Variation in expenditure for common, high cost surgical procedures in a working age population: implications for reimbursement reform.

BACKGROUND: In the move toward value-based care, bundled payments are believed to reduce waste and improve coordination. Some commercial insurers have addressed this through the use of bundled payment, the provision of one fee for all care associated with a given index procedure. This system was pioneered by Medicare, using a population generally over 65 years of age, and despite its adoption by mainstream insurers, little is known of bundled payments' ability to reduce variation or cost in a working-age population. This study uses a universally-insured, nationally-representative population of adults aged 18-65 to examine the effect of bundled payments for five high-cost surgical procedures which are known to vary widely in Medicare reimbursement: hip replacement, knee replacement, coronary artery bypass grafting (CABG), lumbar spinal fusion, and colectomy. METHODS: Five procedures conducted on adults aged 18-65 were identified from the TRICARE database from 2011 to 2014. A 90-day period from index procedure was used to determine episodes of associated post-acute care. Data was sorted by Zip code into hospital referral regions (HRR). Payments were determined from TRICARE reimbursement records, they were subsequently price standardized and adjusted for patient and surgical characteristics. Variation was assessed by stratifying the HRR into quintiles by spending for each index procedure. RESULTS: After adjusting for case mix, significant inter-quintile variation was observed for all procedures, with knee replacement showing the greatest variation in both index surgery (107%) and total cost of care (75%). Readmission was a driver of variation for colectomy and CABG, with absolute cost variation of $17,257 and $13,289 respectively. Other post-acute care spending was low overall (≤$1606, for CABG). CONCLUSIONS: This study demonstrates significant regional variation in total spending for these procedures, but much lower spending for post-acute care than previously demonstrated by similar procedures in Medicare. Targeting post-acute care spending, a common approach taken by providers in bundled payment arrangements with Medicare, may be less fruitful in working aged populations.

Minimally invasive surgery and its impact on 30-day postoperative complications, unplanned readmissions and mortality.

BACKGROUND: A critical appraisal of the benefits of minimally invasive surgery (MIS) is needed, but is lacking. This study examined the associations between MIS and 30-day postoperative outcomes including complications graded according to the Clavien-Dindo classification, unplanned readmissions, hospital stay and mortality for five common surgical procedures. METHODS: Patients undergoing appendicectomy, colectomy, inguinal hernia repair, hysterectomy and prostatectomy were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Non-parsimonious propensity score methods were used to construct procedure-specific matched-pair cohorts that reduced baseline differences between patients who underwent MIS and those who did not. Bonferroni correction for multiple comparisons was applied and P < 0·006 was considered significant. RESULTS: Of the 532 287 patients identified, 53·8 per cent underwent MIS. Propensity score matching yielded an overall sample of 327 736 patients (appendicectomy 46 688, colectomy 152 114, inguinal hernia repair 59 066, hysterectomy 59 066, prostatectomy 10 802). Within the procedure-specific matched pairs, MIS was associated with significantly lower odds of Clavien-Dindo grade I-II, III and IV complications (P ≤ 0·004), unplanned readmissions (P < 0·001) and reduced hospital stay (P < 0·001) in four of the five procedures studied, with the exception of inguinal hernia repair. The odds of death were lower in patients undergoing MIS colectomy (P < 0·001), hysterectomy (P = 0·002) and appendicectomy (P = 0·002). CONCLUSION: MIS was associated with significantly fewer 30-day postoperative complications, unplanned readmissions and deaths, as well as shorter hospital stay, in patients undergoing colectomy, prostatectomy, hysterectomy or appendicectomy. No benefits were noted for inguinal hernia repair.

The ins and outs of GroEL-mediated protein folding.

Two papers recently published in Cell investigate the role of protein encapsulation by GroEL in assisting folding. The first shows how encapsulation can "smooth" the folding landscape, accelerating folding of some proteins. The second defines a confinement-independent pathway, which allows GroEL to assist folding of substrates too large to be encapsulated.

Racial differences in cardiac revascularization rates: does "overuse" explain higher rates among white patients?

