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Diaper dermatitis is a common problem in outpatient pediatric office settings. Although most diaper rashes represent a form of contact dermatitis in response to irritants in the diaper environment, other rashes may be the result of an allergen in the diaper. On the basis of clinical examination results for 5 patients and patch testing results for 2 patients, we suspect that the patients demonstrated allergic contact dermatitis in response to the various blue, pink, and green dyes in diapers. Although topically administered corticosteroids are useful in the treatment regimen, the preferred treatment for allergic contact dermatitis in the diaper area is the use of dye-free diapers for allergen avoidance. Patch testing may also be valuable in identifying the allergen, because allergen avoidance is the key to prevention of recurrent disease. [ABSTRACT FROM AUTHOR]

Purpose: Observational clinicogenomic data sets, consisting of tumor next-generation sequencing (NGS) data linked to clinical records, are commonly used for cancer research. However, in real-world practice, oncologists frequently request NGS in search of treatment options for progressive cancer. The extent and impact of this dynamic on analysis of clinicogenomic research data are not well understood., Methods: We analyzed clinicogenomic data for patients with non-small cell lung, colorectal, breast, prostate, pancreatic, or urothelial cancers in the American Association for Cancer Research Biopharmaceutical Consortium cohort. Associations between baseline and time-varying clinical characteristics and time from diagnosis to NGS were measured. To explore the impact of informative cohort entry on biomarker inference, statistical interactions between selected biomarkers and time to NGS with respect to overall survival were calculated., Results: Among 7,182 patients, time from diagnosis to NGS varied significantly by clinical factors, including cancer type, calendar year of sequencing, institution, and age and stage at diagnosis. NGS rates also varied significantly by dynamic clinical status variables; in an adjusted model, compared with patients with stable disease at any given time after diagnosis, patients with progressive disease by imaging or oncologist assessment had higher NGS rates (hazard ratio for NGS, 1.61 [95% CI, 1.45 to 1.78] and 2.32 [95% CI, 2.01 to 2.67], respectively). Statistical interactions between selected biomarkers and time to NGS with respect to survival, potentially indicating biased biomarker inference results, were explored., Conclusion: To evaluate the appropriateness of a data set for a particular research question, it is crucial to measure associations between dynamic cancer status and the timing of NGS, as well as to evaluate interactions involving biomarkers of interest and NGS timing with respect to survival outcomes.

Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment., Significance: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM., (© 2024 The Authors; Published by the American Association for Cancer Research.)

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer., Significance: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC)., Experimental Design: A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies., Results: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients)., Conclusions: The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes., (©2023 The Authors; Published by the American Association for Cancer Research.)

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data. Interoperability and data quality continue to be major challenges when working with different healthcare datasets. Mapping terminology across datasets, missing and incorrect data, and varying data structures make combining data an onerous and largely manual undertaking. Data privacy is another concern addressed by the Health Insurance Portability and Accountability Act, the Common Rule, and the General Data Protection Regulation. The use of big data is now included in the planning and activities of the FDA and the European Medicines Agency. The willingness of organizations to share data in a precompetitive fashion, agreements on data quality standards, and institution of universal and practical tenets on data privacy will be crucial to fully realizing the potential for big data in medicine., (©2023 The Authors; Published by the American Association for Cancer Research.)

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: To examine the association of prior investment on the effectiveness of organizations delivering large-scale external support to improve primary care., Methods: Mixed-methods study of 7 EvidenceNOW grantees (henceforth, Cooperatives) and their recruited practices (n = 1720). Independent Variable : Cooperatives's experience level prior to EvidenceNOW, defined as a sustained track record in delivering large-scale quality improvement (QI) to primary care practices (high, medium, or low). Dependent Variables: Implementation of external support, measured as facilitation dose; effectiveness at improving (1) clinical quality, measured as practices' performance on Aspirin, Blood Pressure, Cholesterol, and Smoking (ABCS); and (2) practice capacity, measured using the Adaptive Reserve (AR) score and Change Process Capacity Questionnaire (CPCQ). Data were analyzed using multivariable linear regressions and a qualitative inductive approach., Results: Cooperatives with High (vs low) levels of prior experience with and investment in large-scale QI before EvidenceNOW recruited more geographically dispersed and diverse practices, with lower baseline ABCS performance (differences ranging from 2.8% for blood pressure to 41.5% for smoking), delivered more facilitation (mean=+20.3 hours, P = .04 ), and made greater improvements in practices' QI capacity (CPCQ: +2.04, P < .001 ) and smoking performance (+6.43%, P = .003 ). These Cooperatives had established networks of facilitators at the start of EvidenceNOW and leadership experienced in supporting this workforce, which explained their better recruitment, delivery of facilitation, and improvement in outcomes., Discussion: Long-term investment that establishes regionwide organizations with infrastructure and experience to support primary care practices in QI is associated with more consistent delivery of facilitation support, and greater improvement in practice capacity and some clinical outcomes., Competing Interests: Conflict of interest: The authors of this manuscript have no conflicts of interest to report., (© Copyright by the American Board of Family Medicine.)

