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Ashley W Collinsworth,1,2 Rachel M Brown,1 Cameron S James,3 Richard H Stanford,3 Daniel Alemayehu,1 Elisa L Priest1 1Center for Clinical Effectiveness, Baylor Scott and White Health, Dallas, TX, USA; 2Robbins Institute for Health Policy & Leadership, Baylor University, Waco, TX, USA; 3GlaxoSmithKline, Research Triangle Park, NC, USA Purpose: Education on the self-management of COPD has been shown to improve patients’ quality of life and reduce hospital admissions. This study aimed to assess the feasibility of a pilot, pragmatic COPD Chronic Care (CCC) education program led by registered respiratory therapists and determine the CCC’s impact on hospital readmissions, patient activation, and health status. Patients and methods: This was a prospective, randomized, pilot study of inpatients with COPD admitted to a US community hospital between August 2014 and February 2016. In total, 308 patients were randomized 1:1 to receive standard care with or without the CCC program. Outcomes included the number of patients completing the program, frequency and time to first all-cause and COPD-related hospital readmissions, and changes in the Patient Activation Measure (PAM) and COPD Assessment Test (CAT). Results: Overall, 37% (n=52) of patients in the CCC group and 29% (n=48) of patients in the control group remained in the study for 6 months and completed all follow-up phone calls. In total, 74% (n=105) of patients in the CCC group and 69% (n=115) of patients in the control group had at least one readmission (P=0.316). The time to first all-cause and COPD-related readmission appeared shorter for patients in the CCC group compared with the control group (mean [standard deviation]: 50.2 [54.5] vs 59.9 [63.1] days and 95.1 [80.2] vs 113.7 [82.4] days, respectively; both P=0.231). Patients experienced significant improvement from baseline in mean PAM (both groups) and CAT (CCC group) scores. Conclusion: Utilizing respiratory therapists to lead a chronic care education program for COPD in a community hospital was feasible. Although CCC patients showed improvements in perceived symptom severity, they were readmitted sooner than control group patients. However, the program did not impact the frequency of hospital readmissions. A more comprehensive disease management program may be needed to improve outcomes. Keywords: COPD, patient education, shared decision making, hospital readmission, chronic disease management

The contemporary health care resource utilization after an acute myocardial infarction (MI) is not well-known. All patients admitted because of MI between January 2015 and December 2021 across 28 hospitals in the Baylor Scott & White Health system were studied. Patient characteristics and outcomes, including all-cause and cardiovascular (CV) rehospitalizations, emergency department (ED) visits, and outpatient visits were evaluated. Of 6,804 patients admitted because of MI, 6,556 were discharged alive. The median age was 69 years, 60% were men, and 77% had non-ST-elevation MI; 17% (1,090) had multivessel disease. The number of patients with first all-cause readmissions within 30 days, 3 months, and 12 months of discharge were 844 (13%), 1,372 (21%), and 2,306 (35%), respectively, with a higher readmission rate in patients with non-ST-elevation MI, previous heart failure (HF), new-onset HF, and left ventricular ejection fraction ≤40%. ED visits at 12 months for any cause were 2,401 (37%), of which 1,321 (55%) were for any CV cause, with a higher incidence in patients with previous HF. Of the 6,556 patients, 4,102 (63%) had at least 1 primary care visit in the past year, 5,009 (76%) had CV specialty visits, and 3,860 (59%) had non-CV visits, with a similar distribution across subgroups. Patients hospitalized with an MI had a high risk of subsequent hospital readmissions and ED and outpatient visits, especially those with a previous HF diagnosis and those discharged with an MI and HF diagnosis., Competing Interests: Declaration of competing interest Dr. Butler reports financial support was provided by Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Dr. Afzal reports a relationship with AstraZeneca that includes: speaking and lecture fees. Dr. Alhamdow reports a relationship with Boehringer Ingelheim GmbH that includes: employment. Dr. Hartgers-Gubbels reports a relationship with Boehringer Ingelheim GmbH that includes: employment. Dr. Martinez-Traba reports a relationship with Boehringer Ingelheim GmbH that includes: employment. Dr. Butler reports a relationship with Abbott that includes: consulting or advisory. Dr. Butler reports a relationship with American Regent Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Amgen Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Applied Therapeutics Inc that includes: consulting or advisory. Dr. Butler reports a relationship with AskBio that includes: consulting or advisory. Dr. Butler reports a relationship with Astellas that includes: consulting or advisory. Dr. Butler reports a relationship with AstraZeneca that includes: consulting or advisory and speaking and lecture fees. Dr. Butler reports a relationship with Bayer that includes: consulting or advisory. Dr. Butler reports a relationship with Boehringer Ingelheim that includes: consulting or advisory and speaking and lecture fees. Dr. Butler reports a relationship with Boston Scientific Corporation that includes: consulting or advisory. Dr. Butler reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Dr. Butler reports a relationship with Cardiac Dimensions Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Cardiocell that includes: consulting or advisory. Dr. Butler reports a relationship with Cardior that includes: consulting or advisory. Dr. Butler reports a relationship with Cardiorem that includes: consulting or advisory. Dr. Butler reports a relationship with CSL Behring that includes: consulting or advisory. Dr. Butler reports a relationship with CVRx Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Cytokinetics Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Edwards Lifesciences Corporation that includes: consulting or advisory. Dr. Butler reports a relationship with Daxor that includes: consulting or advisory. Dr. Butler reports a relationship with Element Science that includes: consulting or advisory. Dr. Butler reports a relationship with Faraday that includes: consulting or advisory. Dr. Butler reports a relationship with Foundry that includes: consulting or advisory. Dr. Butler reports a relationship with G3P that includes: consulting or advisory. Dr. Butler reports a relationship with Innolife that includes: consulting or advisory. Dr. Butler reports a relationship with Impulse Dynamics that includes: consulting or advisory and speaking and lecture fees. Dr. Butler reports a relationship with Imbria that includes: consulting or advisory. Dr. Butler reports a relationship with Inventiva that includes: consulting or advisory. Dr. Butler reports a relationship with Ionis that includes: consulting or advisory. Dr. Butler reports a relationship with Lexicon that includes: consulting or advisory. Dr. Butler reports a relationship with Eli Lilly and Company that includes: consulting or advisory and speaking and lecture fees. Dr. Butler reports a relationship with LivaNova that includes: consulting or advisory. Dr. Butler reports a relationship with Janssen that includes: consulting or advisory. Dr. Butler reports a relationship with Medtronics that includes: consulting or advisory. Dr. Butler reports a relationship with Merck & Co Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Occlutech that includes: consulting or advisory. Dr. Butler reports a relationship with Owkin Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Dr. Butler reports a relationship with Novo Nordisk Inc that includes: consulting or advisory. Dr. Butler reports a relationship with Pfizer that includes: consulting or advisory. Dr. Butler reports a relationship with Pharmacosmos that includes: consulting or advisory. Dr. Butler reports a relationship with PharmaIN that includes: consulting or advisory. Dr. Butler reports a relationship with Prolaio that includes: consulting or advisory. Dr. Butler reports a relationship with Regeneron that includes: consulting or advisory. Dr. Butler reports a relationship with Renibus Therapeutics, Inc. that includes: consulting or advisory. Dr. Butler reports a relationship with Roche that includes: consulting or advisory. Dr. Butler reports a relationship with Salamandra that includes: consulting or advisory. Dr. Butler reports a relationship with Sanofi that includes: consulting or advisory. Dr. Butler reports a relationship with SC Pharma that includes: consulting or advisory. Dr. Butler reports a relationship with Secretome that includes: consulting or advisory. Dr. Butler reports a relationship with Sequana that includes: consulting or advisory. Dr. Butler reports a relationship with SQ Innovation that includes: consulting or advisory. Dr. Butler reports a relationship with Tenex that includes: consulting or advisory. Dr. Butler reports a relationship with Tricog that includes: consulting or advisory. Dr. Butler reports a relationship with Ultromics that includes: consulting or advisory. Dr. Butler reports a relationship with Vifor that includes: consulting or advisory. Dr. Butler reports a relationship with ZOLL that includes: consulting or advisory. Dr. Gottlieb reports a relationship with Alnylam Pharmaceuticals Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Dr. Gottlieb reports a relationship with AstraZeneca that includes: consulting or advisory and funding grants. Dr. Gottlieb reports a relationship with Eli Lilly and Company that includes: consulting or advisory and funding grants. Dr. Gottlieb reports a relationship with Pfizer that includes: funding grants and speaking and lecture fees. Dr. Gottlieb reports a relationship with Johnson & Johnson that includes: funding grants. Dr. Priest reports a relationship with AstraZeneca that includes: funding grants. Dr. Priest reports a relationship with Owkin Inc that includes: funding grants. The remaining authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Candida albicans causes millions of mucosal infections in humans annually. Hyphal overgrowth on mucosal surfaces is frequently associated with tissue damage caused by candidalysin, a secreted peptide toxin that destabilizes the plasma membrane of host cells thereby promoting disease and immunopathology. Candidalysin was first identified in C. albicans strain SC5314, but recent investigations have revealed candidalysin "variants" of differing amino acid sequence in isolates of C. albicans , and the related species C. dubliniensis , and C tropicalis , suggesting that sequence variation among candidalysins may be widespread in natural populations of these Candida species. Here, we analyzed ECE1 gene sequences from 182 C . albicans isolates, 10 C . dubliniensis isolates, and 78 C . tropicalis isolates and identified 10, 3, and 2 candidalysin variants in these species, respectively. Application of candidalysin variants to epithelial cells revealed differences in the ability to cause cellular damage, changes in metabolic activity, calcium influx, MAPK signalling, and cytokine secretion, while biophysical analyses indicated that variants exhibited differences in their ability to interact with and permeabilize a membrane. This study identifies candidalysin variants with differences in biological activity that are present in medically relevant Candida species., Importance: Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis , thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin "variant" toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans , C. dubliniensis , and C. tropicalis and identified candidalysin variants in all three species. When applied to epithelial cells, candidalysin variants differed in their ability to cause damage, activate intracellular signaling pathways, and induce innate immune responses, while biophysical analysis revealed differences in the ability of candidalysin variants to interact with lipid bilayers. These findings suggest that intraspecies variation in candidalysin amino acid sequence may influence fungal pathogenicity., Competing Interests: The authors declare no conflict of interest.

