Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.

Drug resistance continues to impede the success of cancer treatments, creating a need for experimental model systems that are broad, yet simple, to allow the identification of mechanisms and novel countermeasures applicable to many cancer types. To address these needs, we investigated a set of engineered mammalian cell lines with synthetic gene circuits integrated into their genome that evolved resistance to Puromycin. We identified DNA amplification as the mechanism underlying drug resistance in 4 out of 6 replicate populations. Triplex-forming oligonucleotide (TFO) treatment combined with Puromycin could efficiently suppress the growth of cell populations with DNA amplification. Similar observations in human cancer cell lines suggest that TFOs could be broadly applicable to mitigate drug resistance, one of the major difficulties in treating cancer.

Use of Systematic Methods to Improve Disease Identification in Administrative Data: The Case of Severe Sepsis.

BACKGROUND: Selection of International Classification of Diseases (ICD)-based coded information for complex conditions such as severe sepsis is a subjective process and the results are sensitive to the codes selected. We use an innovative data exploration method to guide ICD-based case selection for severe sepsis. METHODS: Using the Nationwide Inpatient Sample, we applied Latent Class Analysis (LCA) to determine if medical coders follow any uniform and sensible coding for observations with severe sepsis. We examined whether ICD-9 codes specific to sepsis (038.xx for septicemia, a subset of 995.9 codes representing Systemic Inflammatory Response syndrome, and 785.52 for septic shock) could all be members of the same latent class. RESULTS: Hospitalizations coded with sepsis-specific codes could be assigned to a latent class of their own. This class constituted 22.8% of all potential sepsis observations. The probability of an observation with any sepsis-specific codes being assigned to the residual class was near 0. The chance of an observation in the residual class having a sepsis-specific code as the principal diagnosis was close to 0. Validity of sepsis class assignment is supported by empirical results, which indicated that in-hospital deaths in the sepsis-specific class were around 4 times as likely as that in the residual class. CONCLUSIONS: The conventional methods of defining severe sepsis cases in observational data substantially misclassify sepsis cases. We suggest a methodology that helps reliable selection of ICD codes for conditions that require complex coding.

Racial/Ethnic disparities in patient experience with communication in hospitals: real differences or measurement errors?

BACKGROUND: An important aspect of medical care is clear and effective communication, which can be particularly challenging for individuals based on race/ethnicity. Quality of communication is measured systematically in the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, and analyzed frequently such as in the National Healthcare Disparities Report. Caution is needed to discern differences in communication quality from racial/ethnic differences in perceptions about concepts or expectations about their fulfillment. OBJECTIVES: To examine assumptions about the degree of commonality across racial/ethnic groups in their perceptions and expectations, and to investigate the validity of conclusions regarding racial/ethnic differences in communication quality. METHODS: We used 2007 HCAHPS data from the National CAHPS Benchmarking Database to construct racial/ethnic samples that controlled for other patient characteristics (828 per group). Using multiple-groups confirmatory factor analyses, we tested whether the factor structure and model parameters (ie, factor loadings, intercepts) differed across groups. RESULTS: We identified support for basic tests of equivalence across 7 racial/ethnic groups in terms of equivalent factor structure and loadings. Even stronger support was found for Communication with Doctors and Nurses. However, potentially important nonequivalence was found for Communication about Medicines, including instances of statistically significant differences between non-Hispanic whites and non-Hispanic blacks, Asians, and Native Hawaiian/other Pacific Islanders. CONCLUSIONS: Our results provide strongest support for racial/ethnic comparisons on Communication with Nurses and Doctors, and reason to caution against comparisons on Communication about Medicines due to significant differences in model parameters across groups; that is, a lack of invariance in the intercept.

Images of imaging: how to process and display imaging utilization for large populations.

OBJECTIVE: We propose a method of processing and displaying imaging utilization data for large populations. CONCLUSION: The comprehensive and finely grained picture of imaging utilization yielded by our methods is a first step toward population-based imaging utilization management. We believe that our methods for the categorization and display of imaging utilization will prove to be widely useful.

Governing board, C-suite, and clinical management perceptions of quality and safety structures, processes, and priorities in U.S. hospitals.

To achieve quality improvement in hospitals requires greater attention to systems thinking than is typical at this time, including a shared understanding across different levels of the hospital of the current state of quality improvement efforts. A self-administered survey assessed the perceptions of board members, C-suite executives, and clinical managers regarding quality activities and structures. This instrument, the Hospital Leadership and Quality Assessment Tool (HLQAT), includes 13 domains in six conceptual areas that we believe are major organizational drivers of quality and safety: (1) commitment of senior leaders, (2) a vision of exemplary quality, (3) a supportive culture, (4) accountable leadership, (5) appropriate organizational structures, and (6) adaptive capability. HLQAT survey results from a convenience sample of more than 300 hospitals were linked to performance on the Centers for Medicare & Medicaid Services (CMS) Core Measures. The results show significantly different perceptions between the groups. Higher HLQAT scores for each respondent group were associated with better hospital performance on the CMS Core Measures. There is no magic bullet--no one domain dominates. Leaders in higher-performing hospitals appear to be more effective at conveying their vision of quality care and creating a culture that supports an expectation that staff and leadership will work across traditional boundaries to improve quality.