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally., Significance: AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data. This article is highlighted in the In This Issue feature, p. 2007., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Practice facilitation is an evidence-informed implementation strategy to support quality improvement (QI) and aid practices in aligning with best evidence. Few studies, particularly of this size and scope, identify strategies that contribute to facilitator effectiveness., Methods: We conducted a sequential mixed methods study, analyzing data from EvidenceNOW, a large-scale QI initiative. Seven regional cooperatives employed 162 facilitators to work with 1,630 small or medium-sized primary care practices. Main analyses were based on facilitators who worked with at least 4 practices. Facilitators were defined as more effective if at least 75% of their practices improved on at least 1 outcome measure-aspirin use, blood pressure control, smoking cessation counseling (ABS), or practice change capacity, measured using Change Process Capability Questionnaire-from baseline to follow-up. Facilitators were defined as less effective if less than 50% of their practices improved on these outcomes. Using an immersion crystallization and comparative approach, we analyzed observational and interview data to identify strategies associated with more effective facilitators., Results: Practices working with more effective facilitators had a 3.6% greater change in the mean percentage of patients meeting the composite ABS measure compared with practices working with less effective facilitators ( P <.001). More effective facilitators cultivated motivation by tailoring QI work and addressing resistance, guided practices to think critically, and provided accountability to support change, using these strategies in combination. They were able to describe their work in detail. In contrast, less effective facilitators seldom used these strategies and described their work in general terms. Facilitator background, experience, and work on documentation did not differentiate between more and less effective facilitators., Conclusions: Facilitation strategies that differentiate more and less effective facilitators have implications for enhancing facilitator development and training, and can assist all facilitators to more effectively support practice changes., (© 2022 Annals of Family Medicine, Inc.)

Importance: Real-world data sets that combine clinical and genomic data may be subject to left truncation (when potential study participants are not included because they have already passed the milestone of interest at the time of study recruitment). The lapse between diagnosis and molecular testing can present analytic challenges and threaten the validity and interpretation of survival analyses., Observations: Effects of ignoring left truncation when estimating overall survival are illustrated using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE BPC), and a straightforward risk-set adjustment approach is described. Ignoring left truncation results in overestimation of overall survival: unadjusted median survival estimates from diagnosis among patients with stage IV non-small cell lung cancer or stage IV colorectal cancer were overestimated by more than 1 year., Conclusions and Relevance: Clinicogenomic data are a valuable resource for evaluation of real-world cancer outcomes and should be analyzed using appropriate methods to maximize their potential. Analysts must become adept at application of appropriate statistical methods to ensure valid, meaningful, and generalizable research findings.

Importance: Contemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized., Objective: To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set., Design, Setting, and Participants: A retrospective cohort study was conducted of patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021., Exposures: Candidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression., Main Outcomes and Measures: The primary outcome was the correlation between candidate surrogate end points and OS., Results: There were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46)., Conclusions and Relevance: This cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.

Purpose: We undertook a study to identify conditions and operational changes linked to improvements in smoking and blood pressure (BP) outcomes in primary care., Methods: We purposively sampled and interviewed practice staff (eg, office managers, clinicians) from a subset of 104 practices participating in EvidenceNOW-a multisite cardiovascular disease prevention initiative. We calculated Clinical Quality Measure improvements, with targets of 10-point or greater absolute improvements in the proportion of patients with smoking screening and, if relevant, counseling and in the proportion of hypertensive patients with adequately controlled BP. We analyzed interview data to identify operational changes, transforming these into numeric data. We used Configurational Comparative Methods to assess the joint effects of multiple factors on outcomes., Results: In clinician-owned practices, implementing a workflow to routinely screen, counsel, and connect patients to smoking cessation resources, or implementing a documentation change or a referral to a resource alone led to an improvement of at least 10 points in the smoking outcome with a moderate level of facilitation support. These patterns did not manifest in health- or hospital system-owned practices or in Federally Qualified Health Centers, however. The BP outcome improved by at least 10 points among solo practices after medical assistants were trained to take an accurate BP. Among larger, clinician-owned practices, BP outcomes improved when practices implemented a second BP measurement when the first was elevated, and when staff learned where to document this information in the electronic health record. With 50 hours or more of facilitation, BP outcomes improved among larger and health- and hospital system-owned practices that implemented these operational changes., Conclusions: There was no magic bullet for improving smoking or BP outcomes. Multiple combinations of operational changes led to improvements, but only in specific contexts of practice size and ownership, or dose of external facilitation., (© 2021 Annals of Family Medicine, Inc.)

