Back to the future? New cost and access challenges emerge. Initial findings from HSC's recent site visits.

Every two years, researchers at the Center for Studying Health System Change (HSC) interview health care leaders in 12 nationally representative communities to assess changes in local health care markets. The third round of site visits is under-way, and early findings from 2000-2001 indicate significant changes in health care financing and delivery are taking place across the country. This Issue Brief discusses developments in managed care, hospital consolidation, physician-hospital tensions, risk contracting and health plan premiums. State and federal policy makers charged with balancing cost, coverage, access and quality of health care should consider these emerging trends in their decision making.

Emergency room diversions: a symptom of hospitals under stress.

Emergency room (ER) diversions-when ambulances are redirected from one hospital emergency room to another-are becoming common in communities across the country, raising concern that critically ill patients are increasingly confronting obstacles to timely medical care. Although hospitals have long diverted patients during the winter flu season, recent site visits conducted by the Center for Studying Health System Change (HSC) reveal that ER overflows are now a year-round problem. As this Issue Brief describes, difficulty obtaining emergency services may be just the most visible evidence of deeper problems facing many hospitals as they struggle to meet growing demand for services at a time of increasing capacity constraints.

Expression of microbial virulence proteins in Saccharomyces cerevisiae models mammalian infection.

Bacterial virulence proteins that are translocated into eukaryotic cells were expressed in Saccharomyces cerevisiae to model human infection. The subcellular localization patterns of these proteins in yeast paralleled those previously observed during mammalian infection, including localization to the nucleus and plasma membrane. Localization of Salmonella SspA in yeast provided the first evidence that SspA interacts with actin in living cells. In many cases, expression of the bacterial virulence proteins conferred genetically exploitable growth phenotypes. In this way, Yersinia YopE toxicity was demonstrated to be linked to its Rho GTPase activating protein activity. YopE blocked polarization of the yeast cytoskeleton and cell cycle progression, while SspA altered polarity and inhibited depolymerization of the actin cytoskeleton. These activities are consistent with previously proposed or demonstrated effects on higher eukaryotes and provide new insights into the roles of these proteins in pathogenesis: SspA in directing formation of membrane ruffles and YopE in arresting cell division. Thus, study of bacterial virulence proteins in yeast is a powerful system to determine functions of these proteins, probe eukaryotic cellular processes and model mammalian infection.

Local innovations provide managed care for the uninsured.

A number of communities in the United States are adopting a managed care approach to caring for low-income uninsured individuals. This Issue Brief focuses on such programs in five of the 12 communities that the Center for Studying Health System Change (HSC) is tracking intensively. It describes the local market factors that motivated the creation and varying design of these initiatives, all of which seek to increase access to primary and preventive care while managing the use of more costly inpatient and emergency care. The Issue Brief also discusses the long-term viability of these programs as they attempt to simultaneously expand access to services and contain costs for this growing population.

Insolvency and challenges of regulating providers that bear risk.

Risk contracting and capitation are two widely used financial mechanisms that give incentives to health care providers to control costs. Risk-bearing arrangements have failed in a number of communities, however. This has shaken local markets, disrupting consumers' access to health care services and triggering losses for physicians and hospitals. It also has raised questions about the adequacy of related regulatory oversight, which holds important implications for local and national policy makers. This Issue Brief provides case studies of failed risk-contracting arrangements in two of the 12 communities that the Center for Studying Health System Change (HSC) tracks intensively--Northern New Jersey and Orange County, Calif.--and examines implications for policy makers.

Update on the nation's health care system: 1997-1999.

A major component of the Community Tracking Study is biennial site visits to twelve communities randomly selected to be representative of metropolitan areas. In the second round of visits, conducted in 1998 and 1999, we found an intensification of an earlier trend toward looser forms of managed care to be causing enormous turmoil, as health care organizations stumbled over and often abandoned strategies conceived for more tightly managed care. Communities' health care systems are not evolving as many anticipated but rather have focused increasingly on horizontal consolidation and regional scope.

Ovarian decline. In the later reproductive years.

While most healthy older women who become pregnant have uneventful pregnancies and healthy babies, thousands more are unable to achieve pregnancy because of declining ovarian function. A decline in ovarian function is normal with increasing age. A woman's number of eggs steadily decreases from a peak at mid-gestation of 7 million to approximately 400,000 at puberty. Certain tests can reflect gradations in ovarian reserve status and predict a woman's potential fertility. The most important lab test is the day 3 follicle-stimulating hormone level. A constant source of frustration in fertility centers is that patients are referred to the specialty clinic too late, when diminished ovarian reserve is so marked that treatment success is severely limited. Earlier assessment of ovarian function would alter this unfortunate trend.

Managed care and physicians' provision of charity care.