Monitoring Genomic Structural Rearrangements Resulting from Gene Editing.

The cytogenomics-based methodology of directional genomic hybridization (dGH) enables the detection and quantification of a more comprehensive spectrum of genomic structural variants than any other approach currently available, and importantly, does so on a single-cell basis. Thus, dGH is well-suited for testing and/or validating new advancements in CRISPR-Cas9 gene editing systems. In addition to aberrations detected by traditional cytogenetic approaches, the strand specificity of dGH facilitates detection of otherwise cryptic intra-chromosomal rearrangements, specifically small inversions. As such, dGH represents a powerful, high-resolution approach for the quantitative monitoring of potentially detrimental genomic structural rearrangements resulting from exposure to agents that induce DNA double-strand breaks (DSBs), including restriction endonucleases and ionizing radiations. For intentional genome editing strategies, it is critical that any undesired effects of DSBs induced either by the editing system itself or by mis-repair with other endogenous DSBs are recognized and minimized. In this paper, we discuss the application of dGH for assessing gene editing-associated structural variants and the potential heterogeneity of such rearrangements among cells within an edited population, highlighting its relevance to personalized medicine strategies.

Association of military deployment of a parent or spouse and changes in dependent use of health care services.

BACKGROUND: U.S. Armed Forces members and spouses report increased stress associated with combat deployment. It is unknown, however, whether these deployment stressors lead to increased dependent medication use and health care utilization. OBJECTIVE: To determine whether the deployment of Army active duty members (sponsors) is associated with changes in dependent health care utilization. DESIGN: A quasi-experimental, pre-post study of health care patterns of more than 55,000 nonpregnant spouses and 137,000 children of deployed sponsors and a comparison group of dependents. MEASURES: Changes in dependent total utilization in the military health system, and separately in military-provided and purchased care services in the year following the sponsors' deployment month for office visit services (generalist, specialist); emergency department visits; institutional stays; psychotropic medication (any, antidepressant, antianxiety, antistimulant classes). RESULTS: Sponsor deployment was associated with net increased use of specialist office visits (relative percent change 4.2% spouses; 8.8% children), antidepressants (6.7% spouses; 17.2% children), and antianxiety medications (14.2% spouses; 10.0% children; P<0.01) adjusting for group differences. Deployment was consistently associated with increased use of purchased care services, partially, or fully offset by decreased use of military treatment facilities. CONCLUSIONS: These results suggest that emotional or behavioral issues are contributing to increased specialist visits and reliance on medications during sponsors' deployments. A shift to receipt of services from civilian settings raises questions about coordination of care when families temporarily relocate, family preferences, and military provider capacity during deployment phases. Findings have important implications for the military health system and community providers who serve military families, especially those with children.

A reference human induced pluripotent stem cell line for large-scale collaborative studies.

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.

Randomized trial of enhanced profiling in substance abuse treatment.

A randomized trial of substance abuse treatment programs tested whether "enhanced profiles," consisting of feedback and coaching about performance indicators, improved the performance of residential, methadone, and detoxification programs. These enhanced profiles were reviewed during quarterly on-site visits between October 2005 and July 2007. The performance indicators were the percentage of clients completing referrals to a lower level of care, and the percentage of clients admitted to a higher level of care within 30 days of discharge. Control programs received only "basic profiles," consisting of emailed quarterly printouts of these performance indicators. Effectiveness was evaluated using hierarchical linear models with client-level information nested within agencies and regions of the state. Treatment programs receiving enhanced profiles (n = 74) did not perform significantly differently from those receiving only basic profiles (n = 29) on either performance measure. To improve performance, interventions with greater scope and incentives may be needed.

A randomized trial of telemonitoring heart failure patients.

The purpose of this study was to measure the ability of telemonitoring to reduce hospital days and total costs for Medicare managed care enrollees diagnosed with heart failure. Patients were recruited and randomly assigned for six months to either telemonitoring or standard care. Telemonitoring transmitted vital signs and clinical alerts daily to a central nursing station. Utilization of covered services was analyzed for the six-month telemonitoring period to test for hypothesized reductions in hospital days and changes in utilization of the emergency department (ED), urgent care, and primary care. Negative binomial regressions adjusted for gender, age, co-occurring diabetes, co-occurring chronic obstructive pulmonary disease, and residence neighborhood were used to analyze units of service, and two-part (hurdle) multivariable models were used for expenditures. The main finding was a tendency for lower total number of hospital days for patients assigned to telemonitoring. Results for other covered services were generally consistent with hypothesized direction and magnitude; however, statistical power was reduced because of lower-than-expected recruitment rates into the study. Within a managed-care environment, telemonitoring appears to facilitate better ambulatory management of heart failure patients, including fewer ED visits, which were offset by more frequent primary care and urgent care visits.