HIV-related stigma and beliefs about medication necessity and concerns have separately demonstrated significant associations with antiretroviral adherence in people with HIV. However, no work has examined both of these associations in the same model. Based on the necessity-concerns framework, this study examined four alternative models of relationships among HIV-related stigma, medication beliefs, and adherence. Cross-sectional analyses were used to test the four alternative models to best depict associations among HIV-related stigma, medication beliefs, and medication adherence. Models tested included two indirect effects models, an interaction model, and a simple predictors model with no interaction or indirect effects. The outcome variable was HIV medication adherence, and model fit was determined by variance accounted for, Akaike information criterion (AIC), and Bayesian information criterion (BIC) values. An interaction model between internalized stigma and medication concerns accounted for the most variance in adherence. There was also a significant indirect effect of internalized stigma on adherence via medication concerns. Medication concerns are a promising target for interventions focusing on increasing adherence among people with HIV.

AKT inhibitors have promising activity in AKT1 E17K -mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K -mutant ( n = 153) and AKT1 -wild-type ( n = 302) metastatic breast cancer. AKT1 -mutant cases had similar adjusted overall survival (OS) compared with AKT1 -wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1 -mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17K -mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data. See related commentary by Castellanos and Baxi, p. 490 ., (©2020 American Association for Cancer Research.)

Background: Facilitation is an effective approach for helping practices implement sustainable evidence-based practice improvements. Few studies examine the facilitation infrastructure and support needed for large-scale dissemination and implementation initiatives., Methods: The Agency for Health care Research and Quality funded 7 Cooperatives, each of which worked with over 200 primary care practices to rapidly disseminate and implement improvements in cardiovascular preventive care. The intervention target was to improve primary care practice capacity for quality initiative and the ABCS of cardiovascular disease prevention: aspirin in high-risk individuals, blood pressure control, cholesterol management, and smoking cessation. We identified the organizational elements and infrastructures Cooperatives used to support facilitators by reviewing facilitator logs, online diary data, semistructured interviews with facilitators, and fieldnotes from facilitator observations. We analyzed these data using a coding and sorting process., Results: Each Cooperative partnered with 2 to 16 organizations, piecing together 16 to 35 facilitators, often from other quality improvement projects. Quality assurance strategies included establishing initial and ongoing training, processes to support facilitators, and monitoring to assure consistency and quality. Cooperatives developed facilitator toolkits, implemented initiative-specific training, and developed processes for peer-to-peer learning and support., Conclusions: Supporting a large-scale facilitation workforce requires creating an infrastructure, including initial training, and ongoing support and monitoring, often borrowing from other ongoing initiatives. Facilitation that recognizes the need to support the vital integrating functions of primary care might be more efficient and effective than this fragmented approach to quality improvement., Competing Interests: Conflicts of interest: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© Copyright 2020 by the American Board of Family Medicine.)

Primary care practices often engage in quality improvement (QI) in order to stay current and meet quality benchmarks, but the extent to which turnover affects practices' QI ability is not well described. The authors examined qualitative data from practice staff and external facilitators participating in a large-scale QI initiative to understand the relationship between turnover and QI efforts. The examination found turnover can limit practices' ability to engage in QI activities in various ways. When a staff member leaves, remaining staff often absorb additional responsibilities, and QI momentum slows as new staff are trained or existing staff are reengaged. Turnover alters staff dynamics and can create barriers to constructive working relationships and team building. When key practice members leave, they can take with them institutional memory about QI purpose, processes, and long-term vision. Understanding how turnover affects QI may help practices, and those helping them with QI, manage the disruptive effects of turnover.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international data-sharing consortium focused on enabling advances in precision oncology through the gathering and sharing of tumor genetic sequencing data linked with clinical data. The project's history, operational structure, lessons learned, and institutional perspectives on participation in the data-sharing consortium are reviewed. Individuals involved with the inception and execution of AACR Project GENIE from each member institution described their experiences and lessons learned. The consortium was conceived in January 2014 and publicly released its first data set in January 2017, which consisted of 18,804 samples from 18,324 patients contributed by the eight founding institutions. Commitment and contributions from many individuals at AACR and the member institutions were crucial to the consortium's success. These individuals filled leadership, project management, informatics, data curation, contracts, ethics, and security roles. Many lessons were learned during the first 3 years of the consortium, including on how to gather, harmonize, and share data; how to make decisions and foster collaboration; and how to set the stage for continued participation and expansion of the consortium. We hope that the lessons shared here will assist new GENIE members as well as others who embark on the journey of forming a genomic data-sharing consortium.

