Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.

Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant-specific therapeutic vulnerability in both premalignant CH and myeloid malignancy. SIGNIFICANCE: Mutant ASXL1 is a common driver of CH and myeloid malignancy. Using primary human HSPCs, we determine that truncated ASXL1 leads to redistribution of H2AK119Ub and may affect therapeutic vulnerability to PRC1 inhibition.

Preoperative risk factors and postoperative complications associated with mortality after outpatient surgery in a broad surgical population: an analysis of 2.8 million ACS-NSQIP patients.

BACKGROUND: Thirty-day mortality after outpatient surgery is unexpected and undesired. We investigated preoperative risk factors, operative variables, and postoperative complications associated with 30-day death after outpatient surgery. METHODS: Using the 2005 to 2018 American College of Surgeons National Surgical Quality Improvement Program database, we evaluated 30-day mortality rate trends over time after outpatient operations. We analyzed associations between 37 preoperative variables, operation time, hospital length of stay, and 9 postoperative complications with mortality rate using χ2 analyses for categorical data and tests for continuous data. We used forward selection logistic regression models to determine the best predictors of mortality preoperatively and postoperatively. We also separately analyzed mortality by age group. RESULTS: A total of 2,822,789 patients were included. The 30-day mortality rate did not change significantly over time (P = .34, Cochran-Armitage trend test), remaining steady at around 0.06%. The most significant preoperative predictors of mortality included the patient having disseminated cancer, decreased functional health status, increased American Society of Anesthesiology Physical Status classification, increased age, and ascites, accounting for 95.8% (0.837/0.874) of the full model c-index. The most significant postoperative complications associated with increased risk of mortality included having cardiac (26.95% yes vs 0.04% no), pulmonary (10.25% vs 0.04%), stroke (9.22% vs 0.06%), and renal (9.33% vs 0.06%) complications. Postoperative complications conferred a greater risk for mortality than preoperative variables. Mortality risk increased incrementally with age, particularly past age 80. CONCLUSION: The operative mortality rate after outpatient surgery has not changed over time. Patients over 80 years with disseminated cancer, decreased functional health status, or increased ASA class should generally be considered for inpatient surgery. However, there might be some circumstances where outpatient surgery could be considered.

Training the Workforce to Conduct Embedded Pragmatic Clinical Trials to Improve Care for People Living with Dementia and Their Caregivers.

The National Institute on Aging IMbedded Pragmatic Alzheimer's Disease and Alzheimer's Disease-Related Dementias Clinical Trials (IMPACT) Collaboratory serves as a national resource for the conduct of embedded pragmatic clinical trials to improve the care of people living with dementia (PLWD) in partnership with the healthcare systems that serve them. Inherent in this objective is the need to train and support a cadre of investigators prepared to conduct this work now and in the future. The Training Core of the IMPACT Collaboratory supports the training of investigators to become experts in this field through three objectives: (1) curricula development and dissemination; (2) network generation and navigation; and (3) a career development award program. The innovative approach of the Training Core will require developing content and providing training experiences that recognize the unique challenges of research at the intersection of health systems, pragmatic trials, and PLWD and their caregivers. Ultimately, we seek to build the nation's capacity to conduct research that bridges the gaps between efficacy studies to effectiveness research to implementation science. Although foundational resources in the methods of each of these areas are already available, few actually focus on pragmatic trials embedded within healthcare systems that focus on PLWD. To bring new interventions for PLWD from efficacy to widespread implementation, researchers must build diffusability, adaptability, heterogeneity, and scalability into the design of the intervention. In achieving these objectives, the Training Core will utilize the network of investigators, institutions, and stakeholders represented in the IMPACT Collaboratory. J Am Geriatr Soc 68:S21-S27, 2020.

Photocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary Amines.

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.

Care coordinator assistants: Job satisfaction and the importance of teamwork in delivering person-centered dementia care.

