CSHN due to unique expenditure patterns. The Specialized Managed Care Plan concept appears feasible from a rate design perspective given sufficient enrollees. ^

Evaluation of the impact of access to free influenza vaccine on immunization rates for children with cystic fibrosis

Children with cystic fibrosis are at increased risk of seasonal influenza associated complications, which makes them a judicious target of interventions designed to increase influenza vaccination rates. The Baylor College of Medicine/Texas Children's Hospital Pediatric Cystic Fibrosis (BCM/TCH CF) Care Center implemented an enhanced multi-component initiative designed to increase influenza vaccination rates in its patient population during the 2011-2012 influenza season. We evaluated the impact of specific components of this intervention on vaccination rates among the clinic's patient population via a historical medical chart review and examined the relationship between vaccination status and the number of pulmonary exacerbations requiring hospital admission during the influenza season. The multi-component intervention was comprised of providing influenza free of charge in the CF Care Center, reminders via phone call and letters, and drive through influenza vaccine clinics on nights and weekends. The intervention to increase influenza vaccination rates led to overall improved vaccination rates among the patients at the BCM/TCH CF Care Center, increasing from 90% adherence observed during the 2010-2011 season to 94% adherence during the 2011-2012 season. The availability of free influenza vaccine in the CF Care Center, combined with reminders about being vaccinated early in the season proved to be the most effective practices for improving the vaccination rate in the CF Care Center.^

Self -management behavior in patients with cystic fibrosis

Self-management is being promoted in cystic fibrosis (CF). However, it has not been well studied. Principal aims of this research were (1) to evaluate psychometric properties of a CF disease status measure, the NIH Clinical Score; (2) to develop and validate a measure of self-management behavior, the SMQ-CF scale, and (3) to examine the relation between self-management and disease status in CF patients over two years.^ In study 1, NIH Clinical Scores for 200 patients were used. The scale was examined for internal consistency, interrater reliability, and content validity using factor analysis. The Cronbach's alpha (.81) and interrater reliability (.90) for the total scale were high. General scale items were less reliable. Factor analysis indicated that most of the variance in disease status is accounted for by Factor 1 which consists of pulmonary disease items.^ The SMQ-CF measures the performance of CF self-management. Pilot testing was done with 98 CF primary caregivers. Internal consistency reliability, social desirability bias, and content validity using factor analysis were examined. Internal consistency was good (alpha =.95). Social desirability correlation was low (r =.095). Twelve factors identified were consistent with conceptual groupings of behaviors. Around two hundred caregivers from two CF centers were surveyed and multivariate analysis of variance was used to assess construct validity. Results confirmed expected relations between self-management, patient age, and disease status. Patient age accounted for 50% and disease status 18% of the variance in the SMQ-CF scale.^ It was hypothesized that self-management would positively affect future disease status. Data from 199 CF patients (control and education intervention groups) were examined. Models of hypothesized relations were tested using LISREL structural equation modeling. Results indicated that the relations between baseline self-management and Time 1 disease status were not significant. Significant relations were observed in self-management behaviors from time 1 to time 2 and patterns of significant relations differed between the two groups.^ This research has contributed to refinements in the ability to measure self-management behavior and disease status outcomes in cystic fibrosis. In addition, it provides the first steps in exploratory behavioral analysis with regard to self-management in this disease. ^

Estimation of the incidence of a rare genetic disease through a two-tier mutation survey.

Recent attempts to detect mutations involving single base changes or small deletions that are specific to genetic diseases provide an opportunity to develop a two-tier mutation-screening program through which incidence of rare genetic disorders and gene carriers may be precisely estimated. A two-tier survey consists of mutation screening in a sample of patients with specific genetic disorders and in a second sample of newborns from the same population in which mutation frequency is evaluated. We provide the statistical basis for evaluating the incidence of affected and gene carriers in such two-tier mutation-screening surveys, from which the precision of the estimates is derived. Sample-size requirements of such two-tier mutation-screening surveys are evaluated. Considering examples of cystic fibrosis (CF) and medium-chain acyl-CoA dehydrogenase deficiency (MCAD), the two most frequent autosomal recessive disease in Caucasian populations and the two most frequent mutations (delta F508 and G985) that occur on these disease allele-bearing chromosomes, we show that, with 50-100 patients and a 20-fold larger sample of newborns screened for these mutations, the incidence of such diseases and their gene carriers in a population may be quite reliably estimated. The theory developed here is also applicable to rare autosomal dominant diseases for which disease-specific mutations are found.

Interaction between cell division proteins FtsE and FtsZ.

