Departmental Metrics to Guide Equity, Diversity, and Inclusion for Academic Family Medicine Departments.

PROBLEM: Equity, diversity, and inclusion (EDI) efforts have accelerated over the past several years, without a traditional guidebook that other missions often have. To evaluate progress over time, departments of family medicine are seeking ways to measure their current EDI state. Across the specialty, unity regarding which EDI metrics are meaningful is absent, and discordance even exists about what should be measured. APPROACH: This paper provides a general metrics framework, including a wide array of possibilities to consider measuring, for assessing individual departmental progress in this broad space. These measures are designed to be general enough to provide common language and can be customized to align with strategic priorities of individual family medicine departments. OUTCOMES: The Diversity, Equity, and Inclusion Committee of the Association of Departments of Family Medicine has produced a common framework to facilitate measurement of EDI outcomes in the following areas: care delivery and health, workforce recruitment and retention, learner recruitment and training, and research participation. This framework allows departments to monitor progress across these domains that impact the tripartite mission, providing opportunities to capitalize on measured gains in EDI. NEXT STEPS: Departments can review this framework and consider which metrics are applicable or develop their own metrics to align with their strategic priorities. In the future, collective departments could compare notes and measure aggregate progress together. Evaluating progress is a step in the journey toward the goal of ensuring that departments are operating from inclusive and just academic systems.

Place of death in Parkinson's disease and related disorders in England and Wales: post-pandemic trends and implications for care planning.

BACKGROUND: With growing emphasis on palliative care for neurodegenerative conditions, understanding trends in place of death helps improve quality of end-of-life care for people with Parkinson's disease and related disorders (PDRDs), focusing allocation of resources and training and identifying inequalities. OBJECTIVES: Review national and regional place of death trends for people with PDRD including pre- and post-pandemic trends. METHODS: Mortality data for England and Wales (March 2018 and July 2022) were analysed with summary statistics and interrupted time series, exploring place of death for those who died with PDRD, with and without coexisting dementia, with reference to all deaths in England and Wales. RESULTS: Of 2,415,566 adult deaths, 56,790 included mention of PDRD. Hospital deaths were most common in people with PDRD (39.17%), followed by care homes (38.84%). People with PDRD were half as likely to die in hospice compared with the general population (2.03 vs 4.94%). Proportion of care home deaths fell significantly after March 2020 (40.6-37%, P = 0.035). Regionally, London was an outlier with a lower proportion of deaths occurring in care homes with a higher proportion of hospital deaths. CONCLUSION: Place of death for people with PDRD is changing, with more hospice and home deaths. People with PDRD, particularly those with co-existent dementia, are less likely to access inpatient hospice care than the general population. Since the COVID-19 pandemic, the proportion of care home deaths has reduced significantly with an increase in home deaths, with implications for service and resource allocation.

Parkinson's disease: symptoms and medications at the end of life.

OBJECTIVES: People with Parkinson's disease (PwP) have a high palliative symptom burden throughout their disease course, equivalent to advanced malignancy. We aim to establish trends in symptom frequency and prescribing in the 72 hours prior to death for PwP. METHODS: Retrospective case note review of PwP who died between February 2019 and September 2020. RESULTS: 51 patients were included. 60.78% of patients (n=31) had agitation and 58.82% (n=30) had pain in the final 72 hours. Patients with cognitive impairment were 4.67 times more likely to experience agitation (p=0.035) compared with those without, with higher total midazolam doses (29.18 mg vs 11.4 mg, p=0.21). Terminal motor symptoms were recorded in three patients. 28.57% of patients received the recommended dose of rotigotine for dopaminergic therapy. CONCLUSIONS: PwP have a significant symptom burden at the end of life (EOL) with levels of terminal agitation at the higher end of those expected in the general population. There was a trend towards higher doses of sedation, rather than analgesia, in people with coexistent cognitive impairment.Terminal stiffness, despite being seldom documented in the literature, is an important although infrequent symptom.Rotigotine use at EOL remains commonplace and better understanding of its effect and dosing is required.