Candida albicans can cause mucosal infections in humans. This includes oropharyngeal candidiasis, which is commonly observed in human immunodeficiency virus infected patients, and vulvovaginal candidiasis (VVC), which is the most frequent manifestation of candidiasis. Epithelial cell invasion by C. albicans hyphae is accompanied by the secretion of candidalysin, a peptide toxin that causes epithelial cell cytotoxicity. During vaginal infections, candidalysin-driven tissue damage triggers epithelial signaling pathways, leading to hyperinflammatory responses and immunopathology, a hallmark of VVC. Therefore, we proposed blocking candidalysin activity using nanobodies to reduce epithelial damage and inflammation as a therapeutic strategy for VVC. Anti-candidalysin nanobodies were confirmed to localize around epithelial-invading C. albicans hyphae, even within the invasion pocket where candidalysin is secreted. The nanobodies reduced candidalysin-induced damage to epithelial cells and downstream proinflammatory responses. Accordingly, the nanobodies also decreased neutrophil activation and recruitment. In silico mathematical modeling enabled the quantification of epithelial damage caused by candidalysin under various nanobody dosing strategies. Thus, nanobody-mediated neutralization of candidalysin offers a novel therapeutic approach to block immunopathogenic events during VVC and alleviate symptoms.IMPORTANCEWorldwide, vaginal infections caused by Candida albicans (VVC) annually affect millions of women, with symptoms significantly impacting quality of life. Current treatments are based on anti-fungals and probiotics that target the fungus. However, in some cases, infections are recurrent, called recurrent VVC, which often fails to respond to treatment. Vaginal mucosal tissue damage caused by the C. albicans peptide toxin candidalysin is a key driver in the induction of hyperinflammatory responses that fail to clear the infection and contribute to immunopathology and disease severity. In this pre-clinical evaluation, we show that nanobody-mediated candidalysin neutralization reduces tissue damage and thereby limits inflammation. Implementation of candidalysin-neutralizing nanobodies may prove an attractive strategy to alleviate symptoms in complicated VVC cases., Competing Interests: E.D. is the CEO of Q.V.Q who produced the anti-candidalysin nanobodies.

