Culture That Facilitates Change: A Mixed Methods Study of Hospitals Engaged in Reducing Cesarean Deliveries.

PURPOSE: Large-scale efforts to reduce cesarean deliveries have shown varied levels of impact; yet understanding factors that contribute to hospitals' success are lacking. We aimed to characterize unit culture differences at hospitals that successfully reduced their cesarean rates compared with those that did not. METHODS: A mixed methods study of California hospitals participating in a statewide initiative to reduce cesarean delivery. Participants included nurses, obstetricians, family physicians, midwives, and anesthesiologists practicing at participating hospitals. Hospitals' net change in nulliparous, term, singleton, and vertex cesarean delivery rates classified them as successful if they achieved either a minimum 5 percentage point reduction or rate of fewer than 24%. The Labor Culture Survey was used to quantify differences in unit culture. Key informant interviews were used to explore quantitative findings and characterize additional cultural barriers and facilitators. RESULTS: Out of 55 hospitals, 37 (n = 840 clinicians) meeting inclusion criteria participated in the Labor Culture Survey. Physicians' individual attitudes differed by hospital success on 5 scales: best practices (P = .003), fear (P = .001), cesarean safety (P = .014), physician oversight (P <.001), and microculture (P = .044) scales. Patient ability to make informed decisions showed poor agreement across all hospitals, but was higher at successful hospitals (38% vs 29%, P = .01). Important qualitative themes included: ease of access to shared resources on best practices, fear of bad outcomes, personal resistance to change, collaborative practice and effective communication, leadership engagement, and cultural flexibility. CONCLUSIONS: Successful hospitals' culture and context was measurably different from nonresponders. Leveraging these contextual factors may facilitate success.

Uncovering potential interspecies signaling factors in plant-derived mixed microbial culture.

Microbes use signaling factors for intraspecies and interspecies communications. While many intraspecies signaling factors have been found and characterized, discovery of factors for interspecies communication is lagging behind. To facilitate the discovery of such factors, we explored the potential of a mixed microbial culture (MMC) derived from wheatgrass, in which heterogeneity of this microbial community might elicit signaling factors for interspecies communication. The stability of Wheatgrass MMC in terms of community structure and metabolic output was first characterized by 16S ribosomal RNA amplicon sequencing and liquid chromatography/mass spectrometry (LC/MS), respectively. In addition, detailed MS analyses led to the identification of 12-hydroxystearic acid (12-HSA) as one of the major metabolites produced by Wheatgrass MMC. Stereochemical analysis revealed that Wheatgrass MMC produces mostly the (R)-isomer, although a small amount of the (S)-isomer was also observed. Furthermore, 12-HSA was found to modulate planktonic growth and biofilm formation of various marine bacterial strains. The current study suggests that naturally derived MMCs could serve as a simple and reproducible platform to discover potential signaling factors for interspecies communication. In addition, the study indicates that hydroxylated long-chain fatty acids, such as 12-HSA, may constitute a new class of interspecies signaling factors.

U.S. Internists' Perspectives on Discussing Cost of Care With Patients: Structured Interviews and a Survey.

Background: Rising out-of-pocket costs are creating a need for cost conversations between patients and physicians. Objective: To understand the factors that influence physicians to discuss and consider cost during a patient encounter. Design: Mixed-methods study using semistructured interviews and a survey. Setting: United States. Participants: 20 internal medicine physicians were interviewed; 621 internal medicine physician members of the American College of Physicians completed the survey. Measurements: Interviews were analyzed by using thematic analysis, and surveys were analyzed by using descriptive statistics. Results: From the interviews, 4 themes were identified: Physicians are 1) aware that patients are struggling to afford medical care; 2) relying on clues from patients that hint at their cost sensitivity; 3) relying on experience to anticipate potentially high-cost treatments; and 4) aware that patients are making financial trade-offs to afford their care. Three quarters (n = 466) of survey respondents stated that they consider out-of-pocket costs when making most clinical decisions. For 31% (n = 191) of participants, there were times in the past year that they wanted to discuss out-of-pocket prescription drug costs with patients but did not. The most influential factors for ordering a test are the desire to be as thorough as possible (71% [n = 422]) and insurance coverage for the test (68% [n = 422]). Limitation: Findings are self-reported, the sample is limited to a single specialty, the survey response rate was low, information on the patient population was limited, and the survey instrument is not validated. Conclusion: Physicians are attuned to the burden of health care costs and are willing to consider alternative options based on a patient's cost sensitivity. Primary Funding Source: Robert Wood Johnson Foundation.