The impact of Down syndrome-specific non-malignant hematopoietic regeneration in the bone marrow on the detection of leukemic measurable residual disease.

BACKGROUND: Detection of measurable residual disease detection (MRD) by flow cytometry after the first course of chemotherapy is a standard measure of early response in patients with acute myeloid leukemia (AML). Myeloid leukemia associated with Down Syndrome (ML-DS) is a distinct form of AML. Differences in steady-state and regenerating hematopoiesis between patients with or without DS are not well understood. This understanding is essential to accurately determine the presence of residual leukemia in patients with ML-DS. METHODS: A standardized antibody panel defined quantitative antigen expression in 115 follow-up bone marrow (BM) aspirates from 45 patients following chemotherapy for ML-DS or DS precursor B-cell acute lymphoblastic leukemia (B-ALL-DS) with the "difference from normal (ΔN)" technique. When possible, FISH and SNP/CGH microarray studies were performed on sorted cell fractions. RESULTS: 93% of BM specimens submitted post chemotherapy had a clearly identifiable CD34+ CD56+ population present between 0.06% and 2.6% of total non-erythroid cells. An overlapping CD34+ HLA-DRheterogeneous population was observed among 92% of patients at a lower frequency (0.04%-0.8% of total non-erythroid cells). In B-ALL-DS patients, the same CD34+ CD56+ HLA-DRheterogeneous expression was observed. FACS-FISH/Array studies demonstrated no residual genetic clones in the DS-specific myeloid progenitor cells. CONCLUSIONS: Non-malignant myeloid progenitors in the regenerating BM of patients who have undergone chemotherapy for either ML-DS or B-ALL-DS express an immunophenotype that is different from normal BM of non-DS patients. Awareness of this DS-specific non-malignant myeloid progenitor is essential to the interpretation of MRD by flow cytometry in patients with ML-DS.

Proving promise and support: Preliminary evaluation of the Indiana Family Preservation Services.

BACKGROUND: As part of the implementation of Family First Preservation Services Act, and to meet legal requirements set by the Indiana State Legislature in 2019, Indiana Department of Child Services (DCS) implemented Indiana Family Preservation Services (INFPS) to maintain children in the home when it is deemed safe to do so. OBJECTIVE: This paper explores the effects of INFPS on child removal episodes and repeat maltreatment. PARTICIPANTS AND SETTING: This study compares all children and families receiving INFPS between January 1, 2021 to March 31, 2021 to a similar cohort of in-home cases that opened between January 1, 2019 and March 31, 2019. METHODS: Contribution analysis and a quasi-experimental design are employed by using administrative records and survey data collected from service providers. RESULTS: INFPS is associated with reduced repeat maltreatment by about 3-4 % at the case-level and about 2-3 % at the child-level. In contrast to repeat maltreatment, in both case-level and child-level analyses, INFPS was not significantly associated with decreased likelihood of child removal. CONCLUSION: Overall, these results identify short-term effectiveness of INFPS on reducing repeat maltreatment during the treatment period. Results highlight the potential utility of INFPS to improving such outcomes, through increased use of evidence-based practices (EBP). Current findings demonstrate the need for continued research on the long-term effects of INFPS on child and family outcomes.

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

Diversity, Inclusion, and Health Equity in Academic Family Medicine.