The opportunistic fungal pathogen Candida albicans thrives on human mucosal surfaces as a harmless commensal, but frequently causes infections under certain predisposing conditions. Translocation across the intestinal barrier into the bloodstream by intestine-colonizing C. albicans cells serves as the main source of disseminated candidiasis. However, the host and microbial mechanisms behind this process remain unclear. In this study we identified fungal and host factors specifically involved in infection of intestinal epithelial cells (IECs) using dual-RNA sequencing. Our data suggest that host-cell damage mediated by the peptide toxin candidalysin-encoding gene ECE1 facilitates fungal zinc acquisition. This in turn is crucial for the full virulence potential of C. albicans during infection. IECs in turn exhibit a filamentation- and damage-specific response to C. albicans infection, including NFκB, MAPK, and TNF signaling. NFκB activation by IECs limits candidalysin-mediated host-cell damage and mediates maintenance of the intestinal barrier and cell-cell junctions to further restrict fungal translocation. This is the first study to show that candidalysin-mediated damage is necessary for C. albicans nutrient acquisition during infection and to explain how IECs counteract damage and limit fungal translocation via NFκB-mediated maintenance of the intestinal barrier., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sprague et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The opportunistic fungal pathogen Candida albicans damages host cells via its peptide toxin, candidalysin. Before secretion, candidalysin is embedded in a precursor protein, Ece1, which consists of a signal peptide, the precursor of candidalysin and seven non-candidalysin Ece1 peptides (NCEPs), and is found to be conserved in clinical isolates. Here we show that the Ece1 polyprotein does not resemble the usual precursor structure of peptide toxins. C. albicans cells are not susceptible to their own toxin, and single NCEPs adjacent to candidalysin are sufficient to prevent host cell toxicity. Using a series of Ece1 mutants, mass spectrometry and anti-candidalysin nanobodies, we show that NCEPs play a role in intracellular Ece1 folding and candidalysin secretion. Removal of single NCEPs or modifications of peptide sequences cause an unfolded protein response (UPR), which in turn inhibits hypha formation and pathogenicity in vitro. Our data indicate that the Ece1 precursor is not required to block premature pore-forming toxicity, but rather to prevent intracellular auto-aggregation of candidalysin sequences., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Opioids are a mainstay for acute pain management, but their side effects can adversely impact patient recovery. Multimodal analgesia (MMA) is recommended for treatment of postoperative pain and has been incorporated in enhanced recovery after surgery (ERAS) protocols. The objective of this quality improvement study was to implement an MMA care pathway as part of an ERAS program for colorectal surgery and to measure the effect of this intervention on patient outcomes and costs., Methods: This pre-post study included 856 adult inpatients who underwent an elective colorectal surgery at three hospitals within an integrated healthcare system. The impact of ERAS program implementation on opioid prescribing practices, outcomes, and costs was examined after adjusting for clinical and demographic confounders., Results: Improvements were seen in MMA compliance (34.0% vs 65.5%, P  < 0.0001) and ERAS compliance (50.4% vs 57.6%, P  < 0.0001). Reductions in mean days on opioids (4.2 vs 3.2), daily (51.6 vs 33.4 mg) and total (228.8 vs 112.7 mg) morphine milligram equivalents given during hospitalization, and risk-adjusted length of stay (4.3 vs 3.6 days, P  < 0.05) were also observed., Conclusions: Implementing ERAS programs that include MMA care pathways as standard of care may result in more judicious use of opioids and reduce patient recovery time., Competing Interests: Dr. Wan is the Global Head of Evidence Generation and Data Sciences at Mallinckrodt Pharmaceuticals. Ms. Böing previously served as the Senior Manager for Health Economics and Outcomes Research (HEOR) and Real-World Evidence at Mallinckrodt Pharmaceuticals and is currently the Director of Global HEOR for Rare Disease at Ipsen. Dr. Collinsworth is currently a Senior Research Scientist at 3M. The other authors declare no potential conflicts of interest., (Copyright © 2023 Baylor University Medical Center.)

Background: Many COVID-19 studies are constructed to report hospitalization outcomes, with few large multi-center population-based reports on the time course of intra-hospitalization characteristics, including daily oxygenation support requirements. Comprehensive epidemiologic profiles of oxygenation methods used by day and by week during hospitalization across all severities are important to illustrate the clinical and economic burden of COVID-19 hospitalizations., Methods: This was a retrospective, multi-center observational cohort study of 15,361 consecutive hospitalizations of patients with COVID-19 at 25 adult acute care hospitals in Texas participating in the Society of Critical Care Medicine Discovery Viral Respiratory Illness Universal Study COVID-19 registry., Results: At initial hospitalization, the majority required nasal cannula (44.0%), with an increasing proportion of invasive mechanical ventilation in the first week and particularly the weeks to follow. After 4 weeks of acute illness, 69.9% of adults hospitalized with COVID-19 required intermediate (eg, high-flow nasal cannula, noninvasive ventilation) or advanced respiratory support (ie, invasive mechanical ventilation), with similar proportions that extended to hospitalizations that lasted ≥ 6 weeks., Conclusions: Data representation of intra-hospital processes of care drawn from hospitals with varied size, teaching and trauma designations is important to presenting a balanced perspective of care delivery mechanisms employed, such as daily oxygen method utilization., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

A detailed understanding of the molecular and immunological changes that occur longitudinally across tumors exposed to immune checkpoint inhibitors is a significant knowledge gap in oncology. To address this unmet need, we created a statewide biospecimen collection and clinical informatics system to enable longitudinal tumor and immune profiling and to enhance translational research. The Texas Immuno-Oncology Biorepository (TIOB) consents patients to collect, process, store, and analyze serial biospecimens of tissue, blood, urine, and stool from a diverse population of over 100,000 cancer patients treated each year across the Baylor Scott & White Health system. Here we sought to demonstrate that these samples were fit for purpose with regard to downstream multi-omic assays. Plasma, urine, peripheral blood mononuclear cells, and stool samples from 11 enrolled patients were collected from various cancer types. RNA isolated from extracellular vesicles derived from plasma and urine was sufficient for transcriptomics. Peripheral blood mononuclear cells demonstrated excellent yield and viability. Ten of 11 stool samples produced RNA quality to enable microbiome characterization. Sample acquisition and processing methods are known to impact sample quality and performance. We demonstrate that consistent acquisition methodology, sample preparation, and sample storage employed by the TIOB can produce high-quality specimens, suited for employment in a wide array of multi-omic platforms, enabling comprehensive immune and molecular profiling., Competing Interests: Dr. Kelly has received institutional research support from Bristol Myers Squibb and Eli Lilly and has served on advisory boards for BMS, Merck, EMD Serono, Astra Zeneca, Daiichi Sankyo, Eisai, Astellas, Ipsen, Novartis, Takeda, Novocure, and Eli Lilly. The other authors have no conflicts to disclose., (Copyright © 2022 Baylor University Medical Center.)

