Cost, Quality, and Utilization After Hospital-Physician and Hospital-Post Acute Care Vertical Integration: A Systematic Review.

Vertical integration of health systems-the common ownership of different aspects of the health care system-continues to occur at increasing rates in the United States. This systematic review synthesizes recent evidence examining the association between two types of vertical integration-hospital-physician (n = 43 studies) and hospital-post-acute care (PAC; n = 10 studies)-and cost, quality, and health services utilization. Hospital-physician integration is associated with higher health care costs, but the effect on quality and health services utilization remains unclear. The effect of hospital-PAC integration on these three outcomes is ambiguous, particularly when focusing on hospital-SNF integration. These findings should raise some concern among policymakers about the trajectory of affordable, high-quality health care in the presence of increasing hospital-physician vertical integration but perhaps not hospital-PAC integration.

Where you live matters: Area deprivation predicts poor survival and liver transplant waitlisting.

Social determinants of health (SDOH) are important predictors of poor clinical outcomes in chronic diseases, but their associations among the general cirrhosis population and liver transplantation (LT) are limited. We conducted a retrospective, multiinstitutional analysis of adult (≥18-years-old) patients with cirrhosis in metropolitan Chicago to determine the associations of poor neighborhood-level SDOH on decompensation complications, mortality, and LT waitlisting. Area deprivation index and covariates extracted from the American Census Survey were aspects of SDOH that were investigated. Among 15 101 patients with cirrhosis, the mean age was 57.2 years; 6414 (42.5%) were women, 6589 (43.6%) were non-Hispanic White, 3652 (24.2%) were non-Hispanic Black, and 2662 (17.6%) were Hispanic. Each quintile increase in area deprivation was associated with poor outcomes in decompensation (sHR [subdistribution hazard ratio] 1.07; 95% CI 1.05-1.10; P < .001), waitlisting (sHR 0.72; 95% CI 0.67-0.76; P < .001), and all-cause mortality (sHR 1.09; 95% CI 1.06-1.12; P < .001). Domains of SDOH associated with a lower likelihood of waitlisting and survival included low income, low education, poor household conditions, and social support (P < .001). Overall, patients with cirrhosis residing in poor neighborhood-level SDOH had higher decompensation, and mortality, and were less likely to be waitlisted for LT. Further exploration of structural barriers toward LT or optimizing health outcomes is warranted.

Making respiratory care safe for neonatal and paediatric intensive care unit staff: mitigation strategies and use of filters.

Background: Many medical devices in pediatric and newborn intensive care units can potentially expose healthcare workers (HCWs) and others to transmission of respiratory and other viruses and bacteria. Such fomites include ventilators, nebulizers, and monitoring equipment. Approach: We report the general, novel approach we have taken to identify and mitigate these risks and to protect HCWs, visitors and patients from exposure while maintaining the optimal performance of such respiratory equipment. Findings: The approach combined a high level of personal protective equipment (PPE), strict hand hygiene, air filtration and air conditioning and other relevant viral risk mitigation guidelines. This report describes the experiences from the SARS-CoV-2 pandemic to provide a reference framework that can be applied generally. The steps we took consisted of auditing our equipment and processes to identify risk through sources of potentially contaminated gas that may contain aerosolized virus, seeking advice and liaising with suppliers/manufacturers, devising mitigation strategies using indirect and direct approaches (largely filtering), performing tests on equipment to verify proper function and the absence of negative impacts and the development and implementation of relevant procedures and practices. We had a multidisciplinary team to guide the process. We monitored daily for hospital-acquired infections among staff caring for SARS-CoV-2 patients. Conclusion: Our approach was successful as we have continued to offer optimal intensive care to our patients, and we did not find any healthcare worker who was infected through the course of caring for patients at the bedside. The lessons learnt will be of benefit to future local outbreaks or pandemics.

Shifting Mindsets: The Impact of a Patient Portal on Functioning and Recovery in a Mental Health Setting.

