H3K36 dimethylation shapes the epigenetic interaction landscape by directing repressive chromatin modifications in embryonic stem cells.

Epigenetic modifications on the chromatin do not occur in isolation. Chromatin-associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse embryonic stem cell (mESC) model to describe in detail the relationships within the H3K27-H3K36-DNA methylation subnetwork. In particular, we focus on the major epigenetic reorganization caused by deletion of the histone 3 lysine 36 methyltransferase NSD1, which in mESCs deposits nearly all of the intergenic H3K36me2. Although disturbing the H3K27 and DNA methylation (DNAme) components also affects this network to a certain extent, the removal of H3K36me2 has the most drastic effect on the epigenetic landscape, resulting in full intergenic spread of H3K27me3 and a substantial decrease in DNAme. By profiling DNMT3A and CHH methylation (mCHH), we show that H3K36me2 loss upon Nsd1-KO leads to a massive redistribution of DNMT3A and mCHH away from intergenic regions and toward active gene bodies, suggesting that DNAme reduction is at least in part caused by redistribution of de novo methylation. Additionally, we show that pervasive acetylation of H3K27 is regulated by the interplay of H3K36 and H3K27 methylation. Our analysis highlights the importance of H3K36me2 as a major determinant of the developmental epigenome and provides a framework for further consolidating our knowledge of epigenetic networks.

The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.

Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1-4. They are also implicated in human developmental disorders and cancers5-8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9-11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation.

Hotspot histone H3 mutations have emerged as drivers of oncogenesis in cancers of multiple lineages. Specifically, H3 lysine 36 to methionine (H3K36M) mutations are recurrently identified in chondroblastomas, undifferentiated sarcomas, and head and neck cancers. While the mutation reduces global levels of both H3K36 dimethylation (H3K36me2) and trimethylation (H3K36me3) by dominantly inhibiting their respective specific methyltransferases, the relative contribution of these methylation states to the chromatin and phenotypic changes associated with H3K36M remains unclear. Here, we specifically deplete H3K36me2 or H3K36me3 in mesenchymal cells, using CRISPR-Cas9 to separately knock out the corresponding methyltransferases NSD1/2 or SETD2. By profiling and comparing the epigenomic and transcriptomic landscapes of these cells with cells expressing the H3.3K36M oncohistone, we find that the loss of H3K36me2 could largely recapitulate H3.3K36M's effect on redistribution of H3K27 trimethylation (H3K27me3) and gene expression. Consistently, knockout of Nsd1/2, but not Setd2, phenocopies the differentiation blockade and hypersensitivity to the DNA-hypomethylating agent induced by H3K36M. Together, our results support a functional divergence between H3K36me2 and H3K36me3 and their nonredundant roles in H3K36M-driven oncogenesis.

Size-Dependent Lattice Symmetry Breaking Determines the Exciton Fine Structure of Perovskite Nanocrystals.

The order of bright and dark excitonic states in lead-halide perovskite nanocrystals is debated. It has been proposed that the Rashba effect, driven by lattice-induced symmetry breaking, causes a bright excitonic ground state. Direct measurements of excitonic spectra, however, show the signatures of a dark ground state, bringing the role of the Rashba effect into question. We use an atomistic theory to model the exciton fine structure of perovskite nanocrystals, accounting for realistic lattice distortions. We calculate optical gaps and excitonic features that compare favorably with experimental works. The exciton fine structure splittings show a nonmonotonic size dependence due to a structural transition between cubic and orthorhombic phases. Additionally, the excitonic ground state is found to be dark with spin triplet character, exhibiting a small Rashba coupling. We additionally explore the effects of nanocrystal shape on the fine structure, clarifying observations on polydisperse nanocrystals.

Energy Funneling in a Noninteger Two-Dimensional Perovskite.

Energy funneling is a phenomenon that has been exploited in optoelectronic devices based on low-dimensional materials to improve their performance. Here, we introduce a new class of two-dimensional semiconductor, characterized by multiple regions of varying thickness in a single confined nanostructure with homogeneous composition. This "noninteger 2D semiconductor" was prepared via the structural transformation of two-octahedron-layer-thick (n = 2) 2D cesium lead bromide perovskite nanosheets; it consisted of a central n = 2 region surrounded by edge-lying n = 3 regions, as imaged by electron microscopy. Thicker noninteger 2D CsPbBr3 nanostructures were obtained as well. These noninteger 2D perovskites formed a laterally coupled quantum well band alignment with virtually no strain at the interface and no dielectric barrier, across which unprecedented intramaterial funneling of the photoexcitation energy was observed from the thin to the thick regions using time-resolved absorption and photoluminescence spectroscopy.

Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression.

A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.

Simulations of nonradiative processes in semiconductor nanocrystals.

The description of carrier dynamics in spatially confined semiconductor nanocrystals (NCs), which have enhanced electron-hole and exciton-phonon interactions, is a great challenge for modern computational science. These NCs typically contain thousands of atoms and tens of thousands of valence electrons with discrete spectra at low excitation energies, similar to atoms and molecules, that converge to the continuum bulk limit at higher energies. Computational methods developed for molecules are limited to very small nanoclusters, and methods for bulk systems with periodic boundary conditions are not suitable due to the lack of translational symmetry in NCs. This perspective focuses on our recent efforts in developing a unified atomistic model based on the semiempirical pseudopotential approach, which is parameterized by first-principle calculations and validated against experimental measurements, to describe two of the main nonradiative relaxation processes of quantum confined excitons: exciton cooling and Auger recombination. We focus on the description of both electron-hole and exciton-phonon interactions in our approach and discuss the role of size, shape, and interfacing on the electronic properties and dynamics for II-VI and III-V semiconductor NCs.

PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor.

A lysine-to-methionine mutation at lysine 27 of histone 3 (H3K27M) has been shown to promote oncogenesis in a subset of pediatric gliomas. While there is evidence that this "oncohistone" mutation acts by inhibiting the histone methyltransferase PRC2, the details of this proposed mechanism nevertheless continue to be debated. Recent evidence suggests that PRC2 must simultaneously bind both H3K27M and H3K27me3 to experience competitive inhibition of its methyltransferase activity. In this work, we used PRC2 inhibitor treatments in a transgenic H3K27M cell line to validate this dependence in a cellular context. We further used designer chromatin inhibitors to probe the geometric constraints of PRC2 engagement of H3K27M and H3K27me3 in a biochemical setting. We found that PRC2 binds to a bivalent inhibitor unit consisting of an H3K27M and an H3K27me3 nucleosome and exhibits a distance dependence in its affinity for such an inhibitor, which favors closer proximity of the 2 nucleosomes within a chromatin array. Together, our data precisely delineate fundamental aspects of the H3K27M inhibitor and support a model wherein PRC2 becomes trapped at H3K27M-H3K27me3 boundaries.

Safety of laparoscopic sacrocolpopexy with concurrent rectopexy: peri-operative morbidity in a nationwide cohort.

INTRODUCTION AND HYPOTHESIS: Rectopexy and sacrocolpopexy can be performed concurrently to treat rectal and vaginal prolapse. We hypothesized that concurrent procedures might be associated with more complications than rectopexy and sacrocolpopexy alone. METHODS: Patients undergoing laparoscopic sacrocolpopexy or rectopexy, or concurrent laparoscopic sacrocolpopexy and rectopexy were identified in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database from 2013 to 2016. Preoperative characteristics, operative time, and 30-day post-operative complications were compared between groups. Complications were those defined by the ACS Risk Calculator. Descriptive tests and regression methods were utilized for group comparisons. Significance was set at p < 0.05. RESULTS: We identified 7,232 laparoscopic sacrocolpopexy, 1,560 laparoscopic rectopexy, and 123 concurrent laparoscopic sacrocolpopexy and rectopexy cases. Patients undergoing concurrent procedures were more commonly white, non-Hispanic, non-diabetic, and smokers. Operative time was longest for concurrent procedures, followed by sacrocolpopexy and rectopexy (p < 0.0001). Patients undergoing isolated rectopexy were more commonly ≥ American Society of Anesthesiologists class 3 (p < 0.0001). Rates of any complication for colpopexy, rectopexy, and concurrent procedures did not differ (6.18%, 7.63%, 8.94%; p = 0.058). Serious complication rates for colpopexy, rectopexy, and concurrent procedures did not differ (5.52%, 6.35%, 8.13%; p = 0.222). Odds of experiencing any complication were higher comparing rectopexy with colpopexy alone (adjusted odds ratio = 1.252, 95% CI 1.002-1.565). Comparing all groups, rectopexy had the highest mortality, reoperation, and transfusion rates (all p < 0.05). Concurrent procedures had the highest surgical site and urinary tract infection rates (all p < 0.05). CONCLUSIONS: Complications were low for all three procedures. Concurrent repair may be appropriate in well-selected patients.

Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial.

BACKGROUND: Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. OBJECTIVE: Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. STUDY DESIGN: At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure ≥160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure ≥150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. RESULTS: We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, body mass index, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen vs acetaminophen groups (35.3 vs 38.0 hours, P = .30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure ≥150/100 mm Hg, postpartum mean arterial pressure, maximum postpartum systolic or diastolic blood pressures, any postpartum blood pressure ≥160/110 mm Hg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.4 hours and ibuprofen group was 56.7 hours (P = .26). At 6 weeks postpartum, there were no differences between groups in the rates of obstetric triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. CONCLUSION: The first-line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features.

Healthcare Coinsurance Elasticity Coefficient Estimation Using Monthly Cross-sectional, Time-series Claims Data.

Published estimates of the healthcare coinsurance elasticity coefficient have typically relied on annual observations of individual healthcare expenditures even though health plan membership and expenditures are traditionally reported in monthly units and several studies have stressed the need for demand models to recognize the episodic nature of healthcare. Summing individual healthcare expenditures into annual observations complicates two common challenges of statistical inference, heteroscedasticity, and regressor endogeneity. This paper estimates the elasticity coefficient using a monthly panel data model that addresses the heteroscedasticity and endogeneity problems with relative ease. Healthcare claims data from employees of King County, Washington, during 2005 to 2011 were used to estimate the mean point elasticity coefficient: -0.314 (0.015 standard error) to -0.145 (0.015 standard error) depending on model specification. These estimates bracket the -0.2 point estimate (range: -0.22 to -0.17) derived from the famous Rand Health Insurance Experiment. Copyright © 2016 John Wiley & Sons, Ltd.

Unusual placement of intrathecal baclofen pumps: report of two cases.

Intrathecal baclofen delivery via implantable pump represents an important modality for symptomatic relief in patients with chronic spasticity. Pumps are routinely implanted subcutaneously in the anterior abdominal wall. We describe two unusual cases where skin-related complications necessitated revision surgery in order to relocate the pump to alternative sites. The first patient was an international power canoeist, whose strenuous exercise programme interfered with his pump's original siting. The second patient was a cachectic university student with a history of cerebral palsy, who maintained low body mass despite attempted weight gain. The relocation of these two intrathecal devices to the medial compartment of the right thigh and right iliac fossa, respectively, is described.

Twelve tips for medical students to maximise learning in theatre.

BACKGROUND: Introduction into the clinical environment can be a daunting experience for medical students, especially in the operating theatre. Prior knowledge of how to prepare for theatre and cope with surgical placements is advantageous, as learning opportunities can be maximised from the start. AIM: This article provides medical students with 12 tips devised to help make the most out of their initial theatre placements. METHODS: Tips were formulated based on the experiences of three senior medical students and a review of the literature. RESULTS: The 12 tips are (1) Know the patient and procedure, (2) Be familiar with your surgical department, (3) Familiarise yourself with different surgical attire, (4) Revise your clinical skills, (5) Be time-efficient, (6) Learn how to work in a sterile environment, (7) Avoiding syncope, (8) Impress the operating surgeon, (9) Be aware of the professional, ethical, and legal issues in surgery, (10) Use mentors to enhance your learning, (11) Embrace extra-curricular activities to enhance your insight into surgery and (12) Be acquainted with relevant support systems. CONCLUSIONS: These 12 tips provide guidance and opportunities to maximise learning for new clinical-phase medical students being introduced to the operating theatre for the first time.

An examination of longitudinal CAUTI, SSI, and CDI rates from key HHS data systems.