Background: Although frequently used in the early pandemic, data on the effectiveness of COVID-19 convalescent plasma (CCP) remain mixed. We investigated the effectiveness and safety of CCP in hospitalized COVID-19 patients in real-world practices during the first two waves of the pandemic in a multi-hospital healthcare system in Texas., Methods and Findings: Among 11,322 hospitalized patients with confirmed COVID-19 infection from July 1, 2020 to April 15, 2021, we included patients who received CCP and matched them with those who did not receive CCP within ±2 days of the transfusion date across sites within strata of sex, age groups, days and use of dexamethasone from hospital admission to the match date, and oxygen requirements 4-12 hours prior to the match date. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effectiveness outcomes in a propensity score 1:1 matched cohort. Pre-defined safety outcomes were described. We included 1,245 patients each in the CCP treated and untreated groups. Oxygen support was required by 93% of patients at the baseline. The pre-defined primary effectiveness outcome of 28-day in-hospital all-cause mortality (HR = 0.85; 95%CI: 0.66,1.10) were similar between treatment groups. Sensitivity and stratified analyses found similar null results. CCP-treated patients were less likely to be discharged alive (HR = 0.82; 95%CI: 0.74, 0.91), and more likely to receive mechanical ventilation (HR = 1.48; 95%CI: 1.12, 1.96). Safety outcomes were rare and similar between treatment groups., Conclusion: The findings in this large, matched cohort of patients hospitalized with COVID-19 and mostly requiring oxygen support at the time of treatment, do not support a clinical benefit in 28-day in-hospital all-cause mortality for CCP. Future studies should assess the potential benefits with specifically high-titer units in perhaps certain subgroups of patients (e.g. those with early disease or immunocompromised)., Competing Interests: The authors have declared that no conflict of interest exists.

Objectives: Growing evidence supports the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle processes as improving a number of short- and long-term clinical outcomes for patients requiring ICU care. To assess the cost-effectiveness of this intervention, we determined the impact of ABCDE bundle adherence on inpatient and 1-year mortality, quality-adjusted life-years, length of stay, and costs of care., Design: We conducted a 2-year, prospective, cost-effectiveness study in 12 adult ICUs in six hospitals belonging to a large, integrated healthcare delivery system., Setting: Hospitals included a large, urban tertiary referral center and five community hospitals. ICUs included medical/surgical, trauma, neurologic, and cardiac care units., Patients: The study included 2,953 patients, 18 years old or older, with an ICU stay greater than 24 hours, who were on a ventilator for more than 24 hours and less than 14 days., Intervention: ABCDE bundle., Measurements and Main Results: We used propensity score-adjusted regression models to determine the impact of high bundle adherence on inpatient mortality, discharge status, length of stay, and costs. A Markov model was used to estimate the potential effect of improved bundle adherence on healthcare costs and quality-adjusted life-years in the year following ICU admission. We found that patients with high ABCDE bundle adherence (≥ 60%) had significantly decreased odds of inpatient mortality (odds ratio 0.28) and significantly higher costs ($3,920) of inpatient care. The incremental cost-effectiveness ratio of high bundle adherence was $15,077 (95% CI, $13,675-$16,479) per life saved and $1,057 per life-year saved. High bundle adherence was associated with a 0.12 increase in quality-adjusted life-years, a $4,949 increase in 1-year care costs, and an incremental cost-effectiveness ratio of $42,120 per quality-adjusted life-year., Conclusions: The ABCDE bundle appears to be a cost-effective means to reduce in-hospital and 1-year mortality for patients with an ICU stay.

Introduction: Health systems can be supported by collaborative networks focused on data sharing and comparative analytics to identify and rapidly disseminate promising care practices. Standardized data collection, quality assessment, and cleansing is a necessary process to facilitate meaningful analytics for operations, quality improvement, and research. We developed a framework for aligning data from health care delivery systems using the High Value Healthcare Collaborative central registry., Framework: The centralized data registry model allows for multiple layers of data quality assessment. Our framework uses an iterative approach, starting with clear specifications, maintaining ongoing dialogue with diverse stakeholders, and regular checkpoints to assess data conformance, completeness, and plausibility., Lessons Learned: We found that an iterative communication process is critical for a central registry to ensure: 1) clarity of data specifications, 2) appropriate data quality, and 3) thorough understanding of data source, purpose, and context. Engaging teams from all participating institutions and incorporating diverse stakeholders of clinicians, information technologists, data analysts, operations managers, and health services researchers in all decision making processes supports development of high quality datasets for comparative analytics across multiple institutions., Conclusion: A standard data specification and submission process alone does not guarantee aligned data for a collaborative registry. Implementing an iterative data quality improvement framework with extensive communication proved to be effective for aligning data from multiple institutions to support meaningful analytics.

The third paper in a series on how learning health systems can use routinely collected electronic health data (EHD) to advance knowledge and support continuous learning, this review describes how analytical methods for individual-level electronic health data EHD, including regression approaches, interrupted time series (ITS) analyses, instrumental variables, and propensity score methods, can also be used to address the question of whether the intervention "works." The two major potential sources of bias in non-experimental studies of health care interventions are that the treatment groups compared do not have the same probability of treatment or exposure and the potential for confounding by unmeasured covariates. Although very different, the approaches presented in this chapter are all based on assumptions about data, causal relationships, and biases. For instance, regression approaches assume that the relationship between the treatment, outcome, and other variables is properly specified, all of the variables are available for analysis (i.e., no unobserved confounders) and measured without error, and that the error term is independent and identically distributed. The instrumental variables approach requires identifying an instrument that is related to the assignment of treatment but otherwise has no direct on the outcome. Propensity score methods approaches, on the other hand, assume that there are no unobserved confounders. The epidemiological designs discussed also make assumptions, for instance that individuals can serve as their own control. To properly address these assumptions, analysts should conduct sensitivity analyses within the assumptions of each method to assess the potential impact of what cannot be observed. Researchers also should analyze the same data with different analytical approaches that make alternative assumptions, and to apply the same methods to different data sets. Finally, different analytical methods, each subject to different biases, should be used in combination and together with different designs, to limit the potential for bias in the final results.

Learning health systems use routinely collected electronic health data (EHD) to advance knowledge and support continuous learning. Even without randomization, observational studies can play a central role as the nation's health care system embraces comparative effectiveness research and patient-centered outcomes research. However, neither the breadth, timeliness, volume of the available information, nor sophisticated analytics, allow analysts to confidently infer causal relationships from observational data. However, depending on the research question, careful study design and appropriate analytical methods can improve the utility of EHD. The introduction to a series of four papers, this review begins with a discussion of the kind of research questions that EHD can help address, noting how different evidence and assumptions are needed for each. We argue that when the question involves describing the current (and likely future) state of affairs, causal inference is not relevant, so randomized clinical trials (RCTs) are not necessary. When the question is whether an intervention improves outcomes of interest, causal inference is critical, but appropriately designed and analyzed observational studies can yield valid results that better balance internal and external validity than typical RCTs. When the question is one of translation and spread of innovations, a different set of questions comes into play: How and why does the intervention work? How can a model be amended or adapted to work in new settings? In these "delivery system science" settings, causal inference is not the main issue, so a range of quantitative, qualitative, and mixed research designs are needed. We then describe why RCTs are regarded as the gold standard for assessing cause and effect, how alternative approaches relying on observational data can be used to the same end, and how observational studies of EHD can be effective complements to RCTs. We also describe how RCTs can be a model for designing rigorous observational studies, building an evidence base through iterative studies that build upon each other (i.e., confirmation across multiple investigations).

