eScholarship@UMMS

PURPOSE: Observational studies describe high rates of errors in home oral chemotherapy use in children. In hospitals, proactive risk assessment methods help front-line health care workers develop error prevention strategies. Our objective was to engage parents of children with cancer in a multisite study using proactive risk assessment methods to identify how errors occur at home and propose risk reduction strategies.

METHODS: We recruited parents from three outpatient pediatric oncology clinics in the northeast and southeast United States to participate in failure mode and effects analyses (FMEA). An FMEA is a systematic team-based proactive risk assessment approach in understanding ways a process can fail and develop prevention strategies. Steps included diagram the process, brainstorm and prioritize failure modes (places where things go wrong), and propose risk reduction strategies. We focused on home oral chemotherapy administration after a change in dose because prior studies identified this area as high risk.

RESULTS: Parent teams consisted of four parents at two of the sites and 10 at the third. Parents developed a 13-step process map, with two to 19 failure modes per step. The highest priority failure modes included miscommunication when receiving instructions from the clinician (caused by conflicting instructions or parent lapses) and unsafe chemotherapy handling at home. Recommended risk assessment strategies included novel uses of technology to improve parent access to information, clinicians, and other parents while at home.

CONCLUSION: Parents of pediatric oncology patients readily participated in a proactive risk assessment method, identifying processes that pose a risk for medication errors involving home oral chemotherapy.

BACKGROUND: Few population-based studies have reported the prevalence of psoriatic disease.

OBJECTIVE: We validated computerized diagnoses to estimate the prevalence of psoriasis and psoriatic arthritis.

METHOD: We identified adults with >/=1 ICD-9 diagnosis codes of 696.0 (psoriatic arthritis) or 696.1 (psoriasis) in clinical encounter data during 1996-2009 and used chart review to confirm the diagnoses in random samples of patients. We then used the best performing case-finding algorithms to estimate the point prevalence of psoriasis and psoriatic arthritis.

RESULTS: The number of persons with a diagnosis for psoriasis (ICD-9 code 696.1) was 87 827. Chart review of a random sample of 101 cases with at least one dermatologist-rendered psoriasis code revealed a positive predictive value (PPV) of 90% (95% CI, 83-95) with sensitivity of 88% (95% CI, 80-93). Psoriatic arthritis (code 696.0) was recorded for 5187 patients, with the best performing algorithm requiring >/=2 diagnoses recorded by a rheumatologist or >/=1 diagnosis recorded by a rheumatologist together with >/=1 psoriasis diagnoses recorded by a dermatologist; the PPV was 80% (95% CI, 70-88) with sensitivity 73% (95% CI, 63-82). Among KPNC adults, the point prevalence of psoriasis, with or without psoriatic arthritis, was 939 (95% CI, 765-1142) per 100 000, and the overall prevalence of psoriatic arthritis, with or without psoriasis, was 68 (95% CI, 54-84) per 100 000.

CONCLUSION: Within an integrated health care delivery system, the use of computerized diagnoses rendered by relevant disease specialists is a valid method for identifying individuals with psoriatic disease.

Copyright (c) 2013 John Wiley and Sons, Ltd.

OBJECTIVES: To examine the effect of breast cancer and its treatment on fracture risk in older breast cancer survivors.

DESIGN: A 10-year prospective cohort study beginning 5 years after a diagnosis of breast cancer for survivors and match date for comparison women.

SETTING: Six integrated healthcare systems.

PARTICIPANTS: Women aged 65 and older (1,286 survivors, 1,286 comparison women, mean age 77.7 in both groups, white, non-Hispanic: survivors, 81.6%; comparison women, 85.2%) who were alive and recurrence free 5 years after a diagnosis of early-stage breast cancer and matched on age, study site, and enrollment year to a comparison cohort without breast cancer.

MEASUREMENTS: Cox proportional hazards models were used to estimate the association between fracture risk and survivor-comparison status, adjusting for drugs and risk factors associated with bone health. A subanalysis was used to evaluate the association between tamoxifen exposure and fracture risk.

RESULTS: No difference was observed in fracture rates between groups (hazard ratio (HR) = 1.1, 95% confidence interval (CI) = 0.9-1.3). The protective effect of tamoxifen was not statistically significant (HR = 0.9, 95% CI = 0.6-1.2).