Measuring labor and delivery unit culture and clinicians' attitudes toward birth: Revision and validation of the Labor Culture Survey.

BACKGROUND: Cesarean delivery rates in the United States vary widely between hospitals, which cannot be fully explained by hospital or patient factors. Cultural factors are hypothesized to play a role in cesarean overuse, yet tools to measure labor culture are lacking. The aim of this study was to revise and validate a survey tool to measure hospital culture specific to cesarean overuse. METHODS: A panel of clinicians and researchers compiled an item bank from validated surveys, added newly created items, and performed four rounds of iterative revision and consolidation. Obstetricians, family physicians, midwives, anesthesiologists, and labor nurses were recruited from 79 hospitals in California. Exploratory factor analysis was used to reduce the number of survey items and identify latent constructs to form the basis of subscales. Confirmatory factor analysis examined reliability in 31 additional hospitals. Poisson regression assessed associations between hospitals' mean score on each individual item and cesarean rates. RESULTS: A total of 1718 individuals from 70 hospitals were included in the exploratory factor analysis. The final Labor Culture Survey (LCS) consisted of 29 items and six subscales: "Best Practices to Reduce Cesarean Overuse," "Fear of Vaginal Birth," "Unit Microculture," "Physician Oversight," "Maternal Agency," and "Cesarean Safety." CONCLUSIONS: The revised LCS is a valid and reliable tool to measure constructs shown to be associated with cesarean rates. These findings support prior research that has shown that hospital culture is measurable, and that clinician attitudes are predictive of clinician behaviors. Unique to our survey is the construct of labor and delivery unit microculture.

Assessing social values for California's efforts to reduce the overuse of unnecessary medical care.

BACKGROUND: A partnership of large health-care purchasers created a workgroup to reduce the overuse of harmful and wasteful medical care in California. OBJECTIVE: Employ a civic engagement process to identify the social values important to the public in considering different strategies to reduce overuse. INTERVENTION: Use of deliberation techniques for 3 case examples that explore possible strategies: physician oversight, physician compensation, increased patient cost-sharing or taking no definitive action. RESULTS: Five themes were identified, including strong support for physicians' leadership role to reduce overuse; nuanced enthusiasm for increasing patient cost-sharing to discourage excessive demand; and marked disapproval of physician compensation as a motivator. CONCLUSION: Most but not all of the perspectives voiced by participants are congruent with efforts to reduce overuse that is being initiated or discussed at the state, provider and health plan level. As health-care policymakers and leaders consider more targeted approaches to reducing overuse, these findings will inform decision-making.

Characterizing internet health information seeking strategies by socioeconomic status: a mixed methods approach.

BACKGROUND: The Internet is valuable for those with limited access to health care services because of its low cost and wealth of information. Our objectives were to investigate how the Internet is used to obtain health-related information and how individuals with differing socioeconomic resources navigate it when presented with a health decision. METHODS: Study participants were recruited from public settings and social service agencies. Participants listened to one of two clinical scenarios - consistent with influenza or bacterial meningitis - and then conducted an Internet search. Screen-capture video software captured the Internet search. Participant Internet search strategies were analyzed and coded for pre- and post-Internet search guess at diagnosis and information seeking patterns. Individuals who did not have a college degree and were recruited from locations offering social services were categorized as "lower socioeconomic status" (SES); the remainder was categorized as "higher SES." Participants were 78 Internet health information seekers, ranging from 21-35 years of age, who experienced barriers to accessing health care services. RESULTS: Lower-SES individuals were more likely to use an intuitive, rather than deliberative, approach to Internet health information seeking. Lower- and higher-SES participants did not differ in the tendency to make diagnostic guesses based on Internet searches. Lower-SES participants were more likely than their higher-SES counterparts to narrow the scope of their search. CONCLUSIONS: Our findings suggest that individuals with different levels of socioeconomic status vary in the heuristics and search patterns they rely upon to direct their searches. The influence and use of credible information in the process of making a decision is associated with education and prior experiences with healthcare services. Those with limited resources may be disadvantaged when turning to the Internet to make a health decision.