Viral suppression, a critical component of HIV care, is more likely when individuals initiate antiretroviral therapy (ART) early in disease progression and maintain optimal levels of adherence to ART regimens. Although several studies have documented the negative association of depressive symptoms with ART adherence, less is known about how depressed mood relates to intentional versus unintentional lapses in adherence as well as the mechanisms underlying this association. The purpose of the current study was to examine the association of depressive symptoms with ART adherence, assessed as a multidimensional construct. Secondarily, this study conducted preliminary indirect path models to determine if medication self-efficacy could explain the depressed mood-adherence relationship. Depressive symptoms were not associated with 95% ART taken, self-reported viral load, deliberate adjustments to ART regimens or skipped ART doses. However, the indirect association of depressive symptoms via decrements in medication self-efficacy was significant for 95% ART taken, self-reported viral load and skipped ART doses, but not deliberate changes to ART regimens. In this sample of HIV-positive outpatients, there is evidence to support medication self-efficacy as a potential mechanism underlying the association between depressive symptoms and ART adherence. Additional longitudinal studies are needed to formally examine medication taking self-efficacy as a mediator.

Depressive symptoms are highly prevalent among HIV-positive men who have sex with men (MSM) and may contribute to risky health behaviors. However, research linking depressed mood to condomless sex in HIV-positive MSM has yielded mixed findings and has focused primarily on testing for a linear association. In the current study, we tested both linear and curvilinear models to assess the association of depressive symptoms to condomless anal sex for the most recent sexual episode in a sample of MSM living with HIV (N = 96, M age = 44, 57% Caucasian). Participants completed the Center for Epidemiological Studies-Depression Scale and self-reported on their sexual behaviors. Findings confirmed a curvilinear association of depressive symptoms with condomless anal sex for encounters involving non-primary partner: MSM with moderate levels of depressed mood were more likely to report non-condom use compared to those with low and high levels of depressive symptoms. Future research should test whether treatment for depression can serve to enhance the impact of sexual health promotion interventions for MSM.

The original version of this article unfortunately contained a mistake in Fig. 1. The figure was incorrectly presented with the results of an additional path model for forgotten antiretroviral therapy (ART) doses that was dropped from the primary analyses.

Aim: To evaluate the cost-effectiveness of aripiprazole once-monthly 400/300 mg (AOM 400) in maintenance monotherapy treatment of bipolar I disorder (BP-I)., Methods: A de novo lifetime Markov model was developed for BP-I using available data for AOM 400 and relevant comparators. Base-case analysis considered costs and outcomes from the US payer perspective., Results: The cost per quality-adjusted life year gained with AOM 400 versus comparators ranged from US$2007 versus oral asenapine to dominance (i.e., lower cost with quality-adjusted life gain) versus long-acting injectable risperidone, paliperidone palmitate, oral cariprazine and best supportive care. Patients treated with AOM 400 were estimated to have fewer mood episodes and hospitalizations per patient (5.37) than comparators (6.33, asenapine or cariprazine; 6.54, risperidone long-acting injectable; 7.64, paliperidone palmitate; and 8.93, best supportive care). Sensitivity analyses showed results were robust to parameter uncertainty., Conclusion: AOM 400 may be considered cost effective in the maintenance monotherapy treatment of BP-I in adults.

Aim: To estimate the budget impact (BI) of introducing aripiprazole once-monthly 400 mg/300 mg (AOM 400) in the maintenance monotherapy treatment of bipolar I disorder versus long-acting injectables, oral antipsychotics and best supportive care., Methods: A BI model was developed from a US-payer perspective using treatment-related, hospitalization and adverse event management cost estimates for a hypothetical 1,000,000-member health plan over a 5-year period., Results: Market share of AOM 400 was predicted to increase from 0.6% in Year 1 (current scenario) to 1.3% in Year 5 (predicted scenario), with predicted increases for paliperidone palmitate, asenapine and cariprazine. Treatment-related costs explained the BI increase, while adverse event and hospitalization costs were reduced. The per member per month incremental cost ranged from US$0.06 to US$0.26 in Years 1-5. The largest increases were predicted for paliperidone palmitate., Conclusion: As market shares of atypical antipsychotics are predicted to increase, payers may wish to re-evaluate their use.

Engaging primary care practices in initiatives designed to enhance quality, reduce costs, and promote safety is challenging as practices are already participating in numerous projects and mandated programs designed to improve care delivery and quality. Recruiters must expand their recruitment tools to engage today's practices in quality improvement. Using grant proposals, online diaries, observational site visits, and interviews with key stakeholders, the authors identify successful practice recruitment strategies in the EvidenceNOW initiative, which aimed to recruit approximately 1500 small- to medium-sized primary care practices. Recruiters learned they needed to articulate how participation in EvidenceNOW aligned with other initiatives and could help practices succeed with federal and state initiatives, recognition programs, and existing or future payment requirements. Recruiters, initiative leaders, and funders must now consider how their efforts align with ongoing initiatives to successfully recruit and engage practices, ease practice burden, and encourage participation in efforts that support practice transformation.