CONTEXT: Health system changes may be affecting the ability of physicians to provide care with little or no compensation from patients who are uninsured and under-insured and may result in decreased access to physicians for uninsured persons. OBJECTIVE: To examine the association between managed care and physicians' provision of charity care. DESIGN: The 1996-1997 Community Tracking Study physician survey. SETTING AND PARTICIPANTS: A nationally representative sample of 10881 physicians from 60 randomly selected communities. MAIN OUTCOME MEASURE: The number of hours in the month prior to the interview that the physician provided care for free or at reduced fees because of the financial need of the patient. RESULTS: Overall, 77.3% of respondents provided an average of 10.3 hours of charity care per month [corrected]. Physicians who derive at least 85% of their practice revenue from managed care plans were considerably less likely to provide charity care and spend fewer hours providing charity care than physicians with little involvement in managed care plans (P = .01). In addition, physicians who practice in areas with high managed care penetration provided fewer hours of charity care than physicians in other areas, regardless of their own level of involvement with managed care (P<.01). Differences in charity care provision were also shown for other important factors, including ownership of the practice and practice arrangements (more charity care occurred in solo and 2-physician practices; P<.01). CONCLUSION: Physicians involved with managed care plans and those who practice in areas with high managed care penetration tend to provide less charity care.

Medicaid managed care policies affecting children with disabilities: 1995 and 1996.

The authors present findings from a study of State Medicaid managed care enrollment and benefit policies in 1995 and 1996 for children with disabilities. During this time the number of States serving children through fully capitated plans grew by more than one-third, and enrollment of children receiving Supplemental Security Income (SSI) payments and children in subsidized foster care increased. Most States required plans to provide all mandatory and most optional Medicaid services. Although States have begun to make noticeable improvements in their contract language concerning medical necessity and the early and periodic screening, diagnosis, and treatment (EPSDT) benefit, overall State guidance in these areas remains weak.

Mutations in U6 snRNA that alter splice site specificity: implications for the active site.

What determines the precise sites of cleavage in the two transesterification reactions of messenger RNA (mRNA) splicing is a major unsolved question. Mutation of the invariant G (guanosine) at position 5 of 5' splice sites in Saccharomyces cerevisiae introns activates cleavage at nearby aberrant sites. A genetic approach was used to test the hypothesis that a base-pairing interaction between the 5' splice site and the invariant ACAGAG sequence of U6 is a determinant of 5' splice site choice. Mutations in U6 or the intron (or both) that were predicted to stabilize the interaction suppressed aberrant cleavage and increased normal cleavage. In addition, a mutation in the ACAGAG sequence suppressed mutations of the 3' splice site dinucleotide. These data can fit a model for the spliceosomal active site comprised of a set of RNA-RNA interactions between the intron, U2 and U6.

Mutational analysis of pre-mRNA splicing in Saccharomyces cerevisiae using a sensitive new reporter gene, CUP1.

We have developed a new reporter gene fusion to monitor mRNA splicing in yeast. An intron-containing fragment from the Saccharomyces cerevisiae ACT1 gene has been fused to CUP1, the yeast metallothionein homolog. CUP1 is a nonessential gene that allows cells to grow in the presence of copper in a dosage-dependent manner. By inserting previously characterized intron mutations into the fusion construct, we have established that the efficiency of splicing correlates with the level of copper resistance of these strains. A highly sensitive assay for 5' splice site usage was designed by engineering an ACT1-CUP1 construct with duplicated 5' splice sites; mutations were introduced into the upstream splice site in order to evaluate the roles of these highly conserved nucleotides in intron recognition. Almost all mutations in the intron portion of the 5' consensus sequence abolish recognition of the mutated site, while mutations in the exon portion of the consensus sequence have variable affects on cleavage at the mutated site. Interestingly, mutations at intron position 4 demonstrate that this nucleotide plays a role in 5' splice site recognition other than by base pairing with U1 snRNA. The use of CUP1 as a reporter gene may be generally applicable for monitoring cellular processes in yeast.

Sequences beyond the cleavage site influence signal peptide function.

The earliest events in protein secretion include targeting to and translocation across the endoplasmic reticulum membrane. To dissect the mechanism by which signal sequences mediate translocation in eukaryotes, we are examining the behavior of fusion proteins and deletion mutants in cell-free systems. We demonstrate that the protein domain being translocated can have profound impact on the efficiency of the translocation process. Specifically, deletions in the mature prolactin "passenger" domain, beyond the signal cleavage site, reduce the efficiency of signal function. The effect of these deletions on signal function is observed when this signal sequence is in its normal position, at the amino terminus, and when internalized by the addition of 117 amino acids of chimpanzee alpha-globin. Alterations in the interaction of the deletion mutants with the signal recognition particle and with another component of the translocation system, signal peptidase, were observed. Our results suggest that subtle changes in sequences beyond the signal cleavage site can alter the efficiency of co-translational translocation by affecting various signal-receptor interactions.

Structural and regulatory divergence among site-specific recombination genes of lambdoid phage.