OBJECTIVE: This study aims to understand whether higher use of a patient portal can have an impact on mental health functioning and recovery. METHOD: A mixed methods approach was used for this study. In 2019-2021, patients with mental health diagnoses at outpatient clinics in an academic centre were invited to complete World Health Organization Disability Assessment Scale 12 (WHODAS-12) and Mental Health Recovery Measure surveys at baseline, 3 months, and 6 months after signing up for the portal. At the 3-month time point, patients were invited to a semistructured interview with a member of the team to contextualize the findings obtained from the surveys. Analytics data was also collected from the platform to understand usage patterns on the portal. RESULTS: Overall, 113 participants were included in the analysis. There was no significant change in mental health functioning and recovery scores over the 6-month period. However, suboptimal usage was observed as 46% of participants did not complete any tasks within the portal. Thirty-five participants had low use of the portal (1-9 interactions) and 18 participants had high usage (10+ interactions). There were also no differences in mental health functioning and recovery scores between low and high users of the portal. Qualitative interviews highlighted many opportunities where the portal can support overall functioning and mental health recovery. CONCLUSIONS: Collectively, this study suggests that higher use of a portal had no impact, either positive or negative, on mental health outcomes. While it may offer convenience and improved patient satisfaction, adequate support is needed to fully enable these opportunities for patient care. As the type of interaction with the portal was not specifically addressed, future work should focus on looking at ways to support patient engagement and portal usage throughout their care journey.

Population-specific Mutation Patterns in Breast Tumors from African American, European American, and Kenyan Patients.

Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer. SIGNIFICANCE: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients.

Chromatin Accessibility Landscape of Human Triple-negative Breast Cancer Cell Lines Reveals Variation by Patient Donor Ancestry.

African American (AA) women have an excessive risk of developing triple-negative breast cancer (TNBC). We employed Assay for Transposase-Accessible Chromatin using sequencing to characterize differences in chromatin accessibility between nine commonly used TNBC cell lines derived from patients of European and African ancestry. Principal component and chromosome mapping analyses of accessibility peaks with the most variance revealed separation of chromatin profiles by patient group. Motif enrichment and footprinting analyses of disparate open chromatin regions revealed differences in transcription factor activity, identifying 79 with ancestry-associated binding patterns (FDR < 0.01). AA TNBC cell lines exhibited increased accessibility for 62 transcription factors associated with epithelial-to-mesenchymal transition, cancer stemness/chemotherapeutic resistance, proliferation, and aberrant p53 regulation, as well as KAISO, which has been previously linked to aggressive tumor characteristics in AA patients with cancer. Differential Assay for Transposase-Accessible Chromatin signal analysis identified 1,596 genes located within promoters of differentially open chromatin regions in AA-derived TNBC, identifying DNA methyltransferase 1 as the top upregulated gene associated with African ancestry. Pathway analyses with these genes revealed enrichment in several pathways, including hypoxia. Culturing cells under hypoxia showed ancestry-specific stress responses that led to the identification of a core set of AA-associated transcription factors, which included members of the Kruppel-like factor and Sp subfamilies, as well as KAISO, and identified ZDHHC1, a gene previously implicated in immunity and STING activation, as the top upregulated AA-specific gene under hypoxia. Together, these data reveal a differential chromatin landscape in TNBC associated with donor ancestry. The open chromatin structure of AA TNBC may contribute to a more lethal disease. SIGNIFICANCE: We identify an ancestry-associated open chromatin landscape and related transcription factors that may contribute to aggressive TNBC in AA women. Furthermore, this study advocates for the inclusion of diversely sourced cell lines in experimental in vitro studies to advance health equity at all levels of scientific research.

Effects of the energy balance transition on bone mass and strength.

Chronic positive energy balance has surged among societies worldwide due to increasing dietary energy intake and decreasing physical activity, a phenomenon called the energy balance transition. Here, we investigate the effects of this transition on bone mass and strength. We focus on the Indigenous peoples of New Mexico in the United States, a rare case of a group for which data can be compared between individuals living before and after the start of the transition. We show that since the transition began, bone strength in the leg has markedly decreased, even though bone mass has apparently increased. Decreased bone strength, coupled with a high prevalence of obesity, has resulted in many people today having weaker bones that must sustain excessively heavy loads, potentially heightening their risk of a bone fracture. These findings may provide insight into more widespread upward trends in bone fragility and fracture risk among societies undergoing the energy balance transition.