The relationship between Medicare's process of care quality measures and mortality.

Using Medicare inpatient claims and Hospital Compare process of care quality data from the period 2004-2006, we estimate two model specifications to test for the presence of correlational and causal relationships between hospital process of care performance measures and risk-adjusted (RA) 30-day mortality for heart attack, heart failure, and pneumonia. Our analysis indicates that while Hospital Compare process performance measures are correlated with 30-day mortality for each diagnosis, after we account for unobserved heterogeneity, process of care performance is no longer associated with mortality for any diagnosis. This suggests that the relationship between hospital-level process of care performance and mortality is not causal. Implications for pay-for-performance are discussed.

Dual optical force plate for time resolved measurement of forces and pressure distributions beneath shoes and feet.

Frustrated total internal reflection (FTIR) imaging was used to perform remote optical measurements of the forces/pressures exerted beneath shoes and feet during a number of different training activities including countermovement jumps, jogging and drop jumps. A single camera was used to simultaneously image two acrylic, FTIR waveguide imaging elements from below, at frame rates up to 200 frames per second. The images obtained using the camera were converted into pressure/force maps using a previously developed theory which combines the mechanics of contact of soft objects and the scattering of evanescent waves. The forces obtained from the optical measurements were shown to be in good agreement with measurements obtained from load cells placed beneath the FTIR imaging elements. The ability to produce accurate spatial maps of the force/pressure distribution beneath soft contacting objects such as feet and shoe outsoles at high frame rates has numerous potential applications in sports sciences and medicine.

Chromosome Translocations, Inversions and Telomere Length for Retrospective Biodosimetry on Exposed U.S. Atomic Veterans.

It has now been over 60 years since U.S. nuclear testing was conducted in the Pacific islands and Nevada, exposing military personnel to varying levels of ionizing radiation. Actual doses are not well-established, as film badges in the 1950s had many limitations. We sought a means of independently assessing dose for comparison with historical film badge records and dose reconstruction conducted in parallel. For the purpose of quantitative retrospective biodosimetry, peripheral blood samples from 12 exposed veterans and 12 age-matched (>80 years) veteran controls were collected and evaluated for radiation-induced chromosome damage utilizing directional genomic hybridization (dGH), a cytogenomics-based methodology that facilitates simultaneous detection of translocations and inversions. Standard calibration curves were constructed from six male volunteers in their mid-20s to reflect the age range of the veterans at time of exposure. Doses were estimated for each veteran using translocation and inversion rates independently; however, combining them by a weighted-average generally improved the accuracy of dose estimations. Various confounding factors were also evaluated for potential effects on chromosome aberration frequencies. Perhaps not surprisingly, smoking and age-associated increases in background frequencies of inversions were observed. Telomere length was also measured, and inverse relationships with both age and combined weighted dose estimates were observed. Interestingly, smokers in the non-exposed control veteran cohort displayed similar telomere lengths as those in the never-smoker exposed veteran group, suggesting that chronic smoking had as much effect on telomere length as a single exposure to radioactive fallout. Taken together, we find that our approach of combined chromosome aberration-based retrospective biodosimetry provided reliable dose estimation capability, particularly on a group average basis, for exposures above statistical detection limits.

Meaningful Use and Hospital Performance on Post-Acute Utilization Indicators.

OBJECTIVES: To examine trends in hospital post-acute utilization indicators and to determine whether improvement in these indicators is associated with attesting to meaningful use (MU). DATA SOURCES: Medicare claims-based, repeated measures on 30-day hospital-wide all-cause readmission and emergency department (ED) utilization rates for 160 short-stay hospitals (2009-2012); Medicare EHR Incentive Program Payments files (2011-2012); and other hospital and market data. STUDY DESIGN: Interrupted time series with concurrent comparison group. PRINCIPAL FINDINGS: Propensity score-weighted multilevel models for change demonstrate that 30-day readmission rates (unadjusted) fell from 13.4 percent in 2009 to 12.1 percent in 2012. Similarly, 30-day ED utilization declined from 18.9 percent to 17.3 percent during the same period. However, MU and non-MU hospitals were indistinguishable vis-à-vis performance. Controlling for hospital and market characteristics, MU was unrelated to 30-day readmission. In contrast, 30-day ED utilization deteriorated. CONCLUSIONS: Hospitals with MU Stage 1 designation did not show significantly higher improvement on post-acute utilization compared to their counterparts without. To achieve gains in quality and safety, potentially associated with EHRs, and to advance care coordination and patient engagement, the regulators should strengthen accountability by linking comprehensive, outcomes-based performance measures to specific MU objectives.

