BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor.

ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.

Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2.

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.

Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics.

At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule and biologics guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in its physicochemical, absorption, distribution, metabolism and excretion properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the 'siRNA working group' in the IQ Consortium compile a list of reports included in approved siRNA filing packages and discuss the relevance of two in vitro reports-the plasma protein binding evaluation and the drug-drug interaction risk assessment-to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA plasma protein binding and drug-drug interactions in understanding pharmacokinetic/pharmacodynamic relationships, safety and translation. The findings are summarized into two decision trees to help guide industry decide when in vitro siRNA plasma protein binding and drug-drug interaction studies are warranted.

Sexual and gender minority content in undergraduate medical education in the United States and Canada: current state and changes since 2011.

PURPOSE: To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. METHOD: Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. RESULTS: Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6-16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1-6 h] versus 0 h [IQR, 0-0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%). CONCLUSION: Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions' coverage of LGBTQI + health as 'fair,' 'good,' or 'very good,' there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.

The effect of mandatory post-call relief on sleep and wellness in ophthalmology residents.

BACKGROUND: Multiple duty hour reforms have been implemented to optimize resident wellness through increasing opportunities for sleep recovery, but few studies have recorded objectively measured sleep or shown direct sleep and wellness benefits from such interventions. This study seeks to determine whether mandatory post-call relief policies with a partial night float system improved resident sleep, activity, and burnout among ophthalmology residents taking home call. METHODS: We conducted a two group cohort study of ophthalmology residents at the University Washington comparing post graduate year-2 (PGY-2) resident sleep, activity, and burnout between the optional post-call relief group from July 1, 2017 to June 30, 2019 to the mandatory post-call relief group from July 1, 2019 to June 30, 2021. RESULTS: Of twenty total residents participating in the survey portion, 18 residents participated in the sleep and activity tracking portion of the study, 9 in in the optional post-call relief cohort, and 9 in the mandatory post-call relief cohort. The mandatory post-call relief group recorded longer total sleep on call than the optional post-call relief group (p < 0.001). There was no difference in overnight sleep recorded on call (median 3.4 h), but residents recorded more time napping in the mandatory post-call relief cohort (p < 0.001). There was no significant difference between cohorts in amount of sleep while not on call. Residents in the mandatory post-call relief cohort recorded higher average daily steps, higher exercise time, and lower sedentary time than residents in the optional post-call relief cohort (p < 0.001). They also recorded lower median emotional exhaustion on the Maslach Burnout Inventory and lower stress in the Depression and Anxiety Stress Scale in the mandatory post-call relief cohort (p = 0.008). CONCLUSIONS: Implementation of mandatory post-call relief policies with a partial night-float system among PGY-2 residents was associated with more post-call naps with more overall physical activity, lower emotional exhaustion scores, and lower stress scores, despite no changes to overnight sleep on call or total sleep. Although sample size limits interpretation of data, implementation of mandatory post call relief could be considered to improve post-call sleep in programs with home call.

Effects of the COVID-19 pandemic on medical students: a multicenter quantitative study.

BACKGROUND: The COVID-19 pandemic disrupted the United States (US) medical education system with the necessary, yet unprecedented Association of American Medical Colleges (AAMC) national recommendation to pause all student clinical rotations with in-person patient care. This study is a quantitative analysis investigating the educational and psychological effects of the pandemic on US medical students and their reactions to the AAMC recommendation in order to inform medical education policy. METHODS: The authors sent a cross-sectional survey via email to medical students in their clinical training years at six medical schools during the initial peak phase of the COVID-19 pandemic. Survey questions aimed to evaluate students' perceptions of COVID-19's impact on medical education; ethical obligations during a pandemic; infection risk; anxiety and burnout; willingness and needed preparations to return to clinical rotations. RESULTS: Seven hundred forty-one (29.5%) students responded. Nearly all students (93.7%) were not involved in clinical rotations with in-person patient contact at the time the study was conducted. Reactions to being removed were mixed, with 75.8% feeling this was appropriate, 34.7% guilty, 33.5% disappointed, and 27.0% relieved. Most students (74.7%) agreed the pandemic had significantly disrupted their medical education, and believed they should continue with normal clinical rotations during this pandemic (61.3%). When asked if they would accept the risk of infection with COVID-19 if they returned to the clinical setting, 83.4% agreed. Students reported the pandemic had moderate effects on their stress and anxiety levels with 84.1% of respondents feeling at least somewhat anxious. Adequate personal protective equipment (PPE) (53.5%) was the most important factor to feel safe returning to clinical rotations, followed by adequate testing for infection (19.3%) and antibody testing (16.2%). CONCLUSIONS: The COVID-19 pandemic disrupted the education of US medical students in their clinical training years. The majority of students wanted to return to clinical rotations and were willing to accept the risk of COVID-19 infection. Students were most concerned with having enough PPE if allowed to return to clinical activities.