For-Profit Businesses as Public Health Partners to Promote COVID-19 Vaccination: A Multiple Case Study.

OBJECTIVE: This study aimed to describe the actions used by health professionals employed by large, for-profit businesses to promote uptake of COVID-19 vaccines, and factors that facilitated and hindered coordination with local public health leaders. METHODS: In this qualitative multiple case study, we conducted telephone interviews with health professionals from businesses, health department leaders, and others who could provide information about local vaccination efforts (e.g., emergency managers, reporters). RESULTS: Businesses' self-interest (i.e., need to keep employees working), vaccine mandates, and characteristics of the businesses (e.g., ownership, expertise) facilitated leadership in COVID-19 vaccination efforts. Coordination with local health departments was influenced by the resources of the local health department and history of collaboration. CONCLUSIONS: Health professionals employed by large businesses can serve as key public health partners, but their role is shaped by characteristics of the businesses and communities.

Racial and Ethnic Differences in the Use of Electronic Medical Record Messaging Among Patients With Breast Cancer: A Quality Improvement Study.

INTRODUCTION: Despite evidence that use of electronic medical record (EMR) messaging positively impacts patients with cancer, there is little research on utilization patterns. The objective of this study is to describe the use of EMR messaging among breast cancer patients so that future interventions may be developed and targeted appropriately. MATERIALS AND METHODS: Sociodemographic and MyChart usage data were collected. Study eligibility included patients who completed a visit at an academic breast center and sent at least one message to a provider during the study period (May 2021-May 2022). Chi-square and t-tests were used to describe differences between users and nonusers of EMR messaging. ANOVA and chi-square were used to describe differences between race/ethnicity. RESULTS: A total of 4069 patients with activated MyChart accounts were included in the analysis. About 3575 (87.9%) were messaging users and 494 (12.1%) were nonusers. The mean age of users was significantly lower compared to the nonusers (57.7 vs 61.2, P< .001). Compared to non-Hispanic White (NHW) individuals, non-Hispanic Black (NHB) (odds ratio [OR]: 0.38, CI [0.21, 0.37]) and Hispanic individuals (OR: 0.35, CI [0.22, 0.57]) were significantly less likely to use electronic messaging. There were statistically significant racial/ethnic differences in the types of messages sent among EMR users. CONCLUSION: Our study shows disparate EMR messaging utilization based on age, race, and primary language. As the availability of patient portals and electronic messaging increase, it is important to understand the barriers that patients face so that they can be addressed.

A budget impact analysis of cost to implement a whole child health focused, family-based intervention in primary care for children with elevated BMI.

BACKGROUND: Although the cost of implementing evidence-based interventions (EBIs) is a key determinant of adoption, lack of cost information is widespread. We previously evaluated the cost of preparing to implement Family Check-Up 4 Health (FCU4Health), an individually tailored, evidence-based parenting program that takes a whole child approach, with effects on both behavioral health and health behavior outcomes, in primary care settings. This study estimates the cost of implementation, including preparation. METHODS: We assessed the cost of FCU4Health across the preparation and implementation phases spanning 32 months and 1 week (October 1, 2016-June 13, 2019) in a type 2 hybrid effectiveness-implementation study. This family-level randomized controlled trial took place in Arizona with n = 113 predominantly low-income, Latino families with children ages > 5.5 to < 13 years. Using electronic cost capture and time-based activity-driven methods, budget impact analysis from the perspective of a future FCU4Health adopting entity-namely, ambulatory pediatric care clinicians-was used to estimate the cost of implementation. Labor costs were based on 2021 Bureau of Labor Statistics Occupational Employment Statistics, NIH-directed salary cap levels or known salaries, plus fringe benefits at a standard rate of 30%. Non-labor costs were based on actual amounts spent from receipts and invoices. RESULTS: The cost of FCU4Health implementation to 113 families was $268,886 ($2380 per family). Actual per family cost varied widely, as individual tailoring resulted in families receiving a range of 1-15 sessions. The estimated cost of replicating implementation for future sites ranged from $37,636-$72,372 ($333-$641 per family). Using our previously reported preparation costs (i.e., $174,489; $1544 per family), with estimated replication costs of $18,524-$21,836 ($164-$193 per family), the total cost of delivering FCU4Health was $443,375 ($3924 per family), with total estimated replication costs of $56,160-$94,208 ($497-$834 per family). CONCLUSIONS: This study provides a baseline for costs associated with implementation of an individually tailored parenting program. Results provide critical information for decision makers and a model for future economic analysis and can be used to inform optimization thresholds for implementation and, when necessary, benchmarks for program adaptation to promote scale-up. TRIAL REGISTRATION: This trial was prospectively registered on January 6, 2017, at ClinicalTrials.gov (NCT03013309).