The second paper in a series on how learning health systems can use routinely collected electronic health data (EHD) to advance knowledge and support continuous learning, this review summarizes study design approaches, including choosing appropriate data sources, and methods for design and analysis of natural and quasi-experiments. The primary strength of study design approaches described in this section is that they study the impact of a deliberate intervention in real-world settings, which is critical for external validity. These evaluation designs address estimating the counterfactual - what would have happened if the intervention had not been implemented. At the individual level, epidemiologic designs focus on identifying situations in which bias is minimized. Natural and quasi-experiments focus on situations where the change in assignment breaks the usual links that could lead to confounding, reverse causation, and so forth. And because these observational studies typically use data gathered for patient management or administrative purposes, the possibility of observation bias is minimized. The disadvantages are that one cannot necessarily attribute the effect to the intervention (as opposed to other things that might have changed), and the results do not indicate what about the intervention made a difference. Because they cannot rely on randomization to establish causality, program evaluation methods demand a more careful consideration of the "theory" of the intervention and how it is expected to play out. A logic model describing this theory can help to design appropriate comparisons, account for all influential variables in a model, and help to ensure that evaluation studies focus on the critical intermediate and long-term outcomes as well as possible confounders.

Introduction: This study examined change in tobacco use over 4 years among the general population of patients in six diverse health care organizations using electronic medical record data., Methods: The study cohort (N = 34 393) included all patients age 18 years or older who were identified as smokers in 2007, and who then had at least one primary care visit in each of the following 4 years., Results: In the 4 years following 2007, this patient cohort had a median of 13 primary care visits, and 38.6% of the patients quit smoking at least once. At the end of the fourth follow-up year, 15.4% had stopped smoking for 1 year or more. Smokers were more likely to become long-term quitters if they were 65 or older (OR = 1.32, 95% CI = [1.16, 1.49]), or had a diagnoses of cancer (1.26 [1.12, 1.41]), cardiovascular disease (1.22 [1.09, 1.37]), asthma (1.15 [1.06, 1.25]), or diabetes (1.17 [1.09, 1.27]). Characteristics associated with lower likelihood of becoming a long-term quitter were female gender (0.90 [0.84, 0.95]), black race (0.84 [0.75, 0.94]) and those identified as non-Hispanic (0.50 [0.43, 0.59])., Conclusions: Among smokers who regularly used these care systems, one in seven had achieved long-term cessation after 4 years. This study shows the practicality of using electronic medical records for monitoring patient smoking status over time. Similar methods could be used to assess tobacco use in any health care organization to evaluate the impact of environmental and organizational programs., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The American Association for the Surgery of Trauma (AAST) has developed a new grading system for uniform description of anatomic severity of emergency general surgery (EGS) diseases, ranging from Grade I (mild) to Grade V (severe). The purpose of this study was to determine the relationship of AAST grades for acute colonic diverticulitis with patient outcomes. A secondary purpose was to propose an EGS quality improvement program using risk-adjusted center outcomes, similar to National Surgical Quality Improvement Program and Trauma Quality Improvement Program methodologies., Methods: This was a retrospective study of 1,105 patients (one death) from 13 centers. At each center, two reviewers (blinded to each other's assignments) assigned AAST grades. Interrater reliability was measured using κ coefficient. Relationship between AAST grade and clinical events (complications, intensive care unit use, surgical intervention, and 30-day readmission) as well as length of stay was measured using regression analyses to control for age, comorbidities, and physiologic status at the time of admission. Final model was also used to calculate observed-to-expected (O-E) ratios for adverse outcomes (death, complications, readmissions) for each center., Results: Median age was 54 years, 52% were males, 43% were minorities, and 22% required a surgical intervention. Almost two thirds had Grade I or II disease. There was a high level of agreement for grades between reviewers (κ = 0.81). Adverse events increased from 13% for Grade I, to 18% for Grade II, 28% for Grade III, 44% for Grade IV, and 50% for Grade V. Regression analysis showed that higher disease grades were independently associated with all clinical events and length of stay, after adjusting for age, comorbidities, and physiology. O-E ratios showed statistically insignificant variations in risk of death, complications, or readmissions., Conclusion: AAST grades for acute colonic diverticulitis are independently associated with clinical outcomes and resource use. EGS quality improvement program methodology that incorporates AAST grade, age, comorbidities, and physiologic status may be used for measuring quality of EGS care. High-quality EGS registries are essential for developing meaningful quality metrics., Level of Evidence: Prognostic study, level V.

Objective: The objective of this review is to examine the effectiveness, implementation, and costs of multifaceted care approaches, including care bundles, for the prevention and mitigation of delirium in patients hospitalized in intensive care units (ICUs)., Data Sources: A systematic search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted utilizing PubMed, EMBASE, and CINAHL. Searches were limited to studies published in English from January 1, 1988, to March 31, 2014. Randomized controlled trials and comparative studies of multifaceted care approaches with the reduction of delirium in ICU patients as an outcome and evaluations of the implementation or cost-effectiveness of these interventions were included., Data Extraction: Data on study methods including design, cohort size, interventions, and outcomes were abstracted, reviewed, and summarized. Given the variability in study design, populations, and interventions, a qualitative review of findings was conducted., Data Synthesis: In all, 14 studies met our inclusion criteria: 6 examined outcomes, 5 examined implementation, 2 examined outcomes and implementation, and 1 examined cost-effectiveness. The majority of studies indicated that multifaceted care approaches were associated with improved patient outcomes including reduced incidence and duration of delirium. Additionally, improvements in functional status and reductions in coma and ventilator days, hospital length of stay, and/or mortality rates were observed. Implementation strategies included structured quality improvement approaches with ongoing audit and feedback, multidisciplinary care teams, intensive training, electronic reporting systems, and local support teams. The cost-effectiveness analysis indicated an average reduction of $1000 in hospital costs for patients treated with a multifaceted care approach., Conclusion: Although multifaceted care approaches may reduce delirium and improve patient outcomes, greater improvements may be achieved by deploying a comprehensive bundle of care practices including awakening and breathing trials, delirium monitoring and treatment, and early mobility. Further research to address this knowledge gap is essential to providing best care for ICU patients., (© The Author(s) 2014.)