Infections and the relationship to treatment in neuromuscular autoimmunity.

INTRODUCTION: This study aimed to identify infections in patients with myasthenia gravis, dermatomyositis, and chronic inflammatory demyelinating polyradiculoneuropathy, and to investigate the relationship between infection and immunomodulation. METHODS: A retrospective chart review examined 631 patients with myasthenia gravis (n = 358), chronic inflammatory demyelinating polyradiculoneuropathy (n = 124), and dermatomyositis (n = 149) patients over a 10-year time period. RESULTS: Infection rates were similar at approximately 19% in all 3 diseases. Of the infections in which a causative organism was identified, pneumonia, sepsis, and opportunistic infections were the leading diagnoses. A multivariate model demonstrated a significant association between infection and an increased dose of plasma exchange, mycophenolate mofetil, and corticosteroid therapy. DISCUSSION: There are few large studies investigating rates of infections in patients with autoimmune neuromuscular disorders and the relationship to immunomodulation. This study not only demonstrates the remarkably similar infection rates across the 3 diseases studied, but also shows their relationship to commonly used immunotherapies. Muscle Nerve 57: 927-931, 2018.

Time Since First Acting on Same-Sex Attraction and Recreational Drug Use among Men Who Have Sex With Men (MSM): Is There an Effect of "Gay Age"?

BACKGROUND: Men who have sex with men (MSM) have higher rates of substance use compared to men who have sex with women. Among MSM, drug use is linked to higher-risk sexual behavior and acquisition of HIV and other sexually transmitted infections. OBJECTIVES: We hypothesize that time since first acting on one's same sex attraction, or one's "gay age", could be predictive of drug using behavior. METHODS: We examined this question among 176 MSM, aged 18-35, presenting at a public sexual health clinic. Behavioral data were captured using interviewer- and self-administered surveys and clinical data were extracted from medical records. We used modified Poisson regression to examine associations between gay age and recent recreational drug use, and separately, between gay age and recent marijuana use. RESULTS: In total, 43% of participants reported recent marijuana use and 26% of participants reported recent use of other drugs. The associations between gay age and marijuana use and other drug use varied by HIV status. After adjustment for biological age, race, and education, a one-year increase in gay age was associated with significantly increased drug use among HIV-negative men (adjusted prevalence ratio (aPR): 1.08; 95% confidence interval (CI): 1.03-1.14), but we observed no association between gay age and drug use among HIV-positive men (aPR: 0.96, 95% CI: 0.86-1.07). Gay age was not associated with marijuana use in HIV-negative (aPR: 1.00, 95% CI: 0.95-1.04) or HIV-positive (aPR: 1.06, 95% CI: 0.98-1.14) men. CONCLUSIONS: In summary, HIV-negative MSM who had experienced more time since first same-sex experience had significantly increased prevalence of recent drug use.

Group Sex and Prevalent Sexually Transmitted Infections Among Men Who Have Sex with Men.

