Geographic variation in surgical outcomes and cost between the United States and Japan.

OBJECTIVES: Unwarranted geographic variation in spending has received intense scrutiny in the United States. However, few studies have compared variation in spending and surgical outcomes between the United States healthcare system and those of other nations. In this study, we compare the geographic variation in postsurgical outcomes and cost between the United States and Japan. STUDY DESIGN: This retrospective cohort study uses Medicare Part A data from the United States (2010-2011) and similar inpatient data from Japan (2012). Patients 65 years or older undergoing 1 of 5 surgeries (coronary artery bypass graft, abdominal aortic aneurysm repair, colectomy, pancreatectomy, or gastrectomy) were selected in the United States and Japan. METHODS: Reliability- and case-mix-adjusted coefficient of variation (COV) values were calculated using hierarchical modeling and empirical Bayes techniques for the following 5 outcomes: postoperative mortality, the development of a complication, death after complication (failure to rescue), length of stay, and the cost of the hospitalization. Sensitivity analyses were also performed by calculating patient demographic-and case-mix-adjusted COV values for each outcome using weighted age- and sex-standardized values. RESULTS: The variability of the postsurgical outcomes was uniformly lower in the United States compared with Japan. Cost variation was consistently higher in the United States for all surgeries. CONCLUSIONS: Although the US healthcare system may be more inefficient regarding costs, the presence of higher geographic variation in postoperative care in Japan, relative to the United States, suggests that the observed geographic variation in the United States-both for health expenditures and outcomes-is not a unique manifestation of its structural shortcomings.

Adding insult to injury: discontinuous insurance following spine trauma.

BACKGROUND: Spine trauma patients may represent a group for whom insurance fails to provide protection from catastrophic medical expenses, resulting in the transfer of financial burden onto individual families and public payers. This study compares the rate of insurance discontinuation for patients who underwent surgery for traumatic spine injury with and without spinal cord injury with the rate for matched control subjects. METHODS: We used the MarketScan database to perform a retrospective cohort study of privately insured spine trauma patients who underwent surgery from 2006 to 2010. Kaplan-Meier survival analysis was used to assess the time to insurance discontinuation. Cox proportional-hazards regression was used to determine hazard ratios for insurance discontinuation among spine trauma patients compared with the matched control population. RESULTS: The median duration of existing insurance coverage was 20.2 months for those with traumatic spinal cord injury, 25.6 months for those with traumatic spine injury without spinal cord injury, and 48.0 months for the matched control cohort (log-rank p < 0.0001). After controlling for multiple covariates, the hazard ratios for discontinuation of insurance were 2.02 (95% CI [confidence interval], 1.83 to 2.23) and 2.78 (95% CI, 2.31 to 3.35) for the trauma patients without and with spinal cord injury, respectively, compared with matched controls. CONCLUSIONS: Rates of insurance discontinuation are significantly higher for trauma patients with severe spine injury compared with the uninjured population, indicating that patients with disabling injuries are at increased risk for loss of insurance coverage.

Characterizing the relationship between free drug samples and prescription patterns for acne vulgaris and rosacea.

IMPORTANCE: Describing the relationship between the availability of free prescription drug samples and dermatologists' prescribing patterns on a national scale can help inform policy guidelines on the use of free samples in a physician's office. OBJECTIVES: To investigate the relationships between free drug samples and dermatologists' local and national prescribing patterns and between the availability of free drug samples and prescription costs. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study investigating prescribing practices for acne, a common dermatologic condition for which free samples are often available. The settings were, first, the offices of nationally representative dermatologists from the National Disease and Therapeutic Index (an IMS Health Incorporated database) and, second, an academic medical center clinic without samples. Participants were ambulatory patients who received a prescription from a dermatologist for a primary initial diagnosis of acne vulgaris or rosacea in 2010. MAIN OUTCOMES AND MEASURES: National trends in dermatologist prescribing patterns, the degree of correlation between the availability of free samples and the prescribing of brand-name medications, and the mean cost of acne medications prescribed per office visit nationally and at an academic medical center without samples. RESULTS: On a national level, the provision of samples with a prescription by dermatologists has been increasing over time, and this increase is correlated (r = 0.92) with the use of the branded generic drugs promoted by these samples. Branded and branded generic drugs comprised most of the prescriptions written nationally (79%), while they represented only 17% at an academic medical center clinic without samples. Because of the increased use of branded and branded generic drugs, the national mean total retail cost of prescriptions at an office visit for acne was conservatively estimated to be 2 times higher (approximately $465 nationally vs $200 at an academic medical center without samples). CONCLUSIONS AND RELEVANCE: Free drug samples can alter the prescribing habits of physicians away from the use of less expensive generic medications. The benefits of free samples in dermatology must be weighed against potential negative effects on prescribing behavior and prescription costs.

Estimating the risk of chronic kidney disease after nephrectomy.