Background: The American Association for the Surgery of Trauma (AAST) recently developed a grading scale for measuring anatomic severity of emergency general surgery (EGS) diseases. Grades were developed by expert consensus and have not been validated. The study purpose was to measure inter-rater reliability of the grading scale using colonic diverticulitis and to measure the association between disease grade and patient outcomes., Methods: All charts were reviewed and independently assigned AAST grades based on specific disease criteria. Inter-rater reliability was measured using a kappa coefficient. Multivariate regression models were used to determine the relationship between AAST disease grade and patient outcomes adjusted for age, comorbidities, and patient physiology., Results: Over 70% of patients demonstrated mild disease (grades I and II). No deaths were encountered. Inter-rater reliability for grade assignment was moderate (kappa coefficient, 0.43; 95% confidence interval, 0.31-0.56), with 67% concordance in grades. Compared to grade I, complications were similar in grade II but increased significantly with higher grades (grade III odds ratio [OR], 3.13 [1.32-7.41]; grade IV OR, 8.18 [2.09-32.0]; and grade V OR, 10.2 [2.68-38.90]). Compared to grade I, length of stay increased with higher grades (grade II incidence rate ratio [IRR], 1.30 [1.07-1.60]; grade III IRR, 2.4 [1.93-2.98]; grade IV IRR, 3.2 [2.27-4.60]; and grade V IRR, 2.6 [1.82-3.60])., Conclusions: The EGS grading scale for diverticulitis demonstrated moderate inter-rater reliability. Higher grades were independently associated with complications and length of stay. The findings provide a positive validation that the EGS scale is easily used and effective., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: Electronic health records (EHRs) have been promoted as a key driver of improved patient care and outcomes and as an essential component of learning health systems. However, to date, many EHRs are not optimized to support delivery of quality and safety initiatives, particularly in Intensive Care Units (ICUs). Delirium is a common and severe problem for ICU patients that may be prevented or mitigated through the use of evidence-based care processes (daily awakening and breathing trials, formal delirium screening, and early mobility-collectively known as the "ABCDE bundle"). This case study describes how an integrated health care delivery system modified its inpatient EHR to accelerate the implementation and evaluation of ABCDE bundle deployment as a safety and quality initiative., Case Description: In order to facilitate uptake of the ABCDE bundle and measure delivery of the care processes within the bundle, we worked with clinical and technical experts to create structured data fields for documentation of bundle elements and to identify where these fields should be placed within the EHR to streamline staff workflow. We created an "ABCDE" tab in the existing patient viewer that allowed providers to easily identify which components of the bundle the patient had and had not received. We examined the percentage of ABCDE bundle elements captured in these structured data fields over time to track compliance with data entry procedures and to improve documentation of care processes., Major Themes: Modifying the EHR to support ABCDE bundle deployment was a complex and time-consuming process. We found that it was critical to gain buy-in from senior leadership on the importance of the ABCDE bundle to secure information technology (IT) resources, understand the different workflows of members of multidisciplinary care teams, and obtain continuous feedback from staff on the EHR revisions during the development cycle. We also observed that it was essential to provide ongoing training to staff on proper use of the new EHR documentation fields. Lastly, timely reporting on ABCDE bundle performance may be essential to improved practice adoption and documentation of care processes., Conclusion: The creation of learning health systems is contingent on an ability to modify EHRs to meet emerging care delivery and quality improvement needs. Although this study focuses on the prevention and mitigation of delirium in ICUs, our process for identifying key data elements and making modifications to the EHR, as well as the lessons learned from the IT components of this program, are generalizable to other health care settings and conditions.

Context: Collaborative networks support the goals of a learning health system by sharing, aggregating, and analyzing data to facilitate identification of best practices care across delivery organizations. This case study describes the infrastructure and process developed by an integrated health delivery system to successfully prepare and submit a complex data set to a large national collaborative network., Case Description: We submitted four years of data for a diverse population of patients in specific clinical areas: diabetes, chronic heart failure, sepsis, and hip, knee, and spine. The most recent submission included 19 tables, more than 376,000 unique patients, and almost 5 million patient encounters. Data was extracted from multiple clinical and administrative systems., Lessons Learned: We found that a structured process with documentation was key to maintaining communication, timelines, and quality in a large-scale data submission to a national collaborative network. The three key components of this process were the experienced project team, documentation, and communication. We used a formal QA and feedback process to track and review data. Overall, the data submission was resource intensive and required an incremental approach to data quality., Conclusion: Participation in collaborative networks can be time and resource intense, however it can serve as a catalyst to increase the technical data available to the learning health system.

Objective: To examine the association between fitness, BMI, and neutrophil, lymphocyte, monocyte, basophil, and eosinophil concentrations in apparently healthy, non-smoking men., Design: Cross-sectional study of 452 men from the Aerobics Center Longitudinal Study examining the resting concentration of white blood cell subfractions across fitness (maximal METs during a treadmill exercise test) and fatness (BMI) categories after adjusting for age., Results: Fitness was inversely associated with all WBC subfraction concentrations. After further adjustment for BMI, only total WBC, neutrophil, and basophil concentrations remained significantly associated with fitness. BMI was directly associated with total WBC, neutrophil, lymphocyte, monocyte, and basophil concentrations and, when fitness was added to the model, only monocytes lost significance., Conclusion: Fitness (inversely) and fatness (directly) are associated with WBC subfraction populations.

Purpose: Numerous cross-sectional studies have observed an inverse association between C-reactive protein (CRP) and physical activity. Exercise training trials have produced conflicting results, but none of these studies was specifically designed to examine CRP. The objective of the Inflammation and Exercise (INFLAME) study was to examine whether aerobic exercise training without dietary intervention can reduce CRP in individuals with elevated CRP., Methods: The study was a randomized controlled trial of 162 sedentary men and women with elevated CRP (> or = 2.0 mg·L(-1)). Participants were randomized into a nonexercise control group or an exercise group that trained for 4 months. The primary outcome was change in CRP., Results: The study participants had a mean (SD) age of 49.7 (10.9) yr and a mean body mass index of 31.8 (4.0) kg·m(-2). The median (interquartile range (IQR)) and mean baseline CRP levels were 4.1 (2.5-6.1) and 4.8 (3.4) mg·L(-1), respectively. In the exercise group, median exercise compliance was 99.9%. There were no differences in median (IQR) change in CRP between the control and exercise groups (0.0 (-0.5 to 0.9) vs 0.0 (-0.8 to 0.7) mg·L(-1), P = 0.4). The mean (95% confidence interval) change in CRP adjusted for gender and baseline weight was similar in the control and exercise groups, with no significant difference between groups (0.5 (-0.4 to 1.3) vs 0.4 (-0.5 to 1.2) mg·L(-1), P = 0.9). Change in weight was correlated with change in CRP., Conclusions: Exercise training without weight loss is not associated with a reduction in CRP.