We evaluated the direct relation between group sex and prevalent sexually transmitted infections (STI) in a cross-sectional study of men who have sex with men (MSM) presenting at an urban STI clinic in the Midwestern US. Among 231 men who enrolled and reported that they have sex with men, we collected behavioral data using a combination of interviewer and self-administered surveys and extracted STI data from electronic health records. We used modified Poisson regression to examine the unadjusted and adjusted associations between group sex participation and prevalent STI. One-quarter of participants (n = 58) reported group sex participation in the last 3 months. Eighteen percent of participants (n = 42) had gonorrhea and 19 % (n = 45) had chlamydial infection. Men who reported recent group sex were more likely to be HIV-positive, to report recent drug use, and to report unprotected receptive anal intercourse in the past 3 months. After adjustment for age, race, and recent drug use, recent participation in group sex was associated with prevalent gonorrhea infection (prevalence ratio [PR] = 2.11, 95 % confidence interval [CI] = [1.13, 3.95]) but not chlamydia infection (PR = 1.03, 95 % CI = [0.58, 1.84]). We performed a sensitivity analysis in which we also adjusted for unprotected receptive anal intercourse and the results were not substantively changed. In summary, participation in group sex in the past 3 months was associated with a more than twofold increased prevalence of gonorrhea, but not with chlamydia. These findings support group sex participation as a potential contributor to increased STI prevalence.

Snapshot of Teleretinal Screening for Diabetic Retinopathy at the West Los Angeles Medical Center.

INTRODUCTION: The West Los Angeles Veterans Affairs Medical Center is a large urban facility with a robust teleretinal screening program in primary care clinic, established in 2006. The purpose of this article is to provide a snapshot of teleretinal screening at this site. METHODS: Diabetic patients from 2012 were analyzed with a prospective cohort study. Demographic information, results of teleretinal screening, referral to eye clinic, and loss to follow-up (defined as no eye care within 2 years) were collected. RESULTS: Of 516 patients with diabetes screened with teleretinal imaging, 120 patient charts were reviewed for data analysis. Teleretinal imaging diagnosed 15% (18/120) of patients with varying stages of nonproliferative diabetic retinopathy (DR). Of patients screened, 55.8% (67/120) of the patients were referred to an eye clinic for further ophthalmic evaluation. Nondiabetic retinopathy reasons for eye clinic referral included glaucoma suspect (13.3%, 16/120) and age-related macular degeneration (10.0%, 12/120). Of all patients screened, 37.5% (45/120) of them were lost to follow-up, defined as no teleretinal screening or eye clinic appointment within 2 years. Patients who lived farther away from clinic had a higher risk of loss to follow-up (p = 0.04). DISCUSSION: We found, although only 15% of patients were diagnosed with DR from teleretinal screening, more than 50% of patients were referred to eye clinic. In addition, of all screened patients, there was a high rate of not returning to the Veterans Affairs (VA) for eye care.

Cellular contractility changes are sufficient to drive epithelial scattering.

Epithelial scattering occurs when cells disassemble cell-cell junctions, allowing individual epithelial cells to act in a solitary manner. Epithelial scattering occurs frequently in development, where it accompanies epithelial-mesenchymal transitions and is required for individual cells to migrate and invade. While migration and invasion have received extensive research focus, how cell-cell junctions are detached remains poorly understood. An open debate has been whether disruption of cell-cell interactions occurs by remodeling of cell-cell adhesions, increased traction forces through cell substrate adhesions, or some combination of both processes. Here we seek to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/scatter factor-induced EMT. We find that HGF signaling does not alter the strength of cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion strength might not accompany epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role, as cell-substrate adhesions are stronger in cells treated with HGF and since rapid scattering in cells treated with HGF and TGFß is associated with a dramatic increase in focal adhesions. Increases in the pliability of the substratum, reducing cells ability to generate traction on the substrate, alter cells׳ ability to scatter. Further consistent with changes in substrate adhesion being required for cell-cell detachment during EMT, scattering is impaired in cells expressing both active and inactive RhoA mutants, though in different ways. In addition to its roles in driving assembly of both stress fibers and focal adhesions, RhoA also generates myosin-based contractility in cells. We therefore sought to examine how RhoA-dependent contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely an inhibition of cell scattering following HGF treatment. Interestingly, restoration of myosin-based contractility in blebbistatin-treated cells results in cell scattering, including global actin rearrangements. Scattering is reminiscent of HGF-induced epithelial scattering without a concomitant increase in cell migration or decrease in adhesion strength. This scattering is dependent on RhoA, as blebbistatin-induced scattering is reduced in cells expressing dominant-negative RhoA mutants. This suggests that induction of myosin-based cellular contractility may be sufficient for cell-cell detachment during epithelial scattering.