CONCLUSION: Long-term survivors of early-stage breast cancer diagnosed at age 65 and older are not at greater risk of osteoporotic fractures than age-matched women without breast cancer. There appears to be no long-term protection from fractures with tamoxifen use. Geriatrics Society.

Bundled payment entails paying a single price for all services delivered as part of an episode of care for a specific condition. It is seen as a promising way to slow the growth of health care spending while maintaining or improving the quality of care. To implement bundled payment, policy makers must set base payment rates for episodes of care and update the rates over time to reflect changes in the costs of delivering care and the components of care. Adopting the fee-for-service paradigm of adjusting payments with uniform update rates would be fair and accurate if costs increased at a uniform rate across episodes. But our analysis of 2003 and 2007 US commercial claims data showed spending growth to be highly skewed across episodes: 10 percent of episodes accounted for 82.5 percent of spending growth, and within-episode spending growth ranged from a decline of 75 percent to an increase of 323 percent. Given that spending growth was much faster for some episodes than for others, a situation known as skewness, policy makers should not update episode payments using uniform update rates. Rather, they should explore ways to address variations in spending growth, such as updating episode payments one by one, at least at the outset.

BACKGROUND: Papanicolaou (Pap) testing has transitioned from conventional preparations (CPs) to liquid-based preparations (LBPs) because of the perceived superiority of LBPs. Many studies conclude that LBPs reduce unsatisfactory Pap tests; However, some believe that the evidence substantiating this claim is weak. The authors studied the effect of the transition from CPs to LBPs on the proportion of unsatisfactory Pap tests in 4 health care systems in the United States participating in the National Institutes of Health-funded Screening Effectiveness and Research in Community-Based Healthcare (SEARCH) project.

METHODS: The study cohort consisted of 548,174 women ages 21 to 65 years who had 1443,725 total Pap tests between 2000 and 2010. Segmented regression analysis was used to estimate the effect of adopting LBPs on the proportion of unsatisfactory Pap tests after adjusting for age.

RESULTS: Three sites that implemented SurePath LBP experienced significant reductions in unsatisfactory Pap tests (estimated effect: site 1, -2.46%; 95% confidence interval [CI], -1.47%, -3.45%; site 2, -1.78%; 95% CI, -1.54%, -2.02%; site 3, -8.25%; 95% CI, -7.33%, -9.17%). The fourth site that implemented ThinPrep LBP did not experience a reduction in unsatisfactory Pap tests. The relative risk of an unsatisfactory Pap test in women aged >/=50 years increased after the transition to LBPs (SurePath: relative risk, 2.1; 95% CI, 1.9-2.2; ThinPrep: relative risk, 1.7; 95% CI, 1.5-2.0).

CONCLUSIONS: The observed changes in the proportion of unsatisfactory Pap tests varied across the participating sites and depended on the type of LBP technology, the age of women, and the rates before the implementation of this technology. Cancer (Cancer Cytopathol) 2013. (c) 2013 American Cancer Society.

PURPOSE: To evaluate the validity of health plan and birth certificate data for pregnancy research.

METHODS: A retrospective study was conducted using administrative and claims data from 11 U.S. health plans and corresponding birth certificate data from state health departments. Diagnoses, drug dispensings, and procedure codes were used to identify infant outcomes (cardiac defects, anencephaly, preterm birth, and neonatal intensive care unit [NICU] admission) and maternal diagnoses (asthma and systemic lupus erythematosus [SLE]) recorded in the health plan data for live born deliveries between January 2001 and December 2007. A random sample of medical charts (n = 802) was abstracted for infants and mothers identified with the specified outcomes. Information on newborn, maternal, and paternal characteristics (gestational age at birth, birth weight, previous pregnancies and live births, race/ethnicity) was also abstracted and compared to birth certificate data. Positive predictive values (PPVs) were calculated with documentation in the medical chart serving as the gold standard.

RESULTS: PPVs were 71% for cardiac defects, 37% for anencephaly, 87% for preterm birth, and 92% for NICU admission. PPVs for algorithms to identify maternal diagnoses of asthma and SLE were >/= 93%. Our findings indicated considerable agreement (PPVs > 90%) between birth certificate and medical record data for measures related to birth weight, gestational age, prior obstetrical history, and race/ethnicity.