Hospital Postacute Care Referral Networks: Is Referral Concentration Associated with Medicare-Style Bundled Payments?

OBJECTIVE: To evaluate whether Medicare-style bundled payments are lower or higher for beneficiaries discharged from hospitals with postacute care (PAC) referrals concentrated among fewer PAC providers. DATA SOURCE: Medicare Part A and Part B claim (2008-2012) for all beneficiaries residing in any of 17 market areas: the Provider of Service file, the Healthcare Cost Report Information System, and the Dartmouth Atlas. STUDY DESIGN: An observational study in which hospitals were distinguished according to PAC referral concentration, which is the tendency to utilize fewer rather than more PAC providers. We tested the hypothesis that higher referral concentration would be associated with total Medicare bundled payments. DATA COLLECTION/EXTRACTION METHODS: The data represent a convenience sample of market areas that were defined by the locations of grantees from the ONC Beacon Community Program. PRINCIPAL FINDINGS: The four most-used PAC providers accounted for an average of 60 percent of patients discharged from hospitals in the sample. Regression analysis suggested that higher referral concentration was associated with lower Medicare costs per bundle. CONCLUSIONS: Hospitals that tend to use fewer PAC providers may lead to lower costs for payers such as Medicare. The study results reinforce the importance of limited networks for PAC services under bundling arrangements for hospital and PAC payments.

Linking Spending and Quality Indicators to Measure Value and Efficiency in Health Care.

Policy makers and stakeholders have reached a consensus that both quality and spending or resource use indicators should be jointly measured and prioritized to meet the objectives of our health system. However, the relative merits of alternative approaches that combine quality and spending indicators are not well understood. We conducted a literature review to identify different approaches that combine indicators of quality and spending measures to profile provider efficiency in the context of specific applications in health care. Our investigation identified seven alternative models that are either in use or have been proposed to evaluate provider efficiency. We then used publicly available data to profile hospitals using these approaches. Profiles of hospital efficiency using alternative models yielded wide variation in performance, underscoring the importance of model selection. By identifying the current efficiency models and evaluating their trade-offs within specific programmatic contexts, our analysis informs stakeholder and policy maker decisions about how to link quality and spending indicators when measuring efficiency in health care.

The precarious pricing system for hospital services.

Over the past twenty-five years, the average ratio of hospital charges for services (gross revenues) to payments received (net revenues) has grown from 1.1 to 2.6. This reflects a transition from predominantly cost- and charge-based payment systems to regulated and negotiated fixed payments. Hospitals have been able to squeeze additional revenues from remaining charge-based payers and services by sharply increasing charges, negatively affecting the uninsured. Although protection of the uninsured seems warranted, it might be difficult to regulate hospital pricing systems in isolation from other controversial issues, such as the acceptability of cross-subsidies and the role of market forces.

Effects of Expanded Coverage for Chiropractic Services on Medicare Costs in a CMS Demonstration.

BACKGROUND: Moderately convincing evidence supports the benefits of chiropractic manipulations for low back pain. Its effectiveness in other applications is less well documented, and its cost-effectiveness is not known. These questions led the Centers for Medicaid and Medicare Services (CMS) to conduct a two-year demonstration of expanded Medicare coverage for chiropractic services in the treatment of beneficiaries with neuromusculoskeletal (NMS) conditions affecting the back, limbs, neck, or head. METHODS: The demonstration was conducted in 2005-2007 in selected counties of Illinois, Iowa, and Virginia and the entire states of Maine and New Mexico. Medicare claims were compiled for the preceding year and two demonstration years for the demonstration areas and matched comparison areas. The impact of the demonstration was analyzed through multivariate regression analysis with a difference-in-difference framework. RESULTS: Expanded coverage increased Medicare expenditures by $50 million or 28.5% in users of chiropractic services and by $114 million or 10.4% in all patients treated for NMS conditions in demonstration areas during the two-year period. Results varied widely among demonstration areas ranging from increased costs per user of $485 in Northern Illinois and Chicago counties to decreases in costs per user of $59 in New Mexico and $178 in Scott County, Iowa. CONCLUSION: The demonstration did not assess possible decreases in costs to other insurers, out-of-pocket payments by patients, the need for and costs of pain medications, or longer term clinical benefits such as avoidance of orthopedic surgical procedures beyond the two-year period of the demonstration. It is possible that other payers or beneficiaries saved money during the demonstration while costs to Medicare were increased.