Patients' Attitudes Toward Medical Student Participation Across Specialties: A Systematic Review.

UNLABELLED: Phenomenon: Medical students commonly participate in patient care in a variety of different settings. However, a systematic review of patients' attitudes toward medical student participation across specialties has not been performed. APPROACH: The authors searched 7 databases (CINAHL, Cochrane Library, ERIC, MEDLINE, PsycINFO, Scopus, and Web of Science) between January 1, 1999, and August 5, 2014. Two authors independently screened the results and selected articles that were written in English, were published in a peer-reviewed journal, and used a structured or semistructured survey or interview to determine patients' attitudes toward medical student participation in their care. Study quality was assessed using the Medical Education Research Study Quality Instrument. FINDINGS: Fifty-nine studies were included. Average study quality was low. Sixty-one unique evaluation instruments were used, and 34 instruments (56%) lacked validity data. Patient satisfaction was not significantly affected by medical student participation. However, patients' acceptance of medical student participation varied widely between studies and depended on the type of participation. The most common reason for acceptance was a desire to contribute to the education of others, and the most common reason for refusal was concerns about privacy. Minorities were more likely to refuse medical student participation. Patients preferred to be informed before medical students participated in their care. Insights: Patient satisfaction is not significantly affected by medical student participation. However, patient satisfaction may be a poor surrogate marker of patients' acceptance of medical students. Future research should employ validated evaluation instruments to further explore patients' attitudes toward medical student participation.

Prostate-specific antigen is unlikely to be a suitable biomarker of semen exposure from recent unprotected receptive anal intercourse in men who have sex with men.

A biomarker of unprotected receptive anal intercourse could improve validity of sexual behavior measurement. We quantified prostate-specific antigen (PSA) from rectal swabs from men who have sex with men (MSM). One swab was PSA positive. Using current methods, PSA is an inadequate biomarker of recent unprotected receptive anal intercourse in men who have sex with men.

A blinded, randomized controlled trial of high-dose vitamin D supplementation to reduce recurrence of bacterial vaginosis.

OBJECTIVE: Low serum vitamin D levels have been associated with increased prevalence of the reproductive tract condition bacterial vaginosis (BV). The objective of this trial was to evaluate the effect of high-dose vitamin D supplementation on BV recurrence. STUDY DESIGN: This randomized, placebo-controlled, double-blinded trial enrolled 118 women with symptomatic BV from an urban sexually transmitted disease clinic (clinicaltrials.gov registration NCT01450462). All participants received 500 mg of oral metronidazole twice daily for 7 days. Intervention participants (n = 59) also received 9 doses of 50,000 IU of cholecalciferol (vitamin D3) over 24 weeks; control women (n = 59) received matching placebo. Recurrent BV was assessed via Nugent scoring after 4, 12, and 24 weeks. We assessed the effect of the intervention using an intention-to-treat approach, fitting Cox proportional hazards models to evaluate recurrent BV over the follow-up period. RESULTS: Most participants (74%) were black, with a median age of 26 years. Median presupplementation serum 25-hydroxyvitamin D [25(OH)D] was similar across randomization arms: 16.6 ng/mL in the vitamin D arm and 15.8 ng/mL in the control arm. At trial completion, median 25(OH)D among women receiving vitamin D was 30.5 ng/mL, vs 17.8 ng/mL in control women; 16% of women receiving vitamin D and 57% receiving placebo remained vitamin D deficient (<20 ng/mL). BV prevalence among women randomized to vitamin D was very similar to those randomized to placebo at the 4- and 12-week visits, but by the 24-week visit, BV prevalence was 65% among women in the vitamin D arm and 48% among control women. BV recurrence was not reduced by vitamin D supplementation (intention-to-treat hazard ratio, 1.11; 95% confidence interval, 0.68-1.81). Among women experiencing recurrent BV, median time to recurrence was 13.7 weeks in the vitamin D arm and 14.3 weeks in the control arm. CONCLUSION: Women receiving vitamin D experienced significant increases in serum 25(OH)D, but this increase was not associated with decreased BV recurrence in this high-risk sexually transmitted disease clinic population.