The impact of social and environmental factors on cancer biology in Black Americans.

Low socioeconomic status (SES) is associated with early onset of chronic diseases and reduced life expectancy. The involvement of neighborhood-level factors in defining cancer risk and outcomes for marginalized communities has been an active area of research for decades. Yet, the biological processes that underlie the impact of SES on chronic health conditions, such as cancer, remain poorly understood. To date, limited studies have shown that chronic life stress is more prevalent in low SES communities and can affect important molecular processes implicated in tumor biology such as DNA methylation, inflammation, and immune response. Further efforts to elucidate how neighborhood-level factors function physiologically to worsen cancer outcomes for disadvantaged communities are underway. This review provides an overview of the current literature on how socioenvironmental factors within neighborhoods contribute to more aggressive tumor biology, specifically in Black U.S. women and men, including the impact of environmental pollutants, neighborhood deprivation, social isolation, structural racism, and discrimination. We also summarize commonly used methods to measure deprivation, discrimination, and structural racism at the neighborhood-level in cancer health disparities research. Finally, we offer recommendations to adopt a multi-faceted intersectional approach to reduce cancer health disparities and develop effective interventions to promote health equity.

Communities with an anchor institution have higher coronavirus vaccination rates.

PURPOSE: Anchor institutions ("anchors") are large employers, rooted in a community by reason of mission, capital, or relationships. Many anchors have encouraged coronavirus vaccination for employees and their families. Our objective was to determine whether the presence of an anchor was associated with a higher county-level vaccination rate. METHODS: A cross-sectional study focused on 745 small- and mid-sized US counties. We used data from the Centers for Disease Control and Prevention, Reference USA's US Business Database, Economic Innovation Group's Distressed Communities Index database, 2021 County Health Ratings and Rankings, 2020 US Presidential Election popular vote data, and National Center for Health Statistics urban-rural classification data. We constructed 3 explanatory variables of interest: a binary variable indicating whether the county had an anchor; a continuous variable representing the number of anchors within a county; and the percent of all workers in the county who were employed by an anchor. Multivariable linear regression models were adjusted for race/ethnicity, political party allegiance, rurality, economic distress, and prevalence of smoking and adult obesity. FINDINGS: Counties with an anchor had vaccination rates 2.31 (P<.01) percentage points higher than those without an anchor. The number of anchors in a county was also significantly associated with higher vaccination rates. CONCLUSIONS: Efforts by anchors to encourage vaccination may have been successful, and that anchors may be well positioned to amplify public health messages. However, the influence and efforts of anchors to increase vaccination did not fully mitigate disparities in vaccination rates by race, ethnicity, and political party allegiance.

Cultural variation in running techniques among non-industrial societies.

Research among non-industrial societies suggests that body kinematics adopted during running vary between groups according to the cultural importance of running. Among groups in which running is common and an important part of cultural identity, runners tend to adopt what exercise scientists and coaches consider to be good technique for avoiding injury and maximising performance. In contrast, among groups in which running is not particularly culturally important, people tend to adopt suboptimal technique. This paper begins by describing key elements of good running technique, including landing with a forefoot or midfoot strike pattern and leg oriented roughly vertically. Next, we review evidence from non-industrial societies that cultural attitudes about running associate with variation in running techniques. Then, we present new data from Tsimane forager-horticulturalists in Bolivia. Our findings suggest that running is neither a common activity among the Tsimane nor is it considered an important part of cultural identity. We also demonstrate that when Tsimane do run, they tend to use suboptimal technique, specifically landing with a rearfoot strike pattern and leg protracted ahead of the knee (called overstriding). Finally, we discuss processes by which culture might influence variation in running techniques among non-industrial societies, including self-optimisation and social learning.