Characterizing the Processes for Navigating Internet Health Information Using Real-Time Observations: A Mixed-Methods Approach.

BACKGROUND: Little is known about the processes people use to find health-related information on the Internet or the individual characteristics that shape selection of information-seeking approaches. OBJECTIVE: Our aim was to describe the processes by which users navigate the Internet for information about a hypothetical acute illness and to identify individual characteristics predictive of their information-seeking strategies. METHODS: Study participants were recruited from public settings and agencies. Interested individuals were screened for eligibility using an online questionnaire. Participants listened to one of two clinical scenarios­consistent with influenza or bacterial meningitis­and then conducted an Internet search. Screen-capture video software captured Internet search mouse clicks and keystrokes. Each step of the search was coded as hypothesis testing (etiology), evidence gathering (symptoms), or action/treatment seeking (behavior). The coded steps were used to form a step-by-step pattern of each participant's information-seeking process. A total of 78 Internet health information seekers ranging from 21-35 years of age and who experienced barriers to accessing health care services participated. RESULTS: We identified 27 unique patterns of information seeking, which were grouped into four overarching classifications based on the number of steps taken during the search, whether a pattern consisted of developing a hypothesis and exploring symptoms before ending the search or searching an action/treatment, and whether a pattern ended with action/treatment seeking. Applying dual-processing theory, we categorized the four overarching pattern classifications as either System 1 (41%, 32/78), unconscious, rapid, automatic, and high capacity processing; or System 2 (59%, 46/78), conscious, slow, and deliberative processing. Using multivariate regression, we found that System 2 processing was associated with higher education and younger age. CONCLUSIONS: We identified and classified two approaches to processing Internet health information. System 2 processing, a methodical approach, most resembles the strategies for information processing that have been found in other studies to be associated with higher-quality decisions. We conclude that the quality of Internet health-information seeking could be improved through consumer education on methodical Internet navigation strategies and the incorporation of decision aids into health information websites.

[Feverphobia: Frecuency and related factors associated] / Fiebrefobia: Frecuencia y factores asociados

Introduction: Fever is common in childhood and there is a high level of concern on behalf of caregivers to manage it, this is called "feverphobia". Objective: The objective was to evaluate the presence of feverphobia and associated factors in the study population. Methods: observational, cross-sectional, prospective, and analytical study during 2021 to 2022 through an ad hoc survey self-administered to parents and/or caregivers of patients under 6 years of age who consulted the emergency room of the Dr. Roberto del Río Children's Hospital in Santiago, Chile. The association between sociodemographic variables, knowledge, attitudes, and fears regarding febrile children was analyzed by Chi square and Fisher's test in addition to univariate logistic regression analysis. Results: A total of 381 surveys were carried out. 98% presented some degree of feverphobia. A fever below 38°C was defined by 40.6%. Physical measures were used by 56% of caregivers. The main sequelae feared were convulsions in 82% and 42.7% reported that it could be lethal. A total of 92.1% used unreliable sources of information and 66% had never received education from health personnel on this subject. Logistic regression showed that being a parent, basic or high school level and a thermal threshold below 38°C were the most associated variables. Conclusions: Feverphobia is a current phenomenon in our population and health education to the parents and caregivers could prevent it.

Introducción: La fiebre es común en la niñez y existe un alto nivel de preocupación por parte de los cuidadores para manejarla, a esto se le denomina "fiebrefobia". Objetivo: El objetivo fue evaluar la presencia de fiebrefobia y factores asociados en la población de estudio. Materiales y método: estudio observacional, transversal, con recolección prospectiva y analítico durante el 2021 a 2022, a través de una encuesta ad hoc auto administrada a los padres y/o cuidadores de pacientes menores de 6 años que consultaron a la emergencia del Hospital de Niños Dr. Roberto del Río en Santiago de Chile. Se analizó la asociación entre las variables sociodemográficas, conocimientos, actitudes y temores frente al niño febril mediante Chi cuadrado, Fisher además de análisis de regresión logística univariante. Resultados: Se realizaron 381 encuestas. El 98% presentó algún grado de fiebrefobia. El 40,6% definió fiebre bajo los 38°C. El 56 % de los cuidadores utilizaba medidas físicas. La principal secuela temida por los tutores fueron las convulsiones (82 %) y un 42,7% refirió que podía ser letal. La mayoría (92%) utilizó fuentes de información no confiables y dos tercios (66%) nunca recibieron información sobre el tema por parte del personal de salud.  La regresión logística evidenció que el hecho de ser progenitor, el nivel de escolaridad básica o media y un umbral térmico menor a 38°C fueron las variables mayormente asociadas a la fiebrefobia. Conclusiones: La fiebrefobia es un fenómeno vigente en nuestra población y la entrega de información adecuada y oportuna pudiese prevenirlo.