CONCLUSIONS: Health plan and birth certificate data can be useful to accurately identify some infant outcomes, maternal diagnoses, and newborn, maternal, and paternal characteristics. Other outcomes and variables may require medical record review for validation.

OBJECTIVES: To examine the long-term association between midlife physical activity (PA) and lower extremity function (LEF) in late life.

DESIGN: Longitudinal study with an average of 25 years of follow-up. SETTING: Community-dwelling old population in Reykjavik, Iceland.

PARTICIPANTS: Four thousand seven hundred fifty-three community-dwelling men and women (mean age 76 +/- 6) in Reykjavik, Iceland.

MEASUREMENTS: On the basis of weekly hours of regular PA reported at the midlife examination, participants were classified as active or inactive. Measures of LEF in late life were gait speed on a 6-m walk, Timed Up and Go (TUG), and knee extension (KE) strength tests. Linear regression analysis was used to examine the association.

RESULTS: Participants who were active in midlife had significantly better LEF (faster gait speed, beta = 0.50, P

CONCLUSION: Regular PA in midlife is associated with better performance of LEF in later life, even after controlling for late-life cognitive function. Geriatrics Society.

The prescribing of antipsychotic medications persists at high levels in US nursing homes (NHs) despite extensive data demonstrating marginal clinical benefits and serious adverse effects, including death.1- 2 However, imprecise and outdated data have limited the understanding of the current state of antipsychotic medication prescribing in NHs.3 We analyzed recent and detailed NH prescription data to address: (1) What is the current level of antipsychotic use? (2) Does antipsychotic use in NHs display geographic variation? and (3) Which antipsychotics are most commonly prescribed?

INTRODUCTION: Much progress has been made in cancer survivorship research, but there are still many unanswered questions that can and need to be addressed by collaborative research consortia.

METHODS: Since 1999, the National Cancer Institute-funded HMO Cancer Research Network (CRN) has engaged in a wide variety of research focusing on cancer survivorship. With a focus on thematic topics in cancer survivorship, we describe how the CRN has contributed to research in cancer survivorship and the resources it offers for future collaborations.

RESULTS: We identified the following areas of cancer survivorship research: surveillance for and predictors of recurrences, health care delivery and care coordination, health care utilization and costs, psychosocial outcomes, cancer communication and decision making, late effects of cancer and its treatment, use of and adherence to adjuvant therapies, and lifestyle and behavioral interventions following cancer treatment.

CONCLUSIONS: With over a decade of experience using cancer data in community-based settings, the CRN investigators and their collaborators are poised to generate evidence in cancer survivorship research.

IMPLICATIONS FOR CANCER SURVIVORS: Collaborative research within these settings can improve the quality of care for cancer survivors within and beyond integrated health care delivery systems.

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15-45 years in 2001-2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72%) were to women who received an atypical antipsychotic and 548 (0.09%) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33% (95% confidence interval: 0.29%, 0.37%) in 2001 to 0.82% (0.76%, 0.88%) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63%), followed by bipolar disorder (43%) and schizophrenia (13%). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Publisher's description: This book provides an entry point into Systems Biology for researchers in genetics, molecular biology, cell biology, microbiology and biomedical science to understand the key concepts to expanding their work. Chapters organized around broader themes of Organelles and Organisms, Systems Properties of Biological Processes, Cellular Networks, and Systems Biology and Disease discuss the development of concepts, the current applications, and the future prospects. Emphasis is placed on concepts and insights into the multi-disciplinary nature of the field as well as the importance of systems biology in human biological research. Technology, being an extremely important aspect of scientific progress overall, and in the creation of new fields in particular, is discussed in 'boxes' within each chapter to relate to appropriate topics.

Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.

How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data.

BACKGROUND: Many hospitalized Medical Service patients are at risk for venous thromboembolism in the months after discharge. We conducted a multicenter randomized controlled trial to test whether a hospital staff member's thromboprophylaxis alert to an Attending Physician before discharge will increase the rate of extended out-of-hospital prophylaxis and, in turn, reduce the incidence of symptomatic venous thromboembolism at 90 days.