BACKGROUND: Coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) are well-established treatments for symptomatic coronary artery disease. Previous studies have documented racial differences in rates of use of these cardiac revascularization procedures. Other studies suggest that these procedures are overused: that is, they are done for patients with clinically inappropriate indications. OBJECTIVE: To test the hypothesis that the higher rate of cardiac revascularization among white patients is associated with a higher prevalence of overuse (revascularization for clinically inappropriate indications) among white patients than among African-American patients. DESIGN: Observational cohort study using Medicare claims and medical record review. SETTING: 173 hospitals in five U.S. states. PARTICIPANTS: A stratified, weighted, random sample of 3960 Medicare beneficiaries who underwent coronary angiography during 1991 and 1992; 1692 of these patients underwent 1711 revascularization procedures within 90 days. MEASUREMENTS: The proportion of CABG and PTCA procedures rated appropriate, uncertain, and inappropriate according to RAND criteria, and the multivariate odds of undergoing inappropriate revascularization among African-American patients and white patients. RESULTS: After angiography, rates of PTCA (23% vs. 19%) and CABG surgery (29% vs. 17%) were significantly higher among white patients than among African-American patients. The respective rates of inappropriate PTCA and CABG surgery were 14% and 10%. Among the study states, rates of inappropriate use ranged from 4% to 24% for PTCA and 0% to 14% for CABG surgery. White patients were more likely than African-American patients to receive inappropriate PTCA (15% vs. 9%; difference, 6 percentage points [95% CI, -0.4 to 12.7 percentage points]), and difference by race was statistically significant among men (20% vs. 8%; difference, 12 percentage points [CI, 1.2 to 21.7 percentage points]). Rates of inappropriate CABG surgery did not differ by race (10% in both groups). CONCLUSIONS: Among a large and diverse sample of Medicare beneficiaries in five U.S. states, overuse of PTCA was greater among white men than among other groups, but this difference did not fully account for racial disparities in revascularization. Overuse of cardiac revascularization varied significantly by geographic region.

Preparedness for clinical practice: reports of graduating residents at academic health centers.

CONTEXT: Medical educators are seeking improved measures to assess the clinical competency of residents as they complete their graduate medical education. OBJECTIVE: To assess residents' perceptions of their preparedness to provide common clinical services during their last year of graduate medical education. DESIGN, SETTING, AND PARTICIPANTS: A 1998 national survey of residents completing their training in 8 specialties (internal medicine, pediatrics, family practice, obstetrics/gynecology, general surgery, orthopedic surgery, psychiatry, and anesthesiology) at academic health centers in the United States. A total of 2626 residents responded (response rate, 65%). MAIN OUTCOME MEASURES: Residents' reports of their preparedness to perform clinical and nonclinical tasks relevant to their specialties. RESULTS: Residents in all specialties rated themselves as prepared to manage most of the common conditions they would encounter in their clinical career. However, more than 10% of residents in each specialty reported that they felt unprepared to undertake 1 or more tasks relevant to their disciplines, such as caring for patients with human immunodeficiency virus/acquired immunodeficiency syndrome or substance abuse (family practice) or nursing home patients (internal medicine); performance of spinal surgery (orthopedic surgery) or abdominal aortic aneurysm repair (general surgery); and management of chronic pain (anesthesiology). CONCLUSIONS: Overall, residents in their last year of training at academic health centers rate their clinical preparedness as high. However, opportunities for improvement exist in preparing residents for clinical practice.

Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI(+)] prion.

The yeast prion [PSI(+)] results from self-propagating aggregates of Sup35p. De novo formation of [PSI(+)] requires an additional non-Mendelian trait, thought to result from a prion form of one or more unknown proteins. We find that the Gln/Asn-rich prion domains of two proteins, New1p and Rnq1p, can control susceptibility to [PSI(+)] induction as well as enhance aggregation of a human glutamine expansion disease protein. [PSI(+)] inducibility results from gain-of-function properties of New1p and Rnq1p aggregates rather than from inactivation of the normal proteins. These studies suggest a molecular basis for the epigenetic control of [PSI(+)] inducibility and may reveal a broader role for this phenomenon in the physiology of protein aggregation.