Learning Lessons from the COVID-19 Pandemic-A Qualitative Assessment of the Experiences of Pregnant Latinas Infected with COVID-19 and Their Perspectives on Vaccination.

OBJECTIVES: To examine the experiences of pregnant Hispanic/Latine people with COVID-19, as well as their perspectives on COVID-19 vaccination in pregnancy. METHODS: We interviewed birthing parents who received care from a teaching hospital in California and tested positive for COVID-19 during pregnancy or delivery. We analyzed transcripts using the constant comparative method for analyzing data to using a phenomological epidemiological approach. We used root cause analysis to identify consistent themes across interviews and assess relationships between social determinants of health and COVID-19 infectivity. RESULTS: We interviewed 14 women from November 2021 to June 2022. Participants reported COVID-19 adversely impacted their clinical care and well-being during pregnancy or postpartum. Impacts among Spanish-speaking participants included unexpected financial hardships, challenges navigating in-patient experiences, and difficulty securing reliable childcare. While most participants were at least partially vaccinated, participants also described doubts and concerns about the vaccine. CONCLUSIONS: Our findings suggest that Spanish-speaking Hispanic/Latine patients could benefit from receiving more information about COVID-19 in pregnancy from their healthcare providers. Leveraging familial and social networks, providing reliable information in people's preferred language, and increasing communication through trusted partners may also help combat vaccine hesitancy.

Near-miss and maternal sepsis mortality: A qualitative study of survivors and support persons.

BACKGROUND: Prior studies have shown that maternal deaths due to sepsis occur due to delays in recognition, treatment, and escalation of care through medical chart reviews. This study was conducted to obtain the patient perspective for near-miss and maternal mortality cases due to sepsis. OBJECTIVE: To identify quality improvement opportunities for improving maternal sepsis through patient and support person experiences. STUDY DESIGN: Twenty semi-structured interviews and three follow-up focus groups with patients who experienced critical illness from maternal sepsis in the United States and their support persons (when available) were conducted from May 23, 2022, through October 14, 2022. In this qualitative study, data were analyzed using inductive thematic analysis. RESULTS: In this qualitative study of patients with maternal sepsis and their support persons, four main quality improvement themes were identified. The themes were the following: (1) participants reported a lack of awareness of pregnancy-related warning signs and symptoms of when to seek care, (2) many of the presenting symptoms participants experienced were not typical of expected warning signs of maternal sepsis, such as severe pain, overwhelming tiredness, and lack of fever (3) participant concerns were met with dismissal leading to delays in diagnosis, (4) participants experienced long-term sequelae but had difficulty receiving screening and referrals for treatment. CONCLUSIONS: The findings of this study suggest that standardized patient education about the warning signs of maternal sepsis and provider education about the presentation of maternal sepsis, improved listening to patients, and follow-up for sequalae of sepsis are needed.

Assessing aspects of creativity in deaf and hearing high school students.

To address the paucity of current research on the development of creativity in deaf students, and to extend existing research to adolescents, the present study investigated divergent thinking, a method of assessing creativity, in both deaf and hearing adolescents. We assessed divergent thinking in two domains, figural and verbal, while also adjusting the instructional method in written format, sign language, or spoken English. Deaf students' performance was equal to, or more creative than, hearing students on the figural assessment of divergent thinking, but less creative on the verbal assessment. Additional studies should be conducted to determine whether this was an anomalous finding or one that might contribute to hypotheses yielding effective interventions.

Contextual factors influencing parents' assessments of family-centred care in the paediatric emergency department: A qualitative study.