Background: Most treatments deemed effective for Helicobacter pylori eradication in developed countries are less effective in developing countries. Regimens containing clarithromycin, metronidazole, and amoxicillin seem efficacious despite antibiotic resistance, and may be a viable option in developing countries., Materials and Methods: We evaluated the efficacy of a 14-day regimen with 500 mg clarithromycin b.i.d., 500 mg metronidazole t.i.d., and 500 mg amoxicillin t.i.d. (with and without a proton pump inhibitor), and a 10-day regimen containing 500 mg clarithromycin b.i.d., 1 g amoxicillin b.i.d., and 20 mg omeprazole b.i.d. in Pasto, Colombia, using a randomized, single-blind design stratified by presence of atrophic gastritis., Results: H. pylori was eradicated in 86.8% and 85.3% of the participants randomized to a clarithromycin-metronidazole-amoxicillin and clarithromycin-amoxicillin-omeprazole regimens, respectively (p = .79). Per-protocol analyses indicated greater efficacy for the clarithromycin-metronidazole-amoxicillin regimen (97%) versus the clarithromycin-amoxicillin-omeprazole regimen (86%) (p = .04), particularly for participants with atrophic gastritis (clarithromycin-metronidazole-amoxicillin = 100%, clarithromycin-amoxicillin-omeprazole = 81%; p = .02). Adverse events were mild, but adverse event-related non-compliance was reported more often for regimens containing clarithromycin, metronidazole, and amoxicillin., Conclusions: Our results suggest that an eradication rate of > 85% can be achieved with 14-day clarithromycin, metronidazole, and amoxicillin and 10-day clarithromycin, amoxicillin, and omeprazole regimens in Pasto, Colombia. The regimens containing clarithromycin, metronidazole, and amoxicillin appear to be superior to the clarithromycin, amoxicillin, and omeprazole regimen for compliant participants and those with atrophic gastritis. Our findings provide treatment options for a population in a developing country with a high prevalence of H. pylori infections and antibiotic resistance.

Purpose: The INFLAME study is designed to determine the effect of exercise training on elevated high-sensitivity C-Reactive Protein (CRP) concentrations in initially sedentary women and men., Methods: INFLAME will recruit 170 healthy, sedentary women and men with elevated CRP (>or=2.0 mg/L) to be randomized to either an exercise group or non-exercise control group. Exercising individuals will participate in four months of supervised aerobic exercise with a total energy expenditure of 16 kcal kg(-1) week(-1) (KKW). Exercise intensity will be 60-80% of maximal oxygen consumption (VO(2) max)., Outcome: The primary outcome will be changed in plasma CRP concentration. Secondary outcomes include visceral adiposity, the cytokines IL-6 and TNF-alpha, and heart rate variability (HRV) in order to examine potential biological mechanisms whereby exercise might affect CRP concentrations., Summary: INFLAME will help us understand the effects of moderate-to-vigorous exercise on CRP concentrations in sedentary individuals. To our knowledge this will be the largest training study specifically designed to examine the effect of exercise on CRP concentrations. This study has the potential to influence therapeutic applications since CRP measurement is becoming an important clinical measurement in Coronary Heart Disease risk assessment. This study will also contribute to the limited body of literature examining the effect of exercise on the variables of visceral adiposity, cytokines, and heart rate variability.

Background & Aims: There is a need for more work examining the potential of physical activity and/or weight control as a preventive and/or therapeutic option in the treatment of fatty liver diseases. The purpose of this study was to examine the association between cardiorespiratory fitness, body mass index (BMI), and waist circumference with markers of nonalcoholic fatty liver disease (NAFLD)., Methods: Participants consisted of 218 apparently healthy nonsmoking, nonalcoholic men aged 33-73 years. Cardiorespiratory fitness was assessed by a maximal treadmill test. Liver and spleen density were measured using a computed tomography scan. We defined the presence of NAFLD as the following 3 conditions being met: (1) liver to spleen density of 1.0 or less, (2) serum alanine transaminase level greater than 30 U/L, and (3) serum aspartate transaminase/alanine transaminase level less than 1.0., Results: Twenty-four (11%) of the participants met the NAFLD definition. There was an inverse association between fitness categories, and a positive association for BMI categories (and waist circumference categories) with the prevalence of NAFLD (P for trend <.001 for all). Fitness and BMI were independent of each other in their associations with the prevalence of NAFLD. The addition of waist circumference to the regression model attenuated the association with prevalence of NAFLD for both fitness (P value changed from <.0001 to .06) and BMI (P value changed from <.001 to .22)., Conclusions: Fitness (inversely) and BMI (directly) were associated with the prevalence of NAFLD. However, these associations were attenuated when abdominal obesity was included in the statistical model.

Objective: Elevated macrophage migration inhibitory factor (MIF) has been implicated as a causal mechanism in a number of disease conditions including cardiovascular disease (CVD), diabetes, and cancer. Excess body fat is associated with an increased risk of numerous health conditions including CVD, diabetes, and cancer. To our knowledge, the association between MIF and obesity status and the effect of weight loss on serum MIF concentrations have not been reported. In this study, we examined the effects of participation in a behavior-based weight loss program on MIF concentrations in obese individuals., Subjects: Study participants were 71 men and women enrolled in The Cooper Institute Weight Management Program. Participants were predominantly female (68%, n=48), middle-aged (46.5+/-9.8 y), and severely obese (BMI=43.0+/-8.6)., Method: Plasma MIF concentrations and other standard risk factors were measured before and after participation in a diet and physical activity based weight management program., Results: The mean follow-up was 8.5+/-3.0 months with an average weight loss of 14.4 kg (P<0.001). The majority of clinical risk factors significantly improved at follow-up. Median levels of plasma MIF concentration were significantly lower at follow-up (median [IQR]; 5.1[3.6-10.3]) compared to baseline (8.4 [4.3-48.8]; P=0.0005). The percentage of participants with plasma MIF concentration > or =19.5 mg/nl (highest tertile at baseline) decreased from 33.8 to 5.6% (P<0.001). Further, elevated baseline plasma MIF concentration was associated with markers of beta-cell dysfunction and reductions in MIF were associated with improvements in beta-cell function., Conclusions: Circulating MIF concentrations are elevated in obese but otherwise healthy individuals; however, this elevation in MIF is not uniform across individuals. In obese individuals with elevated circulating MIF concentrations, participation in physical activity and a dietary-focused weight management program resulted in substantial reduction in MIF.