Conformational diversity in a yeast prion dictates its seeding specificity.

A perplexing feature of prion-based inheritance is that prions composed of the same polypeptide can evoke different phenotypes (such as distribution of brain lesions), even when propagated in genetically identical hosts. The molecular basis of this strain diversity and the relationship between strains and barriers limiting transmission between species remain unclear. We have used the yeast prion phenomenon [PSI+]4 to investigate these issues and examine the role that conformational differences may have in prion strains. We have made a chimaeric fusion between the prion domains of two species (Saccharomyces cerevisae and Candida albicans) of Sup35, the protein responsible for [PSI+]. Here we report that this chimaera forms alternate prion strains in vivo when initiated by transient overexpression of different Sup35 species. Similarly, in vitro the purified chimaera, when seeded with different species of Sup35 fibres, establishes and propagates distinct amyloid conformations. These fibre conformations dictate amyloid seeding specificity: a chimaera seeded by S. cerevisiae fibres efficiently catalyses conversion of S. cerevisiae Sup35 but not of C. albicans Sup35, and vice versa. These and other considerations argue that heritable prion strains result from self-propagating conformational differences within the prion protein itself. Moreover, these conformational differences seem to act in concert with the primary structure to determine a prion's propensity for transmission across a species barrier.

Biochemical basis of oxidative protein folding in the endoplasmic reticulum.

The endoplasmic reticulum (ER) supports disulfide bond formation by a poorly understood mechanism requiring protein disulfide isomerase (PDI) and ERO1. In yeast, Ero1p-mediated oxidative folding was shown to depend on cellular flavin adenine dinucleotide (FAD) levels but not on ubiquinone or heme, and Ero1p was shown to be a FAD-binding protein. We reconstituted efficient oxidative folding in vitro using FAD, PDI, and Ero1p. Disulfide formation proceeded by direct delivery of oxidizing equivalents from Ero1p to folding substrates via PDI. This kinetic shuttling of oxidizing equivalents could allow the ER to support rapid disulfide formation while maintaining the ability to reduce and rearrange incorrect disulfide bonds.

Unmet health needs of uninsured adults in the United States.

CONTEXT: In 1998, 33 million US adults aged 18 to 64 years lacked health insurance. Determining the unmet health needs of this population may aid efforts to improve access to care. OBJECTIVE: To compare nationally representative estimates of the unmet health needs of uninsured and insured adults, particularly among persons with major health risks. DESIGN AND SETTING: Random household telephone survey conducted in all 50 states and the District of Columbia through the Behavioral Risk Factor Surveillance System. PARTICIPANTS: A total of 105,764 adults aged 18 to 64 years in 1997 and 117,364 in 1998, classified as long-term (>/=1 year) uninsured (9.7%), short-term (<1 year) uninsured (4.3%), or insured (86.0%). MAIN OUTCOME MEASURES: Adjusted proportions of participants who could not see a physician when needed due to cost in the past year, had not had a routine checkup within 2 years, and had not received clinically indicated preventive services, compared by insurance status. RESULTS: Long-term- and short-term-uninsured adults were more likely than insured adults to report that they could not see a physician when needed due to cost (26.8%, 21.7%, and 8.2%, respectively), especially among those in poor health (69.1%, 51.9%, and 21.8%) or fair health (48.8%, 42.4%, and 15.7%) (P<.001). Long-term-uninsured adults in general were much more likely than short-term-uninsured and insured adults not to have had a routine checkup in the last 2 years (42.8%, 22.3%, and 17.8%, respectively) and among smokers, obese individuals, binge drinkers, and people with hypertension, elevated cholesterol, diabetes, or human immunodeficiency virus risk factors (P<.001). Deficits in cancer screening, cardiovascular risk reduction, and diabetes care were most pronounced among long-term-uninsured adults. CONCLUSIONS: In our study, long-term-uninsured adults reported much greater unmet health needs than insured adults. Providing insurance to improve access to care for long-term-uninsured adults, particularly those with major health risks, could have substantial clinical benefits. JAMA. 2000;284:2061-2069

Molecular basis of a yeast prion species barrier.