The lambdoid bacteriophage phi 80 and P22 have site-specific recombination systems similar to that of lambda. Each of the three phage has a different insertion specificity, but structural analysis of their attachment sites suggests that the three recombination pathways share similar features. In this study, we have identified and sequenced the int and xis genes of phi 80 and P22. phi 80 int and xis were identified using a plasmid recombination assay in vivo, and the P22 genes were mapped using Tn1 insertion mutations. In all three phage, the site-specific recombination genes are located directly adjacent to the phage attachment site. Interestingly, the transcriptional orientation of the phi 80 int gene is opposite to that of lambda and P22 int, resulting in convergent transcription of phi 80 int and xis. Because of its transcriptional orientation, phi 80 int cannot be expressed by the major leftward promoter, PL, and the regulatory strategy of phi 80 integration and excision must differ significantly from that of lambda. The deduced amino acid sequences of the recombination proteins of the three systems show surprisingly little homology. Sequences homologous to the lambda PI promoter are more conserved than the protein-coding sequences. Nevertheless, the Int proteins are locally related in the C-terminal sequences, particularly for a stretch of some 25 amino acid residues that lie approximately 50 residues from the C terminus. The Xis proteins can be aligned at their N termini.

The phi 80 and P22 attachment sites. Primary structure and interaction with Escherichia coli integration host factor.

Although the lambdoid bacteriophage phi 80 and P22 possess site-specific recombination systems analogous to bacteriophage lambda, they have different attachment (att) site specificities. We have identified and determined the nucleotide sequences of the att sites of phi 80 and P22 and have examined the interaction of these sites with purified Escherichia coli integration host factor (IHF). The sizes of the homologous core regions of the att sites vary greatly: P22 has a 46-base pair core, while phi 80 and lambda have 17- and 15-base pair cores, respectively. The core sequences of the three phage show no significant homology, although dispersed regions of homology in arm sequences indicate that the three phage att sites are related. All three att sites have a high A + T composition, and restriction fragments carrying these sites migrate anomalously upon polyacrylamide gel electrophoresis. IHF binds to a site to the left of the common core in the phi 80 and P22 phage att sites (attP) and to a site to the right of the core in P22 attP and attB (the bacterial att site). In the lambda system, IHF interacts with three regions on attP (designated H1, H2, and H') and none on attB (Craig N., and Nash, H.A. (1984) Cell 39, 707-716). Alignment of the IHF sites of all three phage results in a consensus sequence for IHF binding, Pyr-AANNNNTTGATAT. Among the three phage, the number of IHF sites differs; however, the location and orientation of the binding sites in relation to the respective core regions are well conserved. An IHF site analogous to lambda H2 is present in both phi 80 and P22 attP, while a site analogous to lambda H' is present in P22 attP. This conservation suggests that IHF plays a very similar role in the site-specific recombination pathways of all three phage, and that the flanking arm sequences are necessary for phi 80 and P22 attP function, as is the case for lambda attP function. These structural similarities presumably reflect a conservation of the mechanism of site-specific recombination for the three phage.

Comparison of extraction and precipitation methods for the HPLC determination of furosemide in plasma and urine.

Comparisons have been made between an ether extraction method and an acetonitrile precipitation method for the HPLC determination of furosemide (frusemide) in human plasma and urine. Recoveries of furosemide were 81-89% (ether extraction method for plasma), 73-103% (acetonitrile precipitation method for plasma) and 62-89% (ether extraction method for urine) for the concentration ranges studied. Values of correlation coefficients were 0.9998, 0.9991 and 0.9997 for standard curves for the three methods, respectively. Accuracy and precision (RSD) were: 92.4-114% +/- 3.57-20% for ether-extracted plasma; 98.1-103% +/- 3.47-19.9% for acetonitrile-precipitated plasma; and 103-107% +/- 4.03-13.2% for ether-extracted urine. Because of carryover of endogenous urine components, the acetonitrile-precipitation assay was unacceptable for urine. Furosemide was stable in frozen plasma for at least 113 days and in frozen urine for at least 204 days. No artifactual appearance of the hydrolysis product of furosemide, 4-chloro-5-sulfamoylanthranilic acid (CSA), was detected by the ether-extraction method under normal assay conditions.

Providing infertility care.

In recent years nurse practitioners have expanded their repertoire of ob/gyn skills to include the provision of infertility care. To minimize the stresses involved in an infertility investigation, couples benefit from a care provider who can educate them about the factors, testing, and treatments involved in infertility. They also need a provider who can support them emotionally through a work-up that touches upon the sensitive aspects of their sexuality, partner relationship, and self-esteem. Nurse practitioners have demonstrated an aptitude in providing competent medical care and health education in the context of a therapeutic relationship. Utilization of the physician/nurse practitioners collaborative team approach offers one successful model for integrating nurse practitioners into the practice of infertility.