Health care extension is an approach to providing external support to primary care practices with the aim of diffusing innovation. EvidenceNOW was launched to rapidly disseminate and implement evidence-based guidelines for cardiovascular preventive care in the primary care setting. Seven regional grantee cooperatives provided the foundational elements of health care extension-technological and quality improvement support, practice capacity building, and linking with community resources-to more than two hundred primary care practices in each region. This article describes how the cooperatives varied in their approaches to extension and provides early empirical evidence that health care extension is a feasible and potentially useful approach for providing quality improvement support to primary care practices. With investment, health care extension may be an effective platform for federal and state quality improvement efforts to create economies of scale and provide practices with more robust and coordinated support services.

The purpose of this study is to assess changes since the launch of the US Surgeon General's campaign in the public's beliefs about the role of genetics in the etiology of cancer, as well as changes in recording family health history. We conducted a survey of 480 Western New York adults, assessing: (1) experiences with cancer, (2) beliefs about cancer and genetics, and (3) practices of recording family health history. Most respondents were aware of the importance of family history. The sample also showed increased knowledge about cancer and genetics compared with a previous survey. However, only 7 % kept written records that included medical conditions, which was not different from a previous survey. Time constraints, apathy, and reluctance to find out negative health information were the most reported barriers. Results suggest a need for continued education of the public, with increased emphasis on written family health records.

This paper provides a review of the quantitative literature on HIV-related stigma and medication adherence, including: (1) synthesis of the empirical evidence linking stigma to adherence, (2) examination of proposed causal mechanisms of the stigma and adherence relationship, and (3) methodological critique and guidance for future research. We reviewed 38 studies reporting either cross-sectional or prospective analyses of the association of HIV-related stigma to medication adherence since the introduction of antiretroviral therapies (ART). Although there is substantial empirical evidence linking stigma to adherence difficulties, few studies provided data on psychosocial mechanisms that may account for this relationship. Proposed mechanisms include: (a) enhanced vulnerability to mental health difficulties, (b) reduction in self-efficacy, and (c) concerns about inadvertent disclosure of HIV status. Future research should strive to assess the multiple domains of stigma, use standardized measures of adherence, and include prospective analyses to test mediating variables.

Background: Active travel to school has been on the decline, despite its beneficial influence on children's current and future well-being. Adults' safety perceptions have been shown to influence children's active travel. Children's perceptions, particularly of safety, may be an important link not only to their present health and travel behaviors, but also their future health and behaviors. This study examined middle school students' perceptions of the built environment and safety., Methods: Overall, 776 students from 3 schools in Hudson County, New Jersey participated in a visual survey and structured, interactive classroom discussions. Emergent themes from the discussions were tested using multivariate statistical models., Results: Findings suggest that older students, boys, and students who self-identified as black, rated built environment scenes as safer. Students also perceived being near adults, traveling in a group, and using crosswalks as significantly safer and want additional recognition of these to further improve safety. Students perceived that being near a school, in daylight, and aesthetics as factors contributing to safety., Conclusions: Schools and municipalities may increase programs for students to travel in groups, prioritize maintenance in school zones, and increase the number of crossing guards, particularly outside the immediate school proximity to further improve safety., (© 2015, American School Health Association.)

This study tested the hypothesis that depressive symptoms would mediate the association of HIV-related stigma to medication adherence. We recruited HIV-infected men who have sex with men (MSM; N = 66; 66 % White, 23 % African-American) from an outpatient infectious disease clinic, and asked them to complete self-report measures. Mediational analyses showed that depressive symptoms fully mediated the association between HIV-related stigma and adherence. That is, stigma-related experiences were positively associated with depressive symptoms and negatively associated with adherence, and, in the final model, depressive symptoms remained a significant correlate of adherence while stigma did not. A test of the indirect effect of stigma on adherence through depressive symptoms was also significant (unstandardized b = -0.19; bootstrap 95 % CI -0.45 to -0.01). These results highlight the importance of treating depressive symptoms in interventions aiming to improve medication adherence among HIV-infected MSM.

The fractal dimension of minimal spanning trees on percolation clusters is estimated for dimensions d up to d=5. A robust analysis technique is developed for correlated data, as seen in such trees. This should be a robust method suitable for analyzing a wide array of randomly generated fractal structures. The trees analyzed using these techniques are built using a combination of Prim's and Kruskal's algorithms for finding minimal spanning trees. This combination reduces memory usage and allows for simulation of larger systems than would otherwise be possible. The path length fractal dimension d&#95;{s} of MSTs on critical percolation clusters is found to be compatible with the predictions of the perturbation expansion developed by T. S. Jackson and N. Read [Phys. Rev. E 81, 021131 (2010)].