Patient-Reported Outcome Dashboards Within the Electronic Health Record to Support Shared Decision-making: Protocol for Co-design and Clinical Evaluation With Patients With Advanced Cancer and Chronic Kidney Disease.

BACKGROUND: Patient-reported outcomes-symptoms, treatment side effects, and health-related quality of life-are important to consider in chronic illness care. The increasing availability of health IT to collect patient-reported outcomes and integrate results within the electronic health record provides an unprecedented opportunity to support patients' symptom monitoring, shared decision-making, and effective use of the health care system. OBJECTIVE: The objectives of this study are to co-design a dashboard that displays patient-reported outcomes along with other clinical data (eg, laboratory tests, medications, and appointments) within an electronic health record and conduct a longitudinal demonstration trial to evaluate whether the dashboard is associated with improved shared decision-making and disease management outcomes. METHODS: Co-design teams comprising study investigators, patients with advanced cancer or chronic kidney disease, their care partners, and their clinicians will collaborate to develop the dashboard. Investigators will work with clinic staff to implement the co-designed dashboard for clinical testing during a demonstration trial. The primary outcome of the demonstration trial is whether the quality of shared decision-making increases from baseline to the 3-month follow-up. Secondary outcomes include longitudinal changes in satisfaction with care, self-efficacy in managing treatments and symptoms, health-related quality of life, and use of costly and potentially avoidable health care services. Implementation outcomes (ie, fidelity, appropriateness, acceptability, feasibility, reach, adoption, and sustainability) during the co-design process and demonstration trial will also be collected and summarized. RESULTS: The dashboard co-design process was completed in May 2020, and data collection for the demonstration trial is anticipated to be completed by the end of July 2022. The results will be disseminated in at least one manuscript per study objective. CONCLUSIONS: This protocol combines stakeholder engagement, health care coproduction frameworks, and health IT to develop a clinically feasible model of person-centered care delivery. The results will inform our current understanding of how best to integrate patient-reported outcome measures into clinical workflows to improve outcomes and reduce the burden of chronic disease on patients and health care systems. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38461.

Revisiting Short-term Outcomes of Conventional and Computer-Assisted Total Knee Arthroplasty: A Population-based Study.

BACKGROUND: Population-based studies showing the advantage of computer-assisted total knee arthroplasty (CATKA) over conventional total knee arthroplasty (TKA) are outdated. More recent institution-based studies with relatively small sample sizes may hinder wider adoption. This cohort-based study aimed to compare postoperative CATKA and TKA in-hospital complications and 90-day all-cause readmissions using 2017-2018 data. METHODS: Patients who underwent a primary unilateral CATKA or TKA were identified in the New York Statewide Planning and Research Cooperative System database. In-hospital complications were defined based on the 2020 Centers for Medicare & Medicaid Services total hip arthroplasty and TKA complications measure. Ninety-day readmissions were identified using unique patient identifiers. Logistic regression with a generalized estimating equation was used to assess associations of computer assistance with in-hospital complications and 90-day all-cause readmissions. RESULTS: A total of 80,468 TKAs were identified during the study period, of which 7,395 (9.2%) were CATKAs. Significantly fewer complications occurred among patients who had CATKAs compared with conventional TKAs (0.4% of total CATKAs vs 2.6% of total conventional TKAs, P < 0.001); patients who had CATKAs had fewer 90-day all-cause readmissions compared with those who underwent TKAs (363 vs 4,169 revisits, P < 0.01). Computer assistance was associated with significantly lower odds of in-hospital complications (odds ratio, 0.15, 95% confidence interval, 0.09 to 0.24; P < 0.05) but not 90-day all-cause readmissions. CONCLUSION: Patients undergoing CATKAs had markedly lower odds of in-hospital complications, compared with patients having TKAs, which has implications for both patient outcomes and hospital reimbursement. These more recent cohort-based findings encourage wider CATKA adoption.

Platinum Chemotherapy Induces Lymphangiogenesis in Cancerous and Healthy Tissues That Can be Prevented With Adjuvant Anti-VEGFR3 Therapy.