FtsE and FtsX, which are widely conserved homologs of ABC transporters and interact with each other, have important but unknown functions in bacterial cell division. Coimmunoprecipitation of Escherichia coli cell extracts revealed that a functional FLAG-tagged version of FtsE, the putative ATP-binding component, interacts with FtsZ, the bacterial tubulin homolog required to assemble the cytokinetic Z ring and recruit the components of the divisome. This interaction is independent of FtsX, the predicted membrane component of the ABC transporter, which has been shown previously to interact with FtsE. The interaction also occurred independently of FtsA or ZipA, two other E. coli cell division proteins that interact with FtsZ. In addition, FtsZ copurified with FLAG-FtsE. Surprisingly, the conserved C-terminal tail of FtsZ, which interacts with other cell division proteins, such as FtsA and ZipA, was dispensable for interaction with FtsE. In support of a direct interaction with FtsZ, targeting of a green fluorescent protein (GFP)-FtsE fusion to Z rings required FtsZ, but not FtsA. Although GFP-FtsE failed to target Z rings in the absence of ZipA, its localization was restored in the presence of the ftsA* bypass suppressor, indicating that the requirement for ZipA is indirect. Coexpression of FLAG-FtsE and FtsX under certain conditions resulted in efficient formation of minicells, also consistent with an FtsE-FtsZ interaction and with the idea that FtsE and FtsX regulate the activity of the divisome.

A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells.

Alveolar epithelial type II (ATII) cells are small, cuboidal cells that constitute approximately 60% of the pulmonary alveolar epithelium. These cells are crucial for repair of the injured alveolus by differentiating into alveolar epithelial type I cells. ATII cells derived from human ES (hES) cells are a promising source of cells that could be used therapeutically to treat distal lung diseases. We have developed a reliable transfection and culture procedure, which facilitates, via genetic selection, the differentiation of hES cells into an essentially pure (>99%) population of ATII cells (hES-ATII). Purity, as well as biological features and morphological characteristics of normal ATII cells, was demonstrated for the hES-ATII cells, including lamellar body formation, expression of surfactant proteins A, B, and C, alpha-1-antitrypsin, and the cystic fibrosis transmembrane conductance receptor, as well as the synthesis and secretion of complement proteins C3 and C5. Collectively, these data document the successful generation of a pure population of ATII cells derived from hES cells, providing a practical source of ATII cells to explore in disease models their potential in the regeneration and repair of the injured alveolus and in the therapeutic treatment of genetic diseases affecting the lung.

BIOCHEMICAL CHARACTERIZATION OF BINDING PARTNERS OF TWO HSP70 CO-CHAPERONES IN SACCHAROMYCES CEREVISIAE

Cells are exposed to a variety of environmental and physiological changes including temperature, pH and nutrient availability. These changes cause stress to cells, which results in protein misfolding and altered cellular protein homeostasis. How proteins fold into their three-dimensional functional structure is a fundamental biological process with important relevance to human health. Misfolded and aggregated proteins are linked to multiple neurodegenerative diseases, cardiovascular disease and cystic fibrosis. To combat proteotoxic stress, cells deploy an array of molecular chaperones that assist in the repair or removal of misfolded proteins. Hsp70, an evolutionarily conserved molecular chaperone, promotes protein folding and helps maintain them in a functional state. Requisite co-chaperones, including nucleotide exchange factors (NEFs) strictly regulate and serve to recruit Hsp70 to distinct cellular processes or locations. In yeast and human cells, three structurally non-related cytosolic NEFs are present: Sse1 (Hsp110), Fes1 (HspBP1) and Snl1 (Bag-1). Snl1 is unique among the cytosolic NEFs as it is localized at the ER membrane with its Hsp70 binding (BAG) domain exposed to the cytosol. I discovered that Snl1 distinctly interacts with assembled ribosomes and several lines of evidence indicate that this interaction is both independent of and concurrent with binding to Hsp70 and is not dependent on membrane localization. The ribosome-binding site is identified as a short lysine-rich motif within the amino terminus of the Snl1 BAG domain distinct from the Hsp70 interaction region. In addition, I demonstrate ribosome association with the Snl1 homolog in the pathogenic fungus, Candida albicans and localize this putative NEF to a perinuclear/ER membrane, suggesting functional conservation in fungal BAG domain-containing proteins. As a first step in determining specific domain architecture in fungal BAG proteins, I present the preliminary steps of protein purification and analysis of the minimal Hsp70 binding region in in both S.cerevisiae and C. albicans Snl1. Contrary to previous in vitro evidence which showed the Fes1 NEF to interact with both cytosolic Hsp70s, Ssa and Ssb, Fes1 is shown to interact specifically with Ssa when expressed under normal cellular conditions in S. cerevisiae. This is the first reported evidence of Hsp70 binding selectivity for a cytosolic NEF, and suggests a possible mechanism to achieve specificity in Hsp70-dependent functions. Taken together, the work presented in this dissertation highlights the striking divergence among Hsp70 co-chaperones in selecting binding partners, which may correlate with their specific roles in the cell.