Climate change has the potential to compromise the sustainability of natural resources in Mediterranean climatic systems, such that short-term reactive responses will increasingly be insufficient to ensure effective management. There is a simultaneous need for both the clear articulation of the vulnerabilities of specific management systems to climate risk, and the development of appropriate short- and long-term strategic planning responses that anticipate environmental change or allow for sustainable adaptive management in response to trends in resource condition. Governments are developing climate change adaptation policy frameworks, but without the recognition of the importance of responding strategically, regional stakeholders will struggle to manage future climate risk. In a partnership between the South Australian Government, the Adelaide and Mt Lofty Ranges Natural Resource Management Board and the regional community, a range of available research approaches to support regional climate change adaptation decision-making, were applied and critically examined, including: scenario modelling; applied and participatory Geographical Information Systems modelling; environmental risk analysis; and participatory action learning. As managers apply ideas for adaptation within their own biophysical and socio-cultural contexts, there would be both successes and failures, but a learning orientation to societal change will enable improvements over time. A base-line target for regional responses to climate change is the ownership of the issue by stakeholders, which leads to an acceptance that effective actions to adapt are now both possible and vitally important. Beyond such baseline knowledge, the research suggests that there is a range of tools from the social and physical sciences available to guide adaptation decision-making.

Recent evidence suggests that ovarian hormones contribute to altered function of skeletal muscle, however the signaling processes thought to regulate muscle function remain undefined in females. Thus, the purpose of this investigation is to determine if ovarian hormone status is critical for contraction-induced activation of AMPK or MAPK in skeletal muscle. Female mice were divided into two groups, ovariectomy (OVX) and SHAM, which were then subjected to in situ isometric contractile protocols. AMPK, ERK 1/2, p38, and JNK phosphorylation were measured in the control and contracting limb. In the in situ protocol, OVX muscles were significantly more resistant to fatigue compared to the SHAM animals. In addition, the muscles from OVX mice demonstrated significantly lower levels of normalized AMPK phosphorylation at rest. AMPK phosphorylation was not increased in the muscles from SHAM mice after the in situ contractile protocol, while the OVX demonstrated significant increases in AMPK phosphorylation. After contraction, normalized ERK2 phosphorylation was significantly higher in the OVX group compared to the SHAM group. Both p38 and JNK phosphorylation increased in response to contraction; but no group differences were detected. A second set of SHAM and OVX animals were subjected to fatigue stimulated under in vitro conditions. Significant increases in AMPK and ERK2 phosphorylation were detected, but no differences were found between groups. In conclusion, removal of the ovaries results in different responses to contraction-induced changes in phosphorylation of AMPK and ERK2 in female mice and suggests hormones secreted from the ovaries significantly impacts cellular signaling in skeletal muscle.

Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.

Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.

The aim of this study was to determine the antitumor activity of 17-(Allylamino)-17-demethoxyge-ldanamycin (17-AAG), a heat shock protein 90(hsp90) inhibitor in patients with metastatic papillary renal cell carcinoma (RCC) or metastatic clear cell RCC. Eligible patients were divided into 2 cohorts based on histological subtype: papillary or clear cell RCC. All patients had advanced RCC with measurable disease, a Karnofsky performance status of at least 70, and no evidence of brain metastases. Twelve patients with clear cell RCC and 8 patients with papillary RCC were treated with 17-AAG on this phase II trial. 17-AAG was given intravenously at 220 mg/m(2) twice weekly for 2 weeks followed by a week of rest. Cycle length was 21 days. No patient in either cohort achieved a complete or partial response. Toxicities included elevated liver function tests, optic neuritis, dyspnea, fatigue, and gastrointestinal side effects. Six of the 20 patients required dose reduction. At the dose and schedule used in this trial, 17-AAG did not achieve objective response in the treatment of clear cell or papillary renal cell carcinoma patients.

Purpose of Review: The purpose of this review is to present an overview of tattoo practices, complications and treatment options relevant to the pediatric population., Recent Findings: Tattoos are popular among adolescents for a variety of reasons and may be associated with other high-risk behaviors. Research indicates that adolescents may not comprehend potential health risks and complications that are related to tattooing. Case reports of infection, tattoo-associated dermatoses, and allergic reactions to tattoos continue to be reported in the literature. Additional cases of allergic contact dermatitis are being reported with temporary henna tattooing and cosmetic tattoos. As the desire for tattoo removal increases, researchers continue to explore safe, innovative and efficacious methods of tattoo removal., Summary: As the popularity of tattooing continues to rise, so do the potential complications and adverse effects. Treatment options for tattoos are well described and must be individualized to each patient. Lasers continue to be a reliable and efficacious tool in treating amateur, professional, cosmetic and traumatic tattoos.