INTRODUCTION: To identify factors associated with the development of chronic kidney disease (CKD) after nephrectomy and to create a clinical model to predict CKD after nephrectomy for kidney cancer for clinical use. MATERIALS AND METHODS: We identified 144 patients who had normal renal function (eGFR > 60) prior to undergoing nephrectomy for kidney cancer. Selected cases occurred between 2007 and 2010 and had at least 30 days follow up. Sixty-six percent (n = 95) underwent radical nephrectomy and 62.5% (n = 90) developed CKD (stage 3 or higher) postoperatively. We used univariable analysis to screen for predictors of CKD and multivariable logistic regression to identify independent predictors of CKD and their corresponding odds ratios. Interaction terms were introduced to test for effect modification. To protect against over-fitting, we used 10-fold cross-validation technique to evaluate model performance in multiple training and testing datasets. Validation against an independent external cohort was also performed. RESULTS: Of the variables associated with CKD in univariable analysis, the only independent predictors in multivariable logistic regression were patient age (OR = 1.27 per 5 years, 95% CI: 1.07-1.51), preoperative glomerular filtration rate (GFR), (OR = 0.70 per 10 mL/min, 95% CI: 0.56-0.89), and receipt of radical nephrectomy (OR = 4.78, 95% CI: 2.08-10.99). There were no significant interaction terms. The resulting model had an area under the curve (AUC) of 0.798. A 10-fold cross-validation slightly attenuated the AUC to 0.774 and external validation yielded an AUC of 0.930, confirming excellent model discrimination. CONCLUSIONS: Patient age, preoperative GFR, and receipt of a radical nephrectomy independently predicted the development of CKD in patients undergoing nephrectomy for kidney cancer in a validated predictive model.

Cost-effectiveness of preoperative imaging for appendicitis after indeterminate ultrasonography in the second or third trimester of pregnancy.

OBJECTIVE: To assess the cost-effectiveness of diagnostic laparoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) after indeterminate ultrasonography in pregnant women with suspected appendicitis. METHODS: A decision-analytic model was developed to simulate appendicitis during pregnancy taking into consideration the health outcomes for both the pregnant women and developing fetuses. Strategies included diagnostic laparoscopy, CT, and MRI. Outcomes included positive appendectomy, negative appendectomy, maternal perioperative complications, preterm delivery, fetal loss, childhood cancer, lifetime costs, discounted life expectancy, and incremental cost-effectiveness ratios. RESULTS: Magnetic resonance imaging is the most cost-effective strategy, costing $6,767 per quality-adjusted life-year gained relative to CT, well below the generally accepted $50,000 per quality-adjusted life-year threshold. In a setting where MRI is unavailable, CT is cost-effective even when considering the increased risk of radiation-associated childhood cancer ($560 per quality-adjusted life-year gained relative to diagnostic laparoscopy). Unless the negative appendectomy rate is less than 1%, imaging of any type is more cost-effective than proceeding directly to diagnostic laparoscopy. CONCLUSIONS: Depending on imaging costs and resource availability, both CT and MRI are potentially cost-effective. The risk of radiation-associated childhood cancer from CT has little effect on population-level outcomes or cost-effectiveness but is a concern for individual patients. For pregnant women with suspected appendicitis, an extremely high level of clinical diagnostic certainty must be reached before proceeding to operation without preoperative imaging.

Differential regulation of myeloid leukemias by the bone marrow microenvironment.

Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-ß1 (TGF-ß1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-ß1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-ß1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.

Comorbidities and kidney transplant evaluation in the elderly.

BACKGROUND/AIMS: The elderly are the fastest growing subpopulation with end-stage renal disease. The goal of our study was to define characteristics of elderly patients who were considered ineligible for transplantation compared to those who were listed. METHODS: 984 patients were referred for evaluation during a 2-year period. Records of patients ≥65 years of age (n = 123) were reviewed. Patients who were listed versus not listed were characterized. Factors associated with waitlisting were determined using standard statistical tools. RESULTS: Half of elderly transplant candidates were accepted for listing compared to 75.4% of those aged <65 years. In multivariable logistic regression, older age (OR 1.29 per year ≥65, 95% CI 1.14-1.45), coronary artery disease (OR 8.57, 95% CI 2.41-30.53), and poor mobility (OR 13.97, 95% CI 4.76-41.00) were independently associated with denial of listing. The receiver operating characteristic curve showed good discrimination for denial of listing (area under the receiver operating characteristic curve of 0.88). CONCLUSION: Elderly candidates carry a heavy burden of comorbidities and over half of those evaluated are deemed unsuitable for waitlisting. Better delineation of characteristics associated with suitability for transplant candidacy in the elderly is warranted to facilitate appropriate referrals by physicians and management of expectations in potential candidates.

Supine exercise echocardiographic measures of systolic and diastolic function in children.