As the prevalence of persons with dementia increases, a larger, trained, and skilled healthcare workforce is needed. Attention has been given to models of person-centered care as a standard for dementia care. One promising role to deliver person-centered care is the care coordinator assistant. An inquiry about care coordinator assistant's job satisfaction is reasonable to consider for retention and quality improvement purposes. We evaluated care coordinator assistants' job satisfaction quantitatively and qualitatively. This study was part of a Centers for Medicare & Medicaid Services Health Care Innovation Award to the Indiana University School of Medicine. Sixteen care coordinator assistants, predominately female, African American or Caucasian, college graduates with a mean age of 43.1 years participated. Care coordinator assistants wrote quarterly case reports to share stories, lessons learned, and/or the impact of their job and completed the revised Job Satisfaction Inventory and Job in General scales during the second year of the Centers for Medicare & Medicaid Services award. For the Job Descriptive Index subscales promotion, supervision, and coworkers and Job in General, care coordinator assistants scored similar to normative means. Care coordinator assistants reported significantly higher satisfaction on the work subscale and significantly lower satisfaction on the pay subscale compared to normative data. Care coordinator assistants completed 119 quarterly case reports. Job satisfaction and teamwork were recurring themes in case reports, referenced in 47.1% and 60.5% of case reports, respectively. To address the demands of increasing dementia diagnoses, care coordinator assistants can constitute a compassionate, competent, and satisfied workforce. Training care coordinator assistants to work together in a team to address the needs of persons with dementia and caregivers provides a viable model of workforce development necessary to meet the growing demands of this population.

An Alternative Payment Model To Support Widespread Use Of Collaborative Dementia Care Models.

The current US system of reimbursement for dementia care does not support the complex biospychosocial needs of families living with Alzheimer disease and related dementias. We propose an alternative payment system for dementia care that would provide insurance coverage for evidence-based, collaborative dementia care models. This payment model involves a per member per month payment for care management services that would target community-dwelling beneficiaries living with dementia and evidence-based education and support programs for unpaid caregivers. This payment model has the potential to align the incentives of payers and providers and create market demand for the implementation of collaborative dementia care models across the nation.

Agile Implementation: A Blueprint for Implementing Evidence-Based Healthcare Solutions.

OBJECTIVES: To describe the essential components of an Agile Implementation (AI) process, which rapidly and effectively implements evidence-based healthcare solutions, and present a case study demonstrating its utility. DESIGN: Case demonstration study. SETTING: Integrated, safety net healthcare delivery system in Indianapolis. PARTICIPANTS: Interdisciplinary team of clinicians and administrators. MEASUREMENTS: Reduction in dementia symptoms and caregiver burden; inpatient and outpatient care expenditures. RESULTS: Implementation scientists were able to implement a collaborative care model for dementia care and sustain it for more than 9 years. The model was implemented and sustained by using the elements of the AI process: proactive surveillance and confirmation of clinical opportunities, selection of the right evidence-based healthcare solution, localization (i.e., tailoring to the local environment) of the selected solution, development of an evaluation plan and performance feedback loop, development of a minimally standardized operation manual, and updating such manual annually. CONCLUSION: The AI process provides an effective model to implement and sustain evidence-based healthcare solutions.

Human factors in mental healthcare: A work system analysis of a community-based program for older adults with depression and dementia.

Mental healthcare is a critical but largely unexplored application domain for human factors/ergonomics. This paper reports on a work system evaluation of a home-based dementia and depression care program for older adults, the Aging Brain Care program. The Workflow Elements Model was used to guide data collection and analysis of 59 h of observation, supplemented by key informant input. We identified four actors, 37 artifacts across seven types, ten action categories, and ten outcomes including improved health and safety. Five themes emerged regarding barriers and facilitators to care delivery in the program: the centrality of relationship building; the use of adaptive workarounds; performance of duplicate work; travel and scheduling challenges; and communication-related factors. Findings offer new insight into how mental healthcare services are delivered in a community-based program and key work-related factors shaping program outcomes.