AIM: To identify the contextual factors influencing parents' assessments of the family-centredness of care received during a paediatric emergency department visit. DESIGN: A qualitative cross-sectional case study. METHODS: We interviewed parents who were at their child's bedside during an emergency department encounter. We independently coded the first 3 transcripts and met to discuss the coding structure and to refine existing codes, add new codes and develop tentative categories. We repeated this process for every 3-5 transcripts until thematic saturation was reached. RESULTS: We conducted 16 interviews and identified 2 themes: (1) Not all parents expected physicians to provide family-centred care in the emergency department and (2) feeling overwhelmed and powerless influenced parents' perceptions of family-centred care. Poor family-centred care worsened parents' sense of powerlessness and reinforced parents' low expectations from physicians. Similarly, low expectations and powerlessness exacerbated poor family-centred care. Interventions are needed to break this cycle and improve family-centredness of care.

Identifying the Information Needs and Format Preferences for Web-Based Content Among Adults With or Parents of Children With Attention-Deficit/Hyperactivity Disorder: Three-Stage Qualitative Analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood and adult behavioral disorder. Internet searches for ADHD information are rising, particularly for diagnosis and treatment. Despite effective ADHD treatments, research suggests that there are delays in seeking help for ADHD. Identifying ways to shorten delays is important for minimizing morbidity associated with ADHD. One way to shorten these delays is to improve internet health information resources. Research shows that parents of children with ADHD feel that much of the information available is technical and not tailored for their child's needs and verbal instructions given by health care providers were too pharmacologically focused with limited information about how to manage and support ADHD symptoms in daily living. A majority of parents search the internet for general and pharmacological information for ADHD and prefer web-based resources for learning about ADHD, but web-based resources may be inaccurate and of low quality. Ensuring accurate information through the internet is an important step in assisting parents and adults in making informed decisions about the diagnosis and treatment of ADHD. OBJECTIVE: Although a great deal of information regarding ADHD is available on the internet, some information is not based on scientific evidence or is difficult for stakeholders to understand. Determining gaps in access to accurate ADHD information and stakeholder interest in the type of information desired is important in improving patient engagement with the health care system, but minimal research addresses these needs. This study aims to determine the information needs and formatting needs of web-based content for adults with ADHD and parents of children with ADHD in order to improve user experience and engagement. METHODS: This was a 3-phase study consisting of in-depth phone interviews about experiences with ADHD and barriers searching for ADHD-related information, focus groups where participants were instructed to consider the pathways by which they made decisions using web-based resources, and observing participants interacting with a newly developed website tailored for adults with potential ADHD and caregivers of children who had or might have ADHD. Phase 1 individual interviews and phase 2 focus groups identified the needs of the ADHD stakeholders related to website content and format. Interview and focus group findings were used to develop a website. Phase 3 used think-aloud interviews to evaluate website usability to inform the tailoring of the website based on user feedback. RESULTS: Interviews and focus group findings revealed preferences for ADHD website information and content, website layout, and information sources. Themes included a preference for destigmatizing information about ADHD, information specific to patient demographics, and evidence-based information tailored to lay audiences. CONCLUSIONS: ADHD stakeholders are specifically seeking positive information about ADHD presented in a user-friendly format.

Development and Psychometric Evaluation of a Caregiver Survey to Assess Family-Centered Care in the Emergency Department.

OBJECTIVE: To develop and evaluate the psychometric properties of a family caregiver-reported survey that assesses family-centeredness of care in the context of pediatric emergency department (ED) encounters. METHODS: We created a caregiver-reported scale, incorporated content expert feedback, and iteratively revised it based on cognitive interviews with caregivers. We then field tested the scale in a survey with caregivers. We dichotomized items using top-box scoring and obtained a summary score per respondent. Using a sample of 191 caregivers recruited from 9 EDs, we analyzed internal consistency reliability, dimensionality via item response theory modeling, and convergent validity with the ED Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. RESULTS: Feedback from the 9 experts led us to remove 4 items. We conducted 16 cognitive interviews and revised the survey in 4 rounds. An 11-item survey was field tested. Mean (standard deviation) respondent 11-item summary score was 77.2 (26.6). We removed 2 items given inconsistent response patterns, poor variability, and poor internal consistency, which increased coefficient alpha from 0.85 to 0.88 for the final scale. A multidimensional model fit the data best, but factor scores correlated strongly with summary scores, suggesting the latter are sufficient for quality improvement and future research. Regarding convergent validity, adjusted partial correlation between our scale's 9-item summary score and the ED CAHPS summary score was 0.75 (95% confidence interval 0.67-0.81). CONCLUSIONS: Psychometric analyses demonstrated strong item performance, reliability, and convergent validity for the 9-item scale. This survey can be used to assess family-centered care in the ED for research and quality improvement purposes.