Objective: To quantify the relation of fitness to mortality among men with diabetes, adjusted for BMI and within levels of BMI., Research Design and Methods: In this observational cohort study, we calculated all-cause death rates in men with diabetes across quartiles of fitness and BMI categories. Study participants were 2,196 men with diabetes (average age 49.3 years, SD 9.5) who underwent a medical examination, including a maximal exercise test, during 1970 to 1995, with mortality follow-up to 31 December 1996., Results: We identified 275 deaths during 32,161 person-years of observation. Risk of all-cause mortality was inversely related to fitness. For example, in the fully adjusted model, the risk of mortality was 4.5 (2.6-7.6), 2.8 (1.6-4.7), and 1.6 (0.93-2.76) for the first, second, and third fitness quartiles, respectively, with the fourth quartile (highest fitness level) as the referent (P for trend <0.0001). There was no significant trend across BMI categories for mortality after adjustment for fitness. Similar results were found when the fitness-mortality relation was examined within levels of body composition. In normal-weight men with diabetes, the relative risks of mortality were 6.6 (2.8-15.0), 3.2 (1.4-7.0), and 2.2 (1.1-4.6) for the first, second, and third quartiles of fitness, respectively, as compared with the fourth quartile (P for trend <0.0001). We found similar results in the overweight and obese weight categories., Conclusions: There was a steep inverse gradient between fitness and mortality in this cohort of men with documented diabetes, and this association was independent of BMI.

Objective: This study examined the association between cardiorespiratory fitness and C-reactive protein (CRP), with adjustment for weight and within weight categories., Methods and Results: We calculated median and adjusted geometric mean CRP levels, percentages of individuals with an elevated CRP (> or =2.00 mg/L), and odds ratios of elevated CRP across 5 levels of cardiorespiratory fitness for 722 men. CRP values were adjusted for age, body mass index, vitamin use, statin medication use, aspirin use, the presence of inflammatory disease, cardiovascular disease, and diabetes, and smoking habit. We found an inverse association of CRP across fitness levels (P for trend<0.001), with the highest adjusted CRP value in the lowest fitness quintile (1.64 [1.27 to 2.11] mg/L) and the lowest adjusted CRP value in the highest fitness quintile (0.70 [0.60 to 0.80] mg/L). Similar results were found for the prevalence of elevated CRP across fitness quintiles. We used logistic regression to model the adjusted odds for elevated CRP and found that compared with the referent first quintile, the second (odds ratio [OR] 0.43, 95% CI 0.22 to 0.85), third (OR 0.33, 95% CI 0.17 to 0.65), fourth (OR 0.23, 95% CI 0.12 to 0.47), and fifth (OR 0.17, 95% CI 0.08 to 0.37) quintiles of fitness had significantly lower odds of elevated CRP. Similar results were found when examining the CRP-fitness relation within categories of body fatness (normal weight, overweight, and obese) and waist girth (<102 or > or =102 cm)., Conclusions: Cardiorespiratory fitness levels were inversely associated with CRP values and the prevalence of elevated CRP values in this sample of men from the Aerobics Center Longitudinal Study.

Murine natural killer (NK) cell activity is both age- and strain-dependent. NK activity does not appear in murine spleen cells until three weeks after birth. Activity peaks at approximately 10 weeks, decreasing thereafter with mice over one year old showing significantly reduced levels. Mice showing low or no NK activity because of age (aged and infant mice, respectively) can be stimulated to show significant levels of NK lysis by i.p. injection of formalin killed Corynebacterium parvum (CP). In addition, CP treatment is also capable of increasing NK activity in mice from the normally low responding AKR strain. The NK activity induced or stimulated by CP appears to be like normal NK reactivity in that it is not decreased by removal of T-cells or adherent cells. Thus, in addition to increasing NK activity in normally responsive mice, CP is capable of augmenting NK activity in mice which normally show low or no levels of NK lysis.

We have examined the reported role of suppressor cells in the regulation of NK activity in mice with naturally low NK activity (infant and aged (C57 X A)F1 hybrids (CAF1) and low responder strain AKR mice). Possible suppressor activity was assayed by mixing, at a 1 : 1 ratio, spleen cells from low activity mice with spleen effector cells from normally active 8 to 10 wk old CAF1 mice. The lytic activity of the mixture was compared with the activity of effector cells diluted with medium alone or diluted 1 : 1 with "non-suppressor" population which served as a control for nonspecific decreases in lysis. The control or "filler" cells employed were suspensions of adult CAF1 thymus, thymus from adult mice exposed to 2,000 R, and adult CAF1 spleen cells cultured for 24 hours, a procedure that depleted NK activity. In no case was the activity observed in the presumed suppressor-effector mixture significantly lower than that observed in the filler-effector cell mixtures. Thus, in infant (1 to 2 wk) and aged (12 to 18 mo) CAF1 mice and in 8 to 10 wk old AKR mice, we found no evidence for specific cell-mediated suppression of natural cytotoxicity.

Because there are conflicting reports regarding the effects of Corynebacterium parvum (CP) on natural killer (NK) cell activity, several different strains of CP were compared. In replicate experiments, age- and sex-matched mice received 0.25-mg i.p. injections of one of four types of CP; formalin-killed strain 6134; heat-killed strain 6134; formalin-killed strain 5888 (actually Corynebacterium granulosum); or formalin-killed CP from the Pasteur Institute. At various days thereafter, two to three mice from each group were sacrificed to determine spleen weight, cellularity, and NK cell activity versus YAC-1 lymphoma cells. The CP from the Pasteur Institute augmented NK cell activity 3 days following injections; however, the activity returned to normal by Day 7 and remained at that level. On the other hand, strain 5888 did not cause as great an increase in lytic activity as did the Pasteur Institute CP at Day 3; but by Day 10 after injection, NK cell levels were above control, and they remained elevated through Day 21. Both the heat-killed and formalin-killed preparations of strain 6134 stimulated NK cell activity initially but resulted in a loss of activity at the later times tested. Experiments done with different doses and routes of injection yielded similar results. Thus, we were able to demonstrate that different types of CP have different effects on NK cell activity in mice and that the general kinetics of these effects were independent of dose or route of administration.