Inhibition of MALT1 and BCL2 induces synergistic anti-tumor activity in models of B cell lymphoma.

The activated B cell (ABC) subset of diffuse large B cell lymphoma (DLBCL) is characterized by chronic B cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small molecule inhibitor, ABBV-MALT1, that potently shuts down B cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

Associations between post-traumatic stress disorders and psychotic symptom severity in adult survivors of developmental trauma: a multisite cross-sectional study in the UK and South Korea.

BACKGROUND: Childhood maltreatment is a risk factor for the development of post-traumatic stress disorders and psychosis. However, the association between post-traumatic stress disorder (PTSD), including complex PTSD, and psychotic symptoms is unknown. We investigated whether the presence of PTSD and complex PTSD was associated with psychotic symptom severity within survivors of developmental trauma. METHODS: As part of the Investigating Mechanisms underlying Psychosis Associated with Childhood Trauma (IMPACT) study, from Aug 20, 2020, to Jan 24, 2021, and from Sept 9, 2022, to Feb 21, 2023, using study advertisement on online platforms we recruited adult (≥18 years) participants who had experienced developmental trauma without a psychiatric diagnosis in the UK and South Korea. We measured whether participants met diagnostic thresholds for PTSD and complex PTSD using the self-reported International Trauma Questionnaire, and psychotic symptoms using the self-reported Community Assessment of Psychic Experiences. We used linear regression, adjusting for sociodemographic variables such as age, sex, ethnicity, educational attainment, and socioeconomic status, to examine whether there was an association between PTSD and complex PTSD and psychotic symptoms. The study is registered in the UK (University College London Research Ethics Committee [14317/001] and the National Health Service Research Ethics Committee [22/YH/0096]) and South Korea (Institutional Review Board of Seoul National University Bundang Hospital [B-2011-648-306]), and is ongoing. FINDINGS: Of the 2675 participants who took part in the study, 1273 had experienced developmental trauma and were included in the study in the UK (n=475) and South Korea (n=798), comprising 422 (33%) men and 851 (67%) women with a mean age of 26·9 years (SD 6, range 18-40), mostly of White British (n=328) or South Korean (n=798) ethnicity. We found no significant association between PTSD and psychotic symptom severity (total severity ß=-2·40 [SE 3·28], p=0·47), compared with participants who did not meet PTSD or complex PTSD caseness. We found a significant relationship between complex PTSD and psychotic symptom severity (total severity ß=22·62 [SE 1·65], p<0·0001), including for positive (ß=12·07 [SE 0·99], p<0·0001) and negative symptoms (ß=10·5 [SE 0·95], p<0·0001), compared with participants who did not meet PTSD or complex PTSD caseness. INTERPRETATION: Health systems must assess individuals with previous developmental trauma for complex PTSD and treat those affected. These individuals should also be assessed for psychotic symptoms, and if necessary, preventative measures should be taken to reduce risk of conversion. Further work should assess whether treating complex PTSD modifies the risk of conversion to psychosis. FUNDING: UKRI Future Leaders Fellowship, British Medical Association Margaret Temple Award for Schizophrenia Research, and the National Research Foundation of Korea-Korea Government.

Electrophysiological evidence for increased auditory crossmodal activity in adult ADHD.

Background: Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by core symptoms of inattention, and/or impulsivity and hyperactivity. In order to understand the basis for this multifaceted disorder, the investigation of sensory processing aberrancies recently reaches more interest. For example, during the processing of auditory stimuli comparable low sensory thresholds account for symptoms like higher distractibility and auditory hypersensitivity in patients with ADHD. It has further been shown that deficiencies not only exist on an intramodal, but also on a multimodal level. There is evidence that the visual cortex shows more activation during a focused auditory task in adults with ADHD than in healthy controls. This crossmodal activation is interpreted as the reallocation of more attentional resources to the visual domain as well as deficient sensory inhibition. In this study, we used, for the first time, electroencephalography to identify a potential abnormal regulated crossmodal activation in adult ADHD. Methods: 15 adult subjects with clinically diagnosed ADHD and 14 healthy controls comparable in age and gender were included. ERP components P50, P100, N100, P200 and N200 were measured during the performance of a unimodal auditory and visual discrimination task in a block design. Sensory profiles and ADHD symptoms were assessed with inattention as well as childhood ADHD scores. For evaluating intramodal and crossmodal activations, we chose four EEG channels for statistical analysis and group-wise comparison. Results: At the occipital channel O2 that reflects possible crossmodal activations, a significantly enhanced P200 amplitude was measured in the patient group. At the intramodal channels, a significantly enhanced N200 amplitude was observed in the control group. Statistical analysis of behavioral data showed poorer performance of subjects with ADHD as well as higher discrimination thresholds. Further, the correlation of the assessed sensory profiles with the EEG parameters revealed a negative correlation between the P200 component and sensation seeking behavior. Conclusion: Our findings show increased auditory crossmodal activity that might reflect an altered stimulus processing resource allocation in ADHD. This might induce consequences for later, higher order attentional deployment. Further, the enhanced P200 amplitude might reflect more sensory registration and therefore deficient inhibition mechanisms in adults with ADHD.

Validation of the Korean Version of the Community Assessment of Psychic Experiences in General Population.