The yeast [PSI+] factor is inherited by a prion mechanism involving self-propagating Sup35p aggregates. We find that Sup35p prion function is conserved among distantly related yeasts. As with mammalian prions, a species barrier inhibits prion induction between Sup35p from different yeast species. This barrier is faithfully reproduced in vitro where, remarkably, ongoing polymerization of one Sup35p species does not affect conversion of another. Chimeric analysis identifies a short domain sufficient to allow foreign Sup35p to cross this barrier. These observations argue that the species barrier results from specificity in the growing aggregate, mediated by a well-defined epitope on the amyloid surface and, together with our identification of a novel yeast prion domain, show that multiple prion-based heritable states can propagate independently within one cell.

A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion.

The yeast [PSI+] factor propagates by a prion-like mechanism involving self-replicating Sup35p amyloids. We identified multiple Sup35p mutants that either are poorly recruited into, or cause curing of, wildtype amyloids in vivo. In vitro, these mutants showed markedly decreased rates of amyloid formation, strongly supporting the protein-only prion hypothesis. Kinetic analysis suggests that the prion state replicates by accelerating slow conformational changes rather than by providing stable nuclei. Strikingly, our mutations map exclusively within a short glutamine/asparagine-rich region of Sup35p, and all but one occur at polar residues. Even after replacement of this region with polyglutamine, Sup35p retains its ability to form amyloids. These and other considerations suggest similarities between the prion-like propagation of [PSI+] and polyglutamine-mediated pathogenesis of several neurodegenerative diseases.

Release of both native and non-native proteins from a cis-only GroEL ternary complex.

Protein folding by the double-ring chaperonin GroEL is initiated in cis ternary complexes, in which polypeptide is sequestered in the central channel of a GroEL ring, capped by the co-chaperonin GroES. The cis ternary complex is dissociated (half-life of approximately 15 s) by trans-sided ATP hydrolysis, which triggers release of GroES. For the substrate protein rhodanese, only approximately 15% of cis-localized molecules attain their native form before hydrolysis. A major question concerning the GroEL mechanism is whether both native and non-native forms are released from the cis complex. Here we address this question using a 'cis-only' mixed-ring GroEL complex that binds polypeptide and GroES on only one of its two rings. This complex mediates refolding of rhodanese but, as with wild-type GroEL, renaturation is quenched by addition of mutant GroEL 'traps', which bind but do not release polypeptide substrate. This indicates that non-native forms are released from the cis complex. Quenching of refolding by traps was also observed under physiological conditions, both in undiluted Xenopus oocyte extract and in intact oocytes. We conclude that release of non-native forms from GroEL in vivo allows a kinetic partitioning among various chaperones and proteolytic components, which determines both the conformation and lifetime of a protein.

Characterization of the active intermediate of a GroEL-GroES-mediated protein folding reaction.

Recent studies of GroE-mediated protein folding indicate that substrate proteins are productively released from a cis ternary complex in which the nonnative substrate is sequestered within the GroEL channel underneath GroES. Here, we examine whether protein folding can occur in this space. Stopped-flow fluorescence anisotropy of a pyrene-rhodanese-GroEl complex indicates that addition of GroES and ATP (but not ADP) leads to a rapid change in substrate flexibility at GroEL. Strikingly, when GroES release is blocked by the use of either a nonhydrolyzable ATP analog or a single-ring GroEL mutant, substrates complete folding while remaining associated with chaperonin. We conclude that the cis ternary complex, in the presence of ATP, is the active state intermediate in the GroE-mediated folding reaction: folding is initiated in this state and for some substrates may be completed prior to the timed release of GroES triggered by ATP hydrolysis.

Mechanism of GroEL action: productive release of polypeptide from a sequestered position under GroES.