Empty toe phenomenon: a big problem for a little toe.

The authors present a case report and review of the sparse literature of a rare closed degloving injury to the toe, referred to by Flaherty as an "empty toe phenomenon." A 25-year-old man sustained a twisting injury to his left foot when he was involved in a motorcycle accident. The skin was not lacerated around the toe but on physical exam it appeared that part of the toe was empty of its bony contents.

Identifying Strategies for the Use of Gender and Sex Language in Clinical One-Liners.

Purpose: The "one-liner," commonly used in clinical communications, summarizes a patient's identity, presenting condition, medical history, and clinical findings. Imprecise, inconsistent use of gender and sex information in one-liners threatens the provision of affirming care to transgender, nonbinary, gender-expansive, and intersex patients and may exacerbate health care disparities. This study aimed to generate guidance for communicating gender and sex information in one-liners. Methods: This is an explanatory sequential, equal status mixed methods study of transgender, nonbinary, gender-expansive, and intersex people and clinicians caring for this population. Survey participants rated one-liners on a five-point Likert-type scale of appropriateness, considering affirmation and clinical utility, and provided open-ended comments. We conducted two focus groups with survey respondents to explore survey results and performed a thematic analysis of survey comments and focus group transcripts. Results: Survey respondents included 57 clinicians and 80 nonclinicians. One-liners containing patient pronouns were rated most appropriate, and appropriate patient descriptors included self-described gender identity or gender-neutral terms. In scenarios where patient sex information was not pertinent to the chief concern (CC), one-liners containing no sex information were rated most appropriate. Four themes were identified: inclusion of sex information based on relevance to the CC, accurate patient representation, influence of clinical setting, and risk of harm from inaccurate one-liners. Conclusion: This study generated data to support the appropriate use of gender and sex language in one-liners. Clinicians, educators, and trainees may use these findings to compose one-liners that are affirming and clinically useful for patients of diverse gender and sex identities.

Training Health Center Staff in the Provision of Culturally Responsive Care for Sexual and Gender Minority Patients: Results of a Randomized Controlled Trial.

Purpose: The study was designed to evaluate whether an educational intervention to train the health center (HC) staff to optimize care for sexual and gender minority (SGM) patients could improve documentation of sexual orientation and gender identity (SOGI) and increase preventive screenings. Methods: Twelve HCs were matched and randomized to either receive a tailored, multicomponent educational intervention or a 1-hour prerecorded webinar. Documentation of SGM status and clinical testing was measured through analysis of data that HCs report annually. Nonparametric statistics were used to assess associations between baseline HC characteristics and outcome measures. Results: The HCs were geographically, racially, and ethnically diverse. In all but one HC, <10% of the patients were identified as SGM. Intervention HCs underwent between 3 and 10 trainings, which were highly acceptable. In 2018, 9 of 12 HCs documented SO and 11 of 12 documented GI for at least 50% of their patients. Five of 6 intervention HCs increased SO documentation by 2020, compared to 3 of 6 control HCs (nonsignificant, NS). Five intervention HCs increased GI documentation, although generally by less than 10%, compared to 2 of the controls (NS). Intervention HCs tended to increase documentation of preventive services more than control HCs, but the changes were NS. Conclusions: An educational intervention designed to train the HC staff to provide culturally responsive services for SGM patients was found to be acceptable, with favorable, but nonsignificant changes. Further refinement of the intervention using a larger sample of HCs might demonstrate the effectiveness of this approach. Clinical trial registration #: NCT03554785.

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM).

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.