The physiologic changes of pregnancy and risks to the fetus require attention during dermatologic surgery. Elective surgery should be performed in the second trimester or the postpartum period. Cosmetic work should occur after delivery to avoid hypertrophic or hyperpigmented scars. Skin preparatory agents and anesthetics may have fetal implications and should be chosen with care. Antibiotic selection for any infections must take into account possible maternal and fetal risks. Attention to detail and awareness of the changes in pregnancy should lead to safe surgery in the pregnant patient.

There are many developmental abnormalities that may appear in the neonate and in infants when critical steps in embryogenesis fail. These steps are often not fatal but can lead to significant morbidity for those patients affected. A logical approach is needed in addressing both the diagnostic and therapeutic issues that arise when caring for these patients, as various lesions will warrant an observational approach, and others may require imaging studies or definitive surgical intervention. Additionally, there are other "lumps and bumps" that are seen in the neonatal and infantile age groups that include malignancies and cutaneous neoplasms with associated systemic sequelae.

Background: Pityrosporum folliculitis is a common inflammatory skin disorder that may mimic acne vulgaris. Some adolescents with recalcitrant follicular pustules or papules may have acne and Pityrosporum folliculitis simultaneously. Clinical response is dependent on treating both conditions., Objectives: To demonstrate the similarity in clinical manifestation between acne vulgaris and Pityrosporum folliculitis, the benefit of potassium hydroxide preparation, and the benefit of appropriate antifungal therapy., Patients: We describe 6 female adolescents with concurrent Pityrosporum folliculitis infection and acne vulgaris., Intervention: A potassium hydroxide examination was performed on all 6 patients from the exudate of follicular pustules exhibiting spores consistent with yeast. All patients were treated with oral antifungals, and 5 of the 6 patients were also treated with topical antifungals., Results: Six of 6 patients improved with antifungal treatment. All patients also required some ongoing therapy for their acne., Conclusions: These patients demonstrate that follicular papulopustular inflammation of the face, back, and chest may be due to a combination of acne vulgaris and Pityrosporum folliculitis, a common yet less frequently identified disorder. Symptoms often wax and wane depending on the patient's activities, time of the year, current treatment regimens, and other factors. Pityrosporum folliculitis will often worsen with traditional acne therapy and dramatically respond to antifungal therapy.

Angiogenesis depends on proper collagen biosynthesis and cross-linking, and type I collagen is an ideal angiogenic scaffold, although its mechanism is unknown. We examined angiogenesis using an assay wherein confluent monolayers of human umbilical vein endothelial cells were overlain with collagen in a serum-free defined medium. Small spaces formed in the cell layer by 2 h, and cells formed net-like arrays by 6-8 h and capillary-like lumens by 24 h. Blocking of alpha2beta1, but not alpha1 or alpha(v)beta3 integrin function halted morphogenesis. We found that a triple-helical, homotrimeric peptide mimetic of a putative alpha2beta1 binding site: alpha1(I)496-507 GARGERGFP*GER (where single-letter amino acid nomenclature is used, P* = hydroxyproline) inhibited tube formation, whereas a peptide carrying another putative site: alpha1(I)127-138 GLP*GERGRP*GAP* or control peptides did not. A chemical inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB202190, blocked tube formation, and p38 MAPK activity was increased in collagen-treated cultures, whereas targeting MAPK kinase (MEK), focal adhesion kinase (FAK), or phosphatidylinositol 3-kinase (PI3K) had little effect. Collagen-treated cells had fewer focal adhesions and 3- to 5-fold less activated FAK. Thus capillary morphogenesis requires endothelial alpha2beta1 integrin engagement of a single type I collagen integrin-binding site, possibly signaling via p38 MAPK and focal adhesion disassembly/FAK inactivation.

Perlecan, a ubiquitous basement membrane heparan sulfate proteoglycan, plays key roles in blood vessel growth and structural integrity. We discovered that the C terminus of perlecan potently inhibited four aspects of angiogenesis: endothelial cell migration, collagen-induced endothelial tube morphogenesis, and blood vessel growth in the chorioallantoic membrane and in Matrigel plug assays. The C terminus of perlecan was active at nanomolar concentrations and blocked endothelial cell adhesion to fibronectin and type I collagen, without directly binding to either protein; henceforth we have named it "endorepellin." We also found that endothelial cells possess a significant number of high affinity (K(d) of 11 nm) binding sites for endorepellin and that endorepellin binds endostatin and counteracts its anti-angiogenic effects. Thus, endorepellin represents a novel anti-angiogenic product, which may retard tumor neovascularization and hence tumor growth in vivo.