Dementia care management in primary care : Current collaborative care models and the case for interprofessional education.

BACKGROUND: Dementia is one of the most prevalent diseases in the older population. Various dementia care models have been developed to address patient's healthcare needs. They can be described as "collaborative care" or "person-centered care". Referring to the needs of the workforce working with persons with dementia, a key element is the use of interprofessional education (IPE). OBJECTIVE: The purpose of this article is to describe different international collaborative care models to define a minimum standard of healthcare professions for collaborative dementia care in primary care. This helps to identify requirements for IPE to optimize care of people with dementia and to support informal caregivers in the future. MATERIAL AND METHODS: In this article six dementia care models from 4 different countries (Germany, USA, UK and Netherlands) are described and compared regarding aims, interventions and healthcare professionals involved. RESULTS: Care teams are minimally comprised of general practitioners or primary care providers, nurses, and social workers. Additional healthcare disciplines may be involved for specific interventions. Mostly, care team members received specific training but such training did not necessarily incorporate the IPE approach. To ensure successful collaboration of professions, IPE training programs should at least consist of the following core topics: (1) early diagnosis, (2) postdiagnostic support, (3) advanced care planning for patients and caregivers and (4) effective collaborative care. CONCLUSION: The IPE programs for dementia should be expanded and must be widely implemented in order to assess the impact on collaborative practice. This study will provide the knowledge base for structuring IPE trainings developing educational agendas and adapting existing guidelines to improve collaborative dementia care in the future.

Redesigning acute care for cognitively impaired older adults: Optimizing health care services.

PURPOSE OF THE STUDY: Cognitive impairment (CI) is one of several factors known to influence hospitalization, hospital length of stay, and rehospitalization among older adults. Redesigning care delivery systems sensitive to the influence of CI may reduce acute care utilization while improving care quality. To develop a foundation of fundamental needs for health care redesign, we conducted focus groups with inpatient and outpatient providers to identify barriers, facilitators, and suggestions for improvements in care delivery for patients with CI. DESIGN AND METHODS: Focus group sessions were conducted with providers to identify their approach to caring for cognitively impaired hospitalized adults; obstacles and facilitators to providing this care; and suggestions for improving the care process. Using a thematic analysis, two reviewers analyzed these transcripts to develop codes and themes. RESULTS: Seven themes emerged from the focus group transcripts. These were: (1) reflections on serving the cognitively impaired population; (2) descriptions of perceived barriers to care; (3) strategies that improve or facilitate caring for hospitalized older adults; (4) the importance of fostering a hospital friendly to the needs of older adults; (5) the need for educating staff, patients, and caregivers; (6) the central role of good communication; and (7) steps needed to provide more effective care. IMPLICATIONS: Providing effective acute care services to older adults with CI is an important challenge in health care reform. An understanding derived from the perspective of multiple professional disciplines is an important first step. Future research will build on this preliminary study in developing new acute care models for patients with CI.

Workforce development to provide person-centered care.

OBJECTIVES: Describe the development of a competent workforce committed to providing patient-centered care to persons with dementia and/or depression and their caregivers; to report on qualitative analyses of our workforce's case reports about their experiences; and to present lessons learned about developing and implementing a collaborative care community-based model using our new workforce that we call care coordinator assistants (CCAs). METHOD: Sixteen CCAs were recruited and trained in person-centered care, use of mobile office, electronic medical record system, community resources, and team member support. CCAs wrote case reports quarterly that were analyzed for patient-centered care themes. RESULTS: Qualitative analysis of 73 cases using NVivo software identified six patient-centered care themes: (1) patient familiarity/understanding; (2) patient interest/engagement encouraged; (3) flexibility and continuity of care; (4) caregiver support/engagement; (5) effective utilization/integration of training; and (6) teamwork. Most frequently reported themes were patient familiarity - 91.8% of case reports included reference to patient familiarity, 67.1% included references to teamwork and 61.6% of case reports included the theme flexibility/continuity of care. CCAs made a mean number of 15.7 (SD = 15.6) visits, with most visits for coordination of care services, followed by home visits and phone visits to over 1200 patients in 12 months. DISCUSSION: Person-centered care can be effectively implemented by well-trained CCAs in the community.