OBJECTIVE: The Community Assessment of Psychic Experiences has been widely translated and commonly used as a measure for psychotic experiences and psychosis proneness in clinical and research environments worldwide. This study aimed to establish the psychometric properties (reliability and validity) and factor structure of a Korean version of the Community Assessment of Psychic Experiences (K-CAPE) in the general population. METHODS: A total of 1,467 healthy participants completed K-CAPE and other psychiatric symptom-related scales (Paranoia scale, Patient Health Questionnaire-9, Dissociative Experiences Scale-II, and Oxford-Liverpool Inventory of Feelings and Experiences) via online survey. K-CAPE's internal reliability was analyzed using Cronbach's alpha coefficient. Confirmatory factor analysis (CFA) was performed to investigate whether the original three-factor model (positive, negative, and depressive) and other hypothesized multidimensional models (including positive and negative subfactors) were suitable for our data. Exploratory factor analysis (EFA) was conducted to explore better alternative factor solutions with a follow-up CFA. To assess convergent and discriminant validity, we examined correlations between K-CAPE subscales with other established measures of psychiatric symptoms. RESULTS: K-CAPE showed good internal consistency in all original three subscales (all greater than α=0.827). The CFA demonstrated that the multidimensional models exhibited relatively better quality than the original three-dimensional model. Although the model fit indices did not reach their respective optimal thresholds, they were within an acceptable range. Results from the EFA indicated 3-5 factor solutions. In 3-factor solution, "negative-avolition" items were founded to be loaded more consistently with depressive items than with the negative dimension. In 4-factor solution, positive items were divided into two subfactors: "positive-bizarre experiences" and "positive-delusional thoughts," while negative symptoms were separated into two distinct subfactors in 5-factor solution: "negative-avolition (expressive)," and "negative-social (experiential)." The correlation coefficients between K-CAPE subscales and corresponding measurements were significant (p<0.001), confirming the convergent and discriminant validity. CONCLUSION: Our study provides evidence to support the reliability and validity of the K-CAPE and its use as a measure of psychotic symptoms in the Korean population. Although alternative factor structures did not improve the model fit, our EFA findings implicate the use of subfactors to investigate more specific domains of positive and negative symptoms. Given the heterogeneous nature of psychotic symptoms, this may be useful in capturing their different underlying mechanisms.

Global phylogeographical distribution of Gloeoporus dichrous.

Phylogeographic analyses are efficient in ecological and evolutionary studies to discover the origin of a lineage, its dispersal routes, and the divergence of ancestral traits. Studies on widespread wood-decay fungi have revealed the phylogenetic division of several polypores based on geographical distribution. In this study, specimens of Gloeoporus dichrous, a cosmopolitan polypore species, were collected globally and analyzed for their geographic distribution. Multi-marker Bayesian molecular clock and haplotype analyses revealed a clear division of G. dichrous populations by continent. The species diverged from its neighboring clades 10.3 (16.0-5.6) million years ago, with Asian and North American populations at the center of divergence. Possible dispersal mechanisms and pathways are predicted and discussed based on the evaluated transfer routes. The biogeography of G. dichrous analyzed in this study represents a fraction of the polypore evolution and may advance the understanding of the overall evolution of wood-decay fungi.

Prognostic factors of local control and progression-free survival in AJCC stages T1 and T2 cervical cancer patients treated with adjuvant brachytherapy after chemoradiotherapy.

Purpose: We assessed prognostic factors of local control and progression-free survival (PFS) of patients treated for AJCC stages T1 and T2 cervical cancer using utero-vaginal brachytherapy after chemoradiotherapy. Material and methods: This retrospective single-institution analysis included patients who underwent brachytherapy after radiochemotherapy between 2005 and 2015 at the Institut de Cancérologie de Lorraine. Adjuvant hysterectomy was optional. A multivariate analysis of prognostic factors was carried out. Results: Of 218 patients, 81 (37.2%) were AJCC stage T1, and 137 (62.8%) were AJCC stage T2. 167 (76.6%) patients had squamous cell carcinoma, 97 (44.5%) patients had pelvic nodal disease, and 30 (13.8%) patients had para-aortic nodal disease. One hundred eighty-four patients (84.4%) underwent concomitant chemotherapy, while adjuvant surgery was performed in 91 patients (41.9%) and 42 (46.2%) patients had pathological complete response. Median follow-up was 4.2 years, and local control was reported in 87.8% (95% CI: 83.0-91.8) and 87.2% (95% CI: 82.3-91.3) of patients at 2 and 5 years, respectively. In multivariate analysis, T stage (hazard ratio [HR] = 3.65, 95% CI: 1.27-10.46, p = 0.016) was associated with local control. PFS was reported in 67.6% (95% CI: 60.9-73.4) and 57.4% (95% CI: 49.3-64.2) of patients at 2 and 5 years, respectively. In multivariate analysis, para-aortic nodal disease (HR = 2.03, 95% CI: 1.16-3.54, p = 0.012), pathological complete response (HR = 0.33, 95% CI: 0.15-0.73, p = 0.006), and intermediate-risk clinical tumor volume of > 60 cc (HR = 1.90, 95% CI: 1.22-2.98, p = 0.005) were associated with PFS. Conclusions: Lower dose brachytherapy may benefit AJCC stages T1 and T2 tumors, whereas higher doses are required for larger tumors and para-aortic nodal disease involvement, respectively. Pathological complete response should be associated with better local control and not surgery.

Influence of Preventive Medicine Residency Programs and Combined Master of Public Health Programs on Specialty Selection.

INTRODUCTION: To determine medical school characteristics that may result in graduates entering the specialty of public health and general preventive medicine (PH&GPM), the authors conducted an analysis comparing the presence of affiliated preventive medicine residency programs and combined Master of Public Health degree programs with the likelihood of graduates entering the specialty of PH&GPM. METHODS: Using data from the American Board of Preventive Medicine and publicly available information on medical schools and residencies, in spring 2022, the authors compared medical schools that produced PH&GPM physicians with the presence of a