Background: Tinea pedis and tinea manuum in children are more common than previously recognized. Clinical presentations of dermatophyte infections may vary in children and may be difficult to diagnose., Objective: To show the necessity of potassium hydroxide preparations and/or fungal cultures in assessing suspicious cases of cellulitis in children who may have dermatophyte infections., Patients: We describe 4 children with inflammatory tinea pedis or tinea manuum who were initially misdiagnosed as having bacterial cellulitis., Intervention: A potassium hydroxide examination was performed on 3 patients. Fungal cultures were performed on 2 patients., Results: Inflammatory/bullous dermatophyte infections were detected by potassium hydroxide examination in all 4 patients and all 4 children successfully responded to topical antifungal therapy., Conclusions: These cases demonstrate that inflammatory tinnea pedis/manuum can masquerade as cellulitis in children. Early potassium hydroxide examination can allow appropriate antifungal treatment to be initiated before fungal culture results are finalized.

Type I collagen is the most abundant protein in humans, and it helps to maintain the integrity of many tissues via its interactions with cell surfaces, other extracellular matrix molecules, and growth and differentiation factors. Nearly 50 molecules have been found to interact with type I collagen, and for about half of them, binding sites on this collagen have been elucidated. In addition, over 300 mutations in type I collagen associated with human connective tissue disorders have been described. However, the spatial relationships between the known ligand-binding sites and mutation positions have not been examined. To this end, here we have created a map of type I collagen that includes all of its ligand-binding sites and mutations. The map reveals the existence of several hot spots for ligand interactions on type I collagen and that most of the binding sites locate to its C-terminal half. Moreover, on the collagen fibril some potentially relevant relationships between binding sites were observed including the following: fibronectin- and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may potentially impact upon collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype. These and other observations presented here may provide novel insights into evaluating type I collagen functions and the relationships between its binding partners and mutations.

BAD, the proapoptotic member of the "BH3-only" subfamily of BCL-2 proteins, is inactivated by phosphorylation at serines 112 and 136 and by sequestration in the cytoplasm where it interacts with members of the 14-3-3 family. In BCR/ABL-expressing cells, BAD is constitutively phosphorylated and mainly cytoplasmic, whereas in cells expressing BCR/ABL mutants unable to protect from apoptosis, BAD is nonphosphorylated. We show here that both the wild-type (WT) and the S112A/ S136A double mutant (DM) BAD are more potent inducers of apoptosis in parental than in BCR/ABL-expressing 32D myeloid precursor cells. Stable lines of parental cells expressing DM BAD could not be established and most clones from WT BAD retrovirus-infected parental cells lost BAD expression. On IL-3 withdrawal from parental 32D cells, BAD was rapidly dephosphorylated by the serine-threonine phosphatase 1 alpha, and localized in the mitochondria, whereas it remained phosphorylated and did not localize to the mitochondria in the cohort of BCR/ABL-expressing cells escaping apoptosis induced by WT BAD. Moreover, these cells showed high levels of BCL-2 and BCL-X(L) expression. The cohort of BCR/ABL-expressing cells resistant to apoptosis induced by DM BAD showed only high levels of BCL-2 and BCL-X(L). These findings suggest that BCR/ABL-expressing cells are more versatile than normal hematopoietic progenitors in counteracting the apoptotic potential of BAD, and raise the possibility that tumor cells activate multiple antiapoptotic pathways for survival in the face of death-inducing stimuli. (Blood. 2000;96:676-684)

Cell surface heparan sulfate proteoglycan (HSPG) interactions with type I collagen may be a ubiquitous cell adhesion mechanism. However, the HSPG binding sites on type I collagen are unknown. Previously we mapped heparin binding to the vicinity of the type I collagen N terminus by electron microscopy. The present study has identified type I collagen sequences used for heparin binding and endothelial cell-collagen interactions. Using affinity coelectrophoresis, we found heparin to bind as follows: to type I collagen with high affinity (Kd approximately 150 nM); triple-helical peptides (THPs) including the basic N-terminal sequence alpha1(I)87-92, KGHRGF, with intermediate affinities (Kd approximately 2 microM); and THPs including other collagenous sequences, or single-stranded sequences, negligibly (Kd >> 10 microM). Thus, heparin-type I collagen binding likely relies on an N-terminal basic triple-helical domain represented once within each monomer, and at multiple sites within fibrils. We next defined the features of type I collagen necessary for angiogenesis in a system in which type I collagen and heparin rapidly induce endothelial tube formation in vitro. When peptides, denatured or monomeric type I collagen, or type V collagen was substituted for type I collagen, no tubes formed. However, when peptides and type I collagen were tested together, only the most heparin-avid THPs inhibited tube formation, likely by influencing cell interactions with collagen-heparin complexes. Thus, induction of endothelial tube morphogenesis by type I collagen may depend upon its triple-helical and fibrillar conformations and on the N-terminal heparin-binding site identified here.