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma, unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We found similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increased cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects.

Advancing Practice-Based Research among Nursing and Health Disciplines Professionals by Creating a Network of Leaders.

Representatives from various practice-based research programs have come together to establish a Canadian Practice-Based Research Network (CP-BRN). CP-BRN is a collective of healthcare leaders focused on identifying approaches and leveraging resources to support clinician-led research to advance evidence-based practice. This paper presents an overview of the development of the CP-BRN, the proceedings from the inaugural meeting of CPBRN members, and recommendations for nursing and allied health profession leaders considering establishing their own practice-based research programs. Next steps for the network are to raise awareness of its mission, expand the network membership as to grow its influence among healthcare leaders and to further advance evidence-based practice across both healthcare and academic institutions.

Designing Patient-Driven, Tissue-Engineered Models of Primary and Metastatic Breast Cancer.

The rising survival rate for early-stage breast cancer in the United States has created an expanding population of women in remission at risk for distant recurrence, with metastatic spread to the brain demonstrating an especially poor prognosis. The current standard of care for breast cancer brain metastases is not well defined or differentiated from the treatment of brain metastases from other primary sites. Here, we present tissue-engineered models of the primary and brain metastatic breast cancer microenvironments informed by analysis of patient tumor resections. We find that metastatic resections demonstrate distinct cellular and matrix components compared with primary resections or non-cancerous controls. Using our model systems, we find that the observed deposition of collagen I after metastasis to the brain may enhance breast cancer invasion. Future optimization of these models will present a novel platform to examine tumor-stroma interactions and screen therapeutics for the management of metastatic breast cancer.

CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of 'STimulator of Interferon Genes' (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP-AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS-STING-TBK1-IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities.

Incorporating Present-on-Admission Indicators in Medicare Claims to Inform Hospital Quality Measure Risk Adjustment Models.

Importance: Present-on-admission (POA) indicators in administrative claims data allow researchers to distinguish between preexisting conditions and those acquired during a hospital stay. The impact of adding POA information to claims-based measures of hospital quality has not yet been investigated to better understand patient underlying risk factors in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision setting. Objective: To assess POA indicator use on Medicare claims and to assess the hospital- and patient-level outcomes associated with incorporating POA indicators in identifying risk factors for publicly reported outcome measures used by the Centers for Medicare & Medicaid Services (CMS). Design, Setting, and Participants: This comparative effectiveness study used national CMS claims data between July 1, 2015, and June 30, 2018. Six hospital quality measures assessing readmission and mortality outcomes were modified to include POA indicators in risk adjustment models. The models using POA were then compared with models using the existing complications-of-care algorithm to evaluate changes in risk model performance. Patient claims data were included for all Medicare fee-for-service and Veterans Administration beneficiaries aged 65 years or older with inpatient hospitalizations for acute myocardial infarction, heart failure, or pneumonia within the measurement period. Data were analyzed between September 2019 and March 2020. Main Outcomes and Measures: Changes in patient-level (C statistics) and hospital-level (quintile shifts in risk-standardized outcome rates) model performance after including POA indicators in risk adjustment. Results: Data from a total of 6 027 988 index admissions were included for analysis, ranging from 491 366 admissions (269 209 [54.8%] men; mean [SD] age, 78.2 [8.3] years) for the acute myocardial infarction mortality outcome measure to 1 395 870 admissions (677 158 [48.5%] men; mean [SD] age, 80.3 [8.7] years) for the pneumonia readmission measure. Use of POA indicators was associated with improvements in risk adjustment model performance, particularly for mortality measures (eg, the C statistic increased from 0.728 [95% CI, 0.726-0.730] to 0.774 [95% CI, 0.773-0.776] when incorporating POA indicators into the acute myocardial infarction mortality measure). Conclusions and Relevance: The findings of this quality improvement study suggest that leveraging POA indicators in the risk adjustment methodology for hospital quality outcome measures may help to more fully capture patients' risk factors and improve overall model performance. Incorporating POA indicators does not require extra effort on the part of hospitals and would be easy to implement in publicly reported quality outcome measures.