METHODS: From April 2009 to January 2010, we enrolled hospitalized Medical Service patients using the point score system developed by Kucher et al to identify those at high risk for venous thromboembolism who were not ordered to receive thromboprophylaxis after discharge. There were 2513 eligible patients from 18 study sites randomized by computer in a 1:1 ratio to the alert group or the control group.

RESULTS: Patients in the alert group were more than twice as likely to receive thromboprophylaxis at discharge as controls (22.0% vs 9.7%, P <.0001). Based on an intention-to-treat analysis, symptomatic venous thromboembolism at 90 days (99.9% follow-up) occurred in 4.5% of patients in the alert group, compared with 4.0% of controls (hazard ratio 1.12; 95% confidence interval, 0.74-1.69). The rate of major bleeding at 30 days in the alert group was similar to that of the control group (1.2% vs 1.2%, hazard ratio 0.94; 95% confidence interval, 0.44-2.01).

CONCLUSIONS: Alerting providers to extend thromboprophylaxis after hospital discharge in Medical Service patients increased the rate of prophylaxis but did not decrease the rate of symptomatic venous thromboembolism.

MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) guide Argonaute proteins to silence mRNA expression. Argonaute binding alters the properties of an RNA guide, creating functional domains. We show that the domains established by Argonaute-the anchor, seed, central, 3' supplementary, and tail regions-have distinct biochemical properties that explain the differences between how animal miRNAs and siRNAs bind their targets. Extensive complementarity between an siRNA and its target slows the rate at which fly Argonaute2 (Ago2) binds to and dissociates from the target. Highlighting its role in antiviral defense, fly Ago2 dissociates so slowly from extensively complementary target RNAs that essentially every fully paired target is cleaved. Conversely, mouse AGO2, which mainly mediates miRNA-directed repression, dissociates rapidly and with similar rates for fully paired and seed-matched targets. Our data narrow the range of biochemically reasonable models for how Argonaute-bound siRNAs and miRNAs find, bind, and regulate their targets.

Small interfering RNAs (siRNAs) direct Argonaute proteins, the core components of the RNA-induced silencing complex (RISC), to cleave complementary target RNAs. Here, we describe a method to purify active RISC containing a single, unique small RNA guide sequence. We begin by capturing RISC using a complementary 2'-O-methyl oligonucleotide tethered to beads. Unlike other methods that capture RISC but do not allow its recovery, our strategy purifies active, soluble RISC in good yield. The method takes advantage of the finding that RISC partially paired to a target through its siRNA guide dissociates more than 300 times faster than a fully paired siRNA in RISC. We use this strategy to purify fly Ago1- and Ago2-RISC, as well as mouse AGO2-RISC. The method can discriminate among RISCs programmed with different guide strands, making it possible to deplete and recover specific RISC populations. Endogenous microRNA:Argonaute complexes can also be purified from cell lysates. Our method scales readily and takes less than a day to complete.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-alpha and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p

Animal germ cells produce PIWI-interacting RNAs (piRNAs), small silencing RNAs that suppress transposons and enable gamete maturation. Mammalian transposon-silencing piRNAs accumulate early in spermatogenesis, whereas pachytene piRNAs are produced later during postnatal spermatogenesis and account for >95% of all piRNAs in the adult mouse testis. Mutants defective for pachytene piRNA pathway proteins fail to produce mature sperm, but neither the piRNA precursor transcripts nor the trigger for pachytene piRNA production is known. Here, we show that the transcription factor A-MYB initiates pachytene piRNA production. A-MYB drives transcription of both pachytene piRNA precursor RNAs and the mRNAs for core piRNA biogenesis factors including MIWI, the protein through which pachytene piRNAs function. A-MYB regulation of piRNA pathway proteins and piRNA genes creates a coherent feedforward loop that ensures the robust accumulation of pachytene piRNAs. This regulatory circuit, which can be detected in rooster testes, likely predates the divergence of birds and mammals.

Several recent studies demonstrate that piRNAs guide Piwi protein to repress transposon transcription in fly ovaries, much as fission yeast use siRNAs to silence repeat sequences. Still mysterious though is how Piwi targets euchromatic transposons for silencing, but not the specialized heterochromatic loci that produce piRNA precursors.