The chaperonin GroEL is a large, double-ring structure that, together with ATP and the cochaperonin GroES, assists protein folding in vivo. GroES forms an asymmetric complex with GroEL in which a single GroES ring binds one end of the GroEL cylinder. Cross-linking studies reveal that polypeptide binding occurs exclusively to the GroEL ring not occupied by GroES (trans). During the folding reaction, however, released GroES can rebind to the GroEL ring containing polypeptide (cis). The polypeptide is held tightly in a proteolytically protected environment in cis complexes, in the presence of ADP. Single turnover experiments with ornithine transcarbamylase reveal that polypeptide is productively released from the cis but not the trans complex. These observations suggest a two-step mechanism for GroEL-mediated folding. First, GroES displaces the polypeptide from its initial binding sites, sequestering it in the GroEL central cavity. Second, ATP hydrolysis induces release of GroES and productive release of polypeptide.

GroEL-mediated protein folding proceeds by multiple rounds of binding and release of nonnative forms.

The chaperonin GroEL is a ribosome-sized double-ring structure that assists in folding a diverse set of polypeptides. We have examined the fate of a polypeptide during a chaperonin-mediated folding reaction. Strikingly, we find that, upon addition of ATP and the cochaperonin GroES, polypeptide is released rapidly from GroEL in a predominantly nonnative conformation that can be trapped by mutant forms of GroEL that are capable of binding but not releasing substrate. Released polypeptide undergoes kinetic partitioning: a fraction completes folding while the remainder is rebound rapidly by other GroEL molecules. Folding appears to occur in an all-or-none manner, as proteolysis and tryptophan fluorescence indicate that after rebinding, polypeptide has the same structure as in the original complex. These observations suggest that GroEL functions by carrying out multiple rounds of binding aggregation-prone or kinetically trapped intermediates, maintaining them in an unfolded state, and releasing them to attempt to fold in solution.

Physician discretion and racial variation in the use of surgical procedures.

BACKGROUND: Racial variation in the use of surgical procedures raises concern about equitable access. The goal of our study was to examine racial differences in utilization across a broad range of procedures in Massachusetts and to assess whether racial variation is related to physician discretion. METHODS: We obtained fiscal year 1988 hospital discharge data for all Massachusetts residents, identified 10 clinically important surgical procedures, and calculated age- and sex-adjusted rate ratios for white and black patients. Level of discretion was determined by using a modified Delphi technique. RESULTS: Whites had higher rates for eight procedures (abdominal aortic aneurysm repair, appendectomy, cardiac valve replacement, carotid endarterectomy, cholecystectomy, lumbar disk procedures, open reduction/internal fixation of the femur, and tonsillectomy) and lower rates for two procedures, hysterectomy and prostatectomy. Of the eight procedures for which utilization was higher among whites, four were ranked as moderate- or high-discretion procedures and four were ranked as low-discretion procedures. Hysterectomy, the only procedure for which utilization was substantially higher among blacks (white:black rate ratio < 0.90), was ranked as a high-discretion procedure. CONCLUSIONS: With the exception of hysterectomy and prostatectomy, procedure rates for whites were greater than those for blacks for a wide range of surgical procedures. Racial variation exists for low-discretion procedures as well as for those associated with moderate and high discretion. Variation among low-discretion procedures that is not explained by medical need suggests the possibility of race-related differences in access to care or in the way patients and physicians make clinical decisions.

The pro region of BPTI facilitates folding.

The in vitro folding pathway of bovine pancreatic trypsin inhibitor (BPTI) has been described previously in terms of the disulfide-bonded intermediates that accumulate during folding of the protein. Folding is slow, occurring in hours at pH 7.3, 25 degrees C. In addition, approximately half of the BPTI molecules become trapped as a dead-end, native-like intermediate. In vivo, BPTI is synthesized as a precursor protein that includes a 13 residue amino-terminal pro region. This pro region contains a cysteine residue. We find that, in vitro, both the rate of formation and the yield of properly folded BPTI are increased substantially in a recombinant model of pro-BPTI. The cysteine residue is necessary for this effect. Moreover, a single cysteine residue, tethered to the carboxy-terminal end of BPTI with a flexible linker of repeating Ser-Gly-Gly residues, is sufficient to assist in disulfide formation. Thus, the pro region appears to facilitate folding by providing a tethered, solvent-accessible, intramolecular thiol-disulfide reagent.