BACKGROUND: In response to the growing concern about healthcare-associated infections (HAIs), US Department of Health and Human Services (HHS) developed the National Action Plan to Prevent Healthcare-associated Infections. A key focus of the Action Plan is the setting of HAI metrics and targets and the enhancement and development of data systems to support HAI surveillance. OBJECTIVES: To identify and assess the strengths and weaknesses of HHS data systems available for surveillance of catheter-associated urinary tract infections, surgical site infections, and Clostridium difficile infections. To present national data from each of the data systems and assess concordance in trends over time. RESEARCH DESIGN: Literature review on data system characteristics and HAI measurement. Graphical and descriptive analyses of longitudinal HAI rates from HHS data systems. MEASURES: HAI rate information expressed as prevalence rates or standardized infection ratios. RESULTS: We identified four HHS data systems--Medicare claims data, Healthcare Cost and Utilization Project, Medicare Patient Safety Monitoring System, and National Healthcare Safety Network--capable of surveillance of at least one of the HAIs under study. Surgical site infection and Clostridium difficile infection rates display concordance in trends, although there is no evidence of concordance in catheter-associated urinary tract infections rates. We have identified a number of desirable HAI data system characteristics: clinically valid; provide information on a broad range of HAIs; have large sample size to support statistical inference; be representative of the United States; and display consistency in cohort, surveillance protocols, and data collection methodology. CONCLUSIONS: Although the data systems included in this study vary along the desirable data system dimensions we identified, trends in HAI rates are generally concordant across the data systems. This increases confidence in observed trends.

From research to nationwide implementation: the impact of AHRQ's HAI prevention program.

INTRODUCTION: The Agency for Healthcare Research and Quality (AHRQ's) Patient Safety Program is responsive to AHRQ's mission of quality improvement in healthcare. As part of this program, AHRQ has invested in projects to prevent healthcare-associated infections (HAIs), and funding has increased significantly over the last decade. AHRQ-funded projects have focused on generating new knowledge and promoting the nationwide implementation of proven HAI prevention measures in diverse healthcare settings. OBJECTIVES: To provide insight to AHRQ's HAI prevention strategies by: first, discussing the context and structure of AHRQ's HAI research portfolio and funding decisions; secondly, describing the process of prevention practice implementation and lessons learned; and third, explaining the outcomes and national impact of the AHRQ program. RESULTS AND CONCLUSIONS: In the early 2000s, AHRQ identified HAIs as an important and preventable public health threat and built their HAI-prevention portfolio based on National Action Plan priorities, available resources, advice from experts, and the state of science. This paper describes major contributions that have emerged from AHRQ-funded HAI projects. The projects examined, many of which focus on implementation of HAI prevention practices, yield useful lessons learned for future implementation and research endeavors and show significant impact of AHRQ's program in reducing HAIs.

The effect of Surgical Care Improvement Project (SCIP) compliance on surgical site infections (SSI).

BACKGROUND: The Surgical Care Improvement Project (SCIP) has developed a set of process compliance measures in an attempt to reduce the incidence of surgical site infections (SSIs). Previous research has been inconclusive on whether compliance with these measures is associated with lower SSI rates. OBJECTIVES: To determine whether hospitals with higher levels of compliance with SCIP measures have lower incidence of SSIs and to identify the measures that are most likely to drive this association. DATA AND METHODS: Analysis of linked SCIP compliance rates and SSIs on 295 hospital groups observed annually over the study period 2007-2010. A hospital group comprises all hospitals sharing identical categories for location by state, teaching status, bed size, and urban/rural location. We used a generalized linear model regression with logistic link and binomial family to estimate the association between 3 SCIP measures and SSI rates. RESULTS: Hospital groups with higher compliance rates had significantly lower SSI rates for 2 SCIP measures: antibiotic timing and appropriate antibiotic selection. For a hospital group of median characteristics, a 10% improvement in the measure provision of antibiotic 1 hour before intervention led to a 5.3% decrease in the SSI rates (P<0.05). Rural hospitals had effect sizes several times larger than urban hospitals (P<0.05). A third-core measure, Timely Antibiotic Stop, showed no robust association. CONCLUSIONS: This analysis supports a clinically and statistically meaningful relationship between adherence to 2 SCIP measures and SSI rates, supporting the validity of the 2 publicly available healthcare-associated infection metrics.

The national response for preventing healthcare-associated infections: infrastructure development.