BACKGROUND AND OBJECTIVES: Diversity, inclusion, and health equity (DIHE) are integral to the practice of family medicine. Academic family medicine has been grappling with these issues in recent years, particularly with a focus on racism and health inequity. We studied the current state of DIHE activities in academic family medicine departments and suggest a framework for departments to become more diverse, inclusive, antiracist, and focused on health equity and racial justice. METHODS: As part of a larger annual membership survey, family medicine department chairs were asked for their assessment of departmental DIHE and antioppression activities, and infrastructure and resources committed to increasing DIHE. RESULTS: More than 60% of family medicine department chairs participating in this study rate their departments highly in promoting DIHE and antioppression, and 66% of chairs report an institutional infrastructure that is working well. Just over half of departments or institutions have had a climate survey in the past 3 years, 47.3% of departments have a diversity officer, and 26% of departments provide protected time or resources for a diversity officer. CONCLUSIONS: The majority of family medicine department chairs rate their departments highly on DIHE. However, only 50% of departments have formally assessed climate in the past 3 years, fewer have diversity officers, and even fewer invest resources in their diversity officers. This disconnect should motivate academic family medicine departments to undertake formal self-assessment and implement a strategic plan that includes resource investment in DIHE, measurable outcomes, and sustainability.

Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells.

Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4000 focal regions that were uniquely hypermethylated in IDHmut samples vs. normal CD34+ cells and other AMLs. These regions had modest hypermethylation in AMLs with biallelic TET2 mutations, and levels of 5-hydroxymethylation that were diminished in IDH and TET-mutant samples, indicating that this hypermethylation results from inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred at regions with low methylation in CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that IDHmut-associated hypermethylation is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.

Environmental impacts on diapause and survival of the alfalfa leafcutting bee, Megachile rotundata.

Megachile rotundata exhibits a facultative prepupal diapause but the cues regulating diapause initiation are not well understood. Possible cues include daylength and temperature. Megachile rotundata females experience changing daylengths over the nesting season that may influence diapause incidence in their offspring through a maternal effect. Juvenile M. rotundata spend their developmental period confined in a nesting cavity, potentially subjected to stressful temperatures that may affect diapause incidence and survival. To estimate the impact of daylength and nest cavity temperature on offspring diapause, we designed a 3D printed box with iButtons that measured nest cavity temperature. We observed nest building throughout the season, monitored nest cavity temperature, and followed offspring through development to measure diapause incidence and mortality. We found that daylength was a cue for diapause, and nest cavity temperature did not influence diapause incidence. Eggs laid during long days had a lower probability of diapause. Siblings tended to have the same diapause status, explaining a lot of the remaining variance in diapause incidence. Some females established nests that contained both diapausing and nondiapausing individuals, which were distributed throughout the nest. Nest cavities reached stressful temperatures, which decreased survival. Mortality was significantly higher in nondiapausing bees and the individuals that were laid first in the nest. In conclusion, we demonstrate a maternal effect for diapause that is mediated by daylength and is independent of nest box temperature.

Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells.

Transcriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture in primary AML samples with the NPM1c mutation identified chromatin loops between the HOXA cluster and loci in the SNX10 and SKAP2 genes, and an intergenic region located 1.4 Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in the NPM1-mutant OCI-AML3 AML cell line reduced multiple long-range interactions, but resulted in CTCF-independent loops with sequences in SKAP2 that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in CTCF binding site mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells may be sustained through persistent interactions with SKAP2 enhancers, or by intrinsic factors within the HOXA gene cluster.

Microclimate Temperatures Impact Nesting Preference in Megachile rotundata (Hymenoptera: Megachilidae).

The temperature of the nest influences fitness in cavity-nesting bees. Females may choose nest cavities that mitigate their offspring's exposure to stressful temperatures. This study aims to understand how cavity temperature impacts the nesting preference of the solitary bee Megachile rotundata (Fabricius) under field conditions. We designed and 3D printed nest boxes that measured the temperatures of 432 cavities. Nest boxes were four-sided with cavity entrances facing northeast, northwest, southeast, and southwest. Nest boxes were placed along an alfalfa field in Fargo, ND and were observed daily for completed nests. Our study found that cavity temperature varied by direction the cavity faced and by the position of the cavity within the nest box. The southwest sides recorded the highest maximum temperatures while the northeast sides recorded the lowest maximum temperatures. Nesting females filled cavities on the north-facing sides faster than cavities on the south-facing sides. The bees preferred to nest in cavities with lower average temperatures during foraging hours, and cavities that faced to the north. The direction the cavity faced was associated with the number of offspring per nest. The southwest-facing cavities had fewer offspring than nests on the northeast side. Our study indicates that the nesting box acts as a microclimate, with temperature varying by position and direction of the cavity. Variation in cavity temperature affected where females chose to nest, but not their reproductive investment.

Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

BACKGROUND: In patients with acute myeloid leukemia (AML), CD56 expression has been associated with adverse clinical outcome. We reported on a phenotype associated with very poor prognosis (RAM) in children enrolled in the Children's Oncology Group trial AAML0531 (Brodersen et al. Leukemia 30 (2016) 2077-2080). RAM is also characterized in part by high-intensity expression of the CD56 antigen. Herein, we investigate underlying biological and clinical differences among CD56-positive AMLs for patients in AAML0531. METHODS: For 769 newly diagnosed pediatric patients with de novo AML enrolled in AAML0531, bone marrow specimens were submitted for flow cytometric analysis. For each patient, an immunophenotypic expression profile (IEP) was defined by mean fluorescent intensities of assayed surface antigens. Unsupervised hierarchical clustering analysis (HCA) was completed to group patients with similar immunophenotypes. Clusters were then evaluated for CD56 expression. Principal component analysis (PCA) was subsequently applied to determine whether CD56-positive patient groups were nonoverlapping. RESULTS: HCA of IEPs revealed three unique phenotypic clusters of patients with CD56-positive AML, and PCA showed that these three cohorts are distinct. Cohort 1 (N = 77) showed a prevalence of t(8;21) patients (72%), Cohort 2 (N = 52) a prevalence of 11q23 patients (69%), and Cohort 3 (RAM) (N = 16) a prevalence of patients with co-occurrence of the CBFA2T3-GLIS2 fusion transcript (63%). The 5-year event-free survival (EFS) for Cohorts 1, 2, and 3 were 69, 39, and 19%, respectively. CONCLUSIONS: When leukemia is considered by its multidimensional immunophenotype and not by the expression of a single antigen, correlations are seen between genotype and there are significant differences in patient outcomes. © 2019 International Clinical Cytometry Society.

TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing.

TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform-specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.

Long-Distance Transportation Causes Temperature Stress in the Honey Bee, Apis mellifera (Hymenoptera: Apidae).

Pollination services provided by the honey bee, Apis mellifera (Hymenoptera: Apidae, Linnaeus, 1758) have broad economic impacts and are necessary for production of a diversity of important crops. Hives may be transported multiple times per year to provide pollination. To test how temperature may contribute to transportation stress, temperature sensors were placed in hives in different locations and orientations on the trailer during shipping. Colony size prior to shipping significantly contributed to loss of population immediately after shipping which contributed to colony failure with smaller colonies more likely to fail and fail faster. Colony size also affects thermoregulation and temperature stress. Internal hive temperature varies significantly based on location and orientation. While colonies near the front and rear of the trailer and those oriented toward the center aisle had significantly different average internal temperatures, colony size best predicts loss of thermoregulation. Additionally, we profiled gene expression at departure, on arrival, and after a recovery period to identify transcriptional responses to transportation. Functional and enrichment analysis identified increased methylation and decreased ribosomal and protein-folding activity. Pheromone and odorant-binding transcripts were up-regulated after transportation. After recovery, transcripts associated with defense response, immune activity, and heat shock decreased, while production of antibiotic peptides increased. We conclude that hives experience considerable temperature stress possibly caused by turbulent airflow in exposed locations. Transportation stress should be considered an important component of annual colony losses which can be mitigated with improved management strategies.

Phenotypic integration in an extended phenotype: among-individual variation in nest-building traits of the alfalfa leafcutting bee (Megachile rotundata).