BACKGROUND: Echocardiography has been used to determine ventricular function, segmental wall motion abnormality, and pulmonary artery pressure before and after peak exercise. No prior study has investigated systolic and diastolic function using echocardiography at various phases of exercise in children. The aim of this study was to determine the fractional shortening (FS), systolic-to-diastolic (S/D) ratio, heart rate-corrected velocity of circumferential fiber shortening (VCFc), circumferential wall stress (WS), ratio of mitral passive inflow to active inflow (E/A), ratio of passive inflow by pulsed-wave to tissue Doppler (E/E'), and right ventricular-to-right atrial pressure gradient from tricuspid valve regurgitation jet velocity (RVP) and time duration at various phases of exercise in children. METHODS: In an 8-month period (December 2007 to July 2008), 100 healthy children were evaluated, and 97 participants aged 8 to 17 years who performed complete cardiopulmonary exercise stress tests using supine cycle ergometry were prospectively enrolled. The participants consisted of 48 female and 49 male subjects with various body sizes, levels of exercise experience, and physical capacities. The cardiopulmonary exercise stress test consisted of baseline pulmonary function testing, continuous gas analysis and monitoring of blood pressure and heart rate responses, electrocardiographic recordings, and oxygen saturation measurement among participants who pedaled against a ramp protocol based on body weight. All participants exercised to exhaustion. Echocardiography was performed during exercise at baseline, at a heart rate of 130 beats/min, at a heart rate of 160 beats/min, at 5 min after exercise, and at 10 min after exercise. FS, S/D ratio, VCFc, WS, E/A, E', E/E', and RVP at these five phases were compared in all subjects. RESULTS: All echocardiographic parameters differed at baseline from 160 beats/min (P < .0001) except E/E', which remained at 5.4 to 5.8. Specifically, FS (from 37% to 46%), S/D ratio, VCFc (from 1.1 to 1.6), WS (from 200 to 258 g/cm(2)), E' (from 0.2 to 0.3), and RVP (from 18 to 35 mm Hg) increased from baseline to 160 beats/min and then subsequently decreased to at or near baseline, while tricuspid valve regurgitation duration decreased (from 370 to 178 msec). CONCLUSIONS: Normal values for systolic and diastolic echocardiographic measurements of function are now available. FS, VCFc, WS, and RVP increase with exercise and then return to near baseline levels. The E/E' ratio is unaltered with exercise in normal subjects.

Altitude and the risk of cardiovascular events in incident US dialysis patients.

BACKGROUND: Altitude is associated with all-cause mortality in US dialysis patients, but its association with cardiovascular outcomes has not been assessed. We hypothesized that higher altitude would be associated with lower rates of cardiovascular events due to an altered physiological response of dialysis patients to altitude induced hypoxia. METHODS: We studied 984,265 patients who initiated dialysis from 1995 to 2006. Patients were stratified by the mean elevation of their residential zip codes and were followed from the start of dialysis to the occurrence of several validated cardiovascular endpoints: myocardial infarction, stroke, cardiovascular death and a composite of these end points. Incidence rate ratios across altitude strata were estimated using proportional hazards regression. RESULTS: All outcomes occurred less frequently among patients living at higher altitude compared with patients living at or near sea level, and the association appeared monotonic for all outcomes except for stroke, which was most incident in the 250-1999 ft group. Compared with otherwise similar patients residing at or near sea level, patients living at ≥ 6000 ft had 31% [95% confidence interval (CI): 21-41%] lower rates of myocardial infarction, 27% (95% CI: 15-37%) lower rates of stroke and 19% (95% CI: 14-24%) lower rates of cardiovascular death. Additional adjustment for biometric information did not materially change these findings. Effect modification between race and altitude was only consistently significant for Native Americans. Altitude did not significantly alter the rates of non-cardiovascular death. CONCLUSION: We conclude that dialysis patients at higher altitude experience lower rates of cardiovascular events compared to otherwise similar patients at lower altitude.

Array analysis of viral gene transcription during lytic infection of cells in tissue culture with Varicella-Zoster virus.

Varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, causes childhood chickenpox (varicella), becomes latent in dorsal root and autonomic ganglia, and reactivates decades later to cause shingles (zoster) and other neurologic complications. Although the sequence and configuration of VZV DNA have been determined, relatively little is known about viral gene expression in productively infected cells. This is in part because VZV is highly cell associated, and sufficient titers of cell-free virus for use in synchronizing infection do not develop. PCR-based transcriptional arrays were constructed to simultaneously determine the relative abundance of the approximately 70 predicted VZV open reading frames (ORFs). Fragments (250 to 600 bp) from the 5' and 3' end of each ORF were PCR amplified and inserted into plasmid vectors. The virus DNA inserts were amplified, quantitated, and spotted onto nylon membranes. Probing the arrays with radiolabeled cDNA synthesized from VZV-infected cells revealed an increase in the magnitude of the expressed VZV genes from days 1 to 3 after low-multiplicity virus infection but little change in their relative abundance. The most abundant VZV transcripts mapped to ORFs 9/9A, 64, 33/33A, and 49, of which only ORF 9 corresponded to a previously identified structural gene. Array analysis also mapped transcripts to three large intergenic regions previously thought to be transcriptionally silent, results subsequently confirmed by Northern blot and reverse transcription-PCR analysis. Array analysis provides a formidable tool to analyze transcription of an important ubiquitous human pathogen.