BACKGROUND: In 2009, the US Department of Health and Human Services (HHS) launched the Action Plan to Prevent Healthcare-associated Infections (HAIs). The Action Plan adopted national targets for reduction of specific infections, making HHS accountable for change across the healthcare system over which federal agencies have limited control. OBJECTIVES: This article examines the unique infrastructure developed through the Action Plan to support adoption of HAI prevention practices. RESEARCH DESIGN: Interviews of federal (n=32) and other stakeholders (n=38), reviews of agency documents and journal articles (n=260), and observations of interagency meetings (n=17) and multistakeholder conferences (n=17) over a 3-year evaluation period. MEASURES: We extract key progress and challenges in the development of national HAI prevention infrastructure--1 of the 4 system functions in our evaluation framework encompassing regulation, payment systems, safety culture, and dissemination and technical assistance. We then identify system properties--for example, coordination and alignment, accountability and incentives, etc.--that enabled or hindered progress within each key development. RESULTS: The Action Plan has developed a model of interagency coordination (including a dedicated "home" and culture of cooperation) at the federal level and infrastructure for stimulating change through the wider healthcare system (including transparency and financial incentives, support of state and regional HAI prevention capacity, changes in safety culture, and mechanisms for stakeholder engagement). Significant challenges to infrastructure development included many related to the same areas of progress. CONCLUSIONS: The Action Plan has built a foundation of infrastructure to expand prevention of HAIs and presents useful lessons for other large-scale improvement initiatives.

The national response for preventing healthcare-associated infections: data and monitoring.

BACKGROUND: Historically, the ability to accurately track healthcare-associated infections (HAIs) was hindered due to a lack of coordination among data sources and shortcomings in individual data sources. OBJECTIVES: This paper presents the results of the evaluation of the HAI data and the monitoring component of the Action Plan, focusing on context (goals), inputs, and processes. RESEARCH DESIGN: We used the Content-Input-Process-Product framework, together with the HAI prevention system framework, to describe the transformative processes associated with data and monitoring efforts. RESULTS: Six HAI priority conditions in the 2009 Action Plan created a focus for the selection of goals and activities. Key Action Plan decisions included a phased-in data and monitoring approach, commitment to linking the selection of priority HAIs to highly visible national 5-year prevention targets, and the development of a comprehensive HAI database inventory. Remaining challenges relate to data validation, resources, and the opportunity to integrate electronic health and laboratory records with other provider data systems. CONCLUSIONS: The Action Plan's data and monitoring program has developed a sound infrastructure that builds upon technological advances and embodies a firm commitment to prioritization, coordination and alignment, accountability and incentives, stakeholder engagement, and an awareness of the need for predictable resources. With time, and adequate resources, it is likely that the investment in data-related infrastructure during the Action Plan's initial years will reap great rewards.

The national response for preventing healthcare-associated infections: system capacity and sustainability for improvement.

BACKGROUND: Strengthening capacity across the healthcare system for improvement is critical to ensuring that past efforts and investments establish a foundation for sustaining progress in patient safety. OBJECTIVES: The objective of this analysis was to identify key system capacity issues for sustainability from evaluation of the Action Plan to prevent healthcare-associated infections, a major national initiative launched by the US Department of Health and Human Services in 2009. RESEARCH DESIGN: The analysis involves the review and synthesis of results across the components of a 3-year evaluation of the Action Plan, as described in the evaluation framework and detailed in separate analyses elsewhere in this special issue. Data collection methods included interviews with government and private stakeholders, document and literature reviews, and observations of meetings and conferences at multiple time points. MEASURES: Key developments in healthcare-associated infection prevention system capacity were extracted on the basis of "major activities" identified through multiple methods and organized into the level of progress based on perspectives of multiple stakeholders. Activities within each level were then examined and compared according to our evaluation's framework of 4 system functions and 5 system properties. RESULTS: Key system capacity and sustainability issues for the Action Plan to be addressed centered on coordination and alignment (among participating agencies, with other federal initiatives, and across levels of healthcare), infrastructure for data and accountability (including more efficient technologies and unintended consequences), cultural embedding of prevention practices, and uncertainty and variability in resources. CONCLUSIONS: Sustainability depends on improvements across system functions and properties and how they reinforce each other. Change is more robust if different system elements support and incentivize behavior in similar directions.