Exploration of the e-patient phenomenon in nursing informatics.

The availability of health information on the Internet has equalized opportunities for knowledge between patients and their health care providers, creating a new phenomenon called the e-patient. E-patients use technology to actively participate in their health care and assume higher levels of responsibility for their own health and wellness. This phenomenon has implications for nursing informatics research related to e-patients and potential collaboration with practitioners in developing a collective wisdom. Nursing informatics can use the data, information, knowledge, and wisdom (DIKW) framework to understand how e-patients and clinicians may achieve this collective wisdom. Nurse informaticists can use constructivism and Gadamerian hermeneutics to bridge each stage of this framework to illustrate the fundamentals of patient and clinician interactions and commonality of language to achieve a collective wisdom. Examining the e-patient phenomenon will help nurse informaticists evaluate, design, develop, and determine the effectiveness of information systems used by e-patients. The Internet can facilitate a partnership between the patient and clinician and cultivate a collective wisdom, enhanced by collaboration between nurse informatics and e-patients.

US county-level prevalence and spatial distribution of optimal birth outcomes 2018-2019.

A shift in focus towards healthy reproductive outcomes may reveal opportunities for novel interventions and strategies to promote optimal health. Using variables from the National Center for Health Statistics restricted use natality files, we calculated Empirical Bayes smoothed (EBS) rates of optimal birth for the all live births-both overall and by maternal race/ethnicity-by applying the smoothing tool in GeoDa version 1.18.0.10 We defined counties achieving greater racial birth equity as those where the overall EBS optimal birth rate was greater than the national 75th percentile and the absolute difference between maternal racial/ethnic categories was smaller than the national 25th percentile difference. During the study period, 49.80% of overall births could be classified as an optimal birth according to the study definition. Of the 3140 US counties, only 282 (8.98%) appeared to advance White-Black equity in optimal births, and 205 (6.53%) appeared to advance White-Hispanic equity in optimal births. In the effort improve maternal health, we should focus not only on the absence of negative outcomes, but also the occurrence of positive outcomes. Our analytic results suggest that optimal births can be measured and that geographic inequities by race occur.

Pathways To Equitable And Antiracist Maternal Mental Health Care: Insights From Black Women Stakeholders.

Structural racism causes significant inequities in the diagnosis of perinatal and maternal mental health disorders and access to perinatal and maternal mental health treatment. Black birthing populations are particularly burdened by disjointed systems of care for mental health. To identify strategies to address racism and inequities in maternal and infant mental health care, we interviewed ten Black women who support Black birthing people, including mental health practitioners, researchers, and activists, in February 2021. The five key pathways to address racism and inequities that we identified from the stakeholder interviews are educating and training practitioners; investing in the Black women mental health workforce; investing in Black women-led community-based organizations; valuing, honoring, and investing in community and traditional healing practices; and promoting integrated care and shared decision making. These pathways highlight critical resources needed to improve the quality of maternal mental health care for Black birthing populations.

The Cycle to Respectful Care: A Qualitative Approach to the Creation of an Actionable Framework to Address Maternal Outcome Disparities.

Despite persistent disparities in maternity care outcomes, there are limited resources to guide clinical practice and clinician behavior to dismantle biased practices and beliefs, structural and institutional racism, and the policies that perpetuate racism. Focus groups and interviews were held in communities in the United States identified as having higher density of Black births. Focus group and interview themes and codes illuminated Black birthing individual's experience with labor and delivery in the hospital setting. Using an iterative process to refine and incorporate qualitative themes, we created a framework in close collaboration with birth equity stakeholders. This is an actionable, cyclical framework for training on anti-racist maternity care. The Cycle to Respectful Care acknowledges the development and perpetuation of biased healthcare delivery, while providing a solution for dismantling healthcare providers' socialization that results in biased and discriminatory care. The Cycle to Respectful Care is an actionable tool to liberate patients, by way of their healthcare providers, from biased practices and beliefs, structural and institutional racism, and the policies that perpetuate racism.

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

INTRODUCTION: MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. METHODS: Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. RESULTS: Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours. CONCLUSIONS: Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00096057.