Structures such as nests and burrows are an essential component of many organisms' life-cycle and require a complex sequence of behaviours. Because behaviours can vary consistently among individuals and be correlated with one another, we hypothesized that these structures would (1) show evidence of among-individual variation, (2) be organized into distinct functional modules and (3) show evidence of trade-offs among functional modules due to limits on energy budgets. We tested these hypotheses using the alfalfa leafcutting bee, Megachile rotundata, a solitary bee and important crop pollinator. Megachile rotundata constructs complex nests by gathering leaf materials to form a linear series of cells in pre-existing cavities. In this study, we examined variation in the following nest construction traits: reproduction (number of cells per nest and nest length), nest protection (cap length and number of leaves per cap), cell construction (cell size and number of leaves per cell) and cell provisioning (cell mass) from 60 nests. We found a general decline in investment in cell construction and provisioning with each new cell built. In addition, we found evidence for both repeatability and plasticity in cell provisioning with little evidence for trade-offs among traits. Instead, most traits were positively, albeit weakly, correlated (r ~ 0.15), and traits were loosely organized into covarying modules. Our results show that individual differences in nest construction are detectable at a level similar to that of other behavioural traits and that these traits are only weakly integrated. This suggests that nest components are capable of independent evolutionary trajectories.

Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children's Oncology Group protocol AAML0531.

Diagnostic biomarkers can be used to determine relapse risk in acute myeloid leukemia, and certain genetic aberrancies have prognostic relevance. A diagnostic immunophenotypic expression profile, which quantifies the amounts of distinct gene products, not just their presence or absence, was established in order to improve outcome prediction for patients with acute myeloid leukemia. The immunophenotypic expression profile, which defines each patient's leukemia as a location in 15-dimensional space, was generated for 769 patients enrolled in the Children's Oncology Group AAML0531 protocol. Unsupervised hierarchical clustering grouped patients with similar immunophenotypic expression profiles into eleven patient cohorts, demonstrating high associations among phenotype, genotype, morphology, and outcome. Of 95 patients with inv(16), 79% segregated in Cluster A. Of 109 patients with t(8;21), 92% segregated in Clusters A and B. Of 152 patients with 11q23 alterations, 78% segregated in Clusters D, E, F, G, or H. For both inv(16) and 11q23 abnormalities, differential phenotypic expression identified patient groups with different survival characteristics (P<0.05). Clinical outcome analysis revealed that Cluster B (predominantly t(8;21)) was associated with favorable outcome (P<0.001) and Clusters E, G, H, and K were associated with adverse outcomes (P<0.05). Multivariable regression analysis revealed that Clusters E, G, H, and K were independently associated with worse survival (P range <0.001 to 0.008). The Children's Oncology Group AAML0531 trial: clinicaltrials.gov Identifier: 00372593.

Meeting Optimization Program: A "Workshop in a Box" to Create Meetings That Are Transformational Tools for Institutional Change.

INTRODUCTION: Stemming from an initiative launched at the University of California, San Francisco, School of Medicine's retreat in 2014, a group of 15 senior faculty and administrators convened to explicitly discuss strategies for creating an institutional culture of leadership. The group agreed to focus on improving a foundational skill involved in almost all leadership activities: running effective meetings. Meetings are necessary to advance institutional vision and growth. Moreover, meetings also can be detrimental if not run effectively, leading to lost productivity and meeting fatigue. METHODS: A working group developed and disseminated a workshop for learners, faculty, and administrators to create an institutional culture where meetings are interactive and transformational events. The resulting Meeting Optimization Program (MOP) is a 75- to 90-minute workshop that contains the key elements of effective meetings culled from existing literature and resources. MOP includes interactive discussion and a role-play to allow participants to practice effective meeting skills. The toolkit includes a facilitator guideline and a companion checklist of skills and resources. RESULTS: Working group members cofacilitated workshops for a variety of divisions across the campus. Participants rated the workshop highly for achieving its goal, for its overall effectiveness, and for the general format. Several participants became facilitators in a modified train-the-trainer model. Feedback highlighted the need for another iteration of the workshop focusing on facilitation. DISCUSSION: Creating change in complex systems inevitably involves meetings. Using MOP, institutions can empower their members with the tools to have effective meetings.