The Aging Brain Care Medical Home: Preliminary Data.

The Aging Brain Care (ABC) Medical Home aims to improve the care, health outcomes, and medical costs of Medicare beneficiaries with dementia or depression across central Indiana. This population health management program, funded by the Centers for Medicare and Medicaid Services Innovation Center, expanded an existing collaborative dementia and depression care program to serve 1,650 older adults in a local safety-net hospital system. During the first year, 20 full-time clinical staff were hired, trained, and deployed to deliver a collaborative care intervention. In the first 18 months, an average of 13 visits was provided per person. Thirty percent of the sample had a diagnosis of dementia, and 77% had a diagnosis of depression. Sixty-six percent of participants with high depression scores (Patient Health Questionnaire-9 score ≥14) had at least a 50% reduction in their depressive symptoms. Fifty-one percent of caregivers of individuals with dementia had at least a 50% reduction in caregiver stress symptoms (measured by the Healthy Aging Brain Care Monitor-Caregiver Version). After 18 months, the ABC Medical Home has demonstrated progress toward improving the health of older adults with dementia and depression. Scalable and practical models like this show initial promise for answering the challenges posed by the nation's rapidly aging population.

New workforce development in dementia care: screening for "caring": preliminary data.

The United States has a significant shortage of trained geriatricians and of nurses, social workers, and paraprofessionals educated to care for elderly adults. As the aging population continues to grow, providing high-quality care will require new models that better address the many needs of aging individuals and their caregivers, using cost-effective strategies. Responding to this need, the Indiana University Center for Aging Research implementation scientists developed, tested, and are now scaling up a successful collaborative care coordination model for older adults with dementia, depression, or both: the Aging Brain Care program. This model now includes a newly created frontline care provider position, the Care Coordinator Assistant. The Care Coordinator Assistant works with individuals and caregivers to monitor biopsychosocial needs and deliver evidence-based and individualized care protocols, with close supervision from the registered nurse Care Coordinator. Recognizing that current hiring practices for frontline providers were insufficient to screen for critical abilities expected in this new position, including the ability to express "caring" and empathy, a new screening process was created building on the Multiple Mini Interview (MMI) format. The Care Coordinator Assistant MMI comprised six stations, each created to simulate challenging scenarios that will be frequently encountered and to assess important candidate abilities. Overall, the six-station MMI, with two to three items per station, provided factorially valid measures and good predictive ability. The process did not appear to be overly burdensome for candidates, and interviewers noted that it was helpful in discriminating between candidates.

Healthy Aging Brain Center improved care coordination and produced net savings.

Over the past two decades the collaborative care model within primary care has proved to be effective in improving care quality, efficiency, and outcomes for older adults suffering from dementia and depression. In collaboration with community partners, scientists from Indiana University have implemented this model at the Healthy Aging Brain Center (HABC), a memory care clinic that is part of Eskenazi Health, an integrated safety-net health care system in Indianapolis, Indiana. The HABC generates an annual net cost savings of up to $2,856 per patient, which adds up to millions of dollars for Eskenazi Health's patients. This article demonstrates the financial sustainability of the care processes implemented in the HABC, as well as the possibility that payers and providers could share savings from the use of the HABC model. If it were implemented nationwide, annual cost savings could be in the billions of dollars.

The Healthy Aging Brain Care (HABC) Monitor: validation of the Patient Self-Report Version of the clinical tool designed to measure and monitor cognitive, functional, and psychological health.

BACKGROUND: Primary care providers need an inexpensive, simple, user-friendly, easily standardized, sensitive to change, and widely available multidomain instrument to measure the cognitive, functional, and psychological symptoms of patients suffering from multiple chronic conditions. We previously validated the Caregiver Report Version of the Healthy Aging Brain Care Monitor (HABC Monitor) for measuring and monitoring the severity of symptoms through caregiver reports. The purpose of this study was to assess the reliability and validity of the Patient Self-Report Version of the HABC Monitor (Self-Report HABC Monitor). DESIGN: Cross-sectional study. SETTING: Primary care clinics affiliated with a safety net urban health care system in Indianapolis, Indiana, USA. SUBJECTS: A total of 291 subjects aged ≥65 years with a mean age of 72.7 (standard deviation 6.2) years, 76% female, and 56% African Americans. ANALYSIS: Psychometric validity and reliability of the Self-Report HABC Monitor. RESULTS: Among 291 patients analyzed, the Self-Report HABC Monitor demonstrated excellent fit for the confirmatory factor analysis model (root mean square error of approximation =0.030, comparative fit index =0.974, weighted root mean square residual =0.837) and good internal consistency (0.78-0.92). Adequate convergent-divergent validity (differences between the Telephone Interview for Cognitive Status test-based cognitive function impairment versus nonimpairment groups) was demonstrated only when patients were removed from analysis if they had both cognitive function test impairment and suspiciously perfect self-report HABC Monitor cognitive floor scores of 0. CONCLUSION: The Self-Report HABC Monitor demonstrates good reliability and validity as a clinically practical multidimensional tool for measuring symptoms. The tool can be used along with its caregiver version to provide useful feedback (via monitoring of symptoms) for modifying care plans. Determining the validity of HABC Monitor scores from patients who self-report a perfect cognitive score of 0 requires cognitive function test results (eg, Telephone Interview for Cognitive Status or Mini Mental State Examination) or Caregiver Report HABC Monitor scores or further clinical examination to rule out the possibility that the patient is denying or unaware of their cognitive symptoms.

Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.

Practical clinical tool to monitor dementia symptoms: the HABC-Monitor.

BACKGROUND: Dementia care providers need a clinical assessment tool similar to the blood pressure cuff (sphygmomanometer) used by clinicians and patients for managing hypertension. A "blood pressure cuff " for dementia would be an inexpensive, simple, user-friendly, easily standardized, sensitive to change, and widely available multidomain instrument for providers and informal caregivers to measure severity of dementia symptoms. The purpose of this study was to assess the reliability and validity of the Healthy Aging Brain Care Monitor (HABC-Monitor) for measuring and monitoring the severity of dementia symptoms through caregiver reports. METHODS: The first prototype of the HABC-Monitor was developed in collaboration with the Indianapolis Discovery Network for Dementia, which includes 200 members representing 20 disciplines from 20 local organizations, and an expert panel of 22 experts in dementia care and research. The HABC-Monitor has three patient symptom domains (cognitive, functional, behavioral/psychological) and a caregiver quality of life domain. Patients (n = 171) and their informal caregivers (n = 171) were consecutively approached and consented during, or by phone shortly following, a patient's routine visit to their memory care provider. RESULTS: The HABC-Monitor demonstrated good internal consistency (0.73-0.92); construct validity indicated by correlations with the caregiver-reported Neuropsychiatric Inventory (NPI) total score and NPI caregiver distress score; sensitivity to three-month change compared with NPI "reliable change" groups; and known-groups validity, indicated by significant separation of Mini-Mental Status Examination severity groups and clinical diagnostic groups. Although not designed as a screening study, there was evidence for good operating characteristics, according to area under the receiver-operator curve with respect to gold standard clinical diagnoses, relative to Mini-Mental Status Examination or NPI. CONCLUSION: The HABC-Monitor demonstrates good reliability and validity as a clinically practical multidimensional tool for monitoring symptoms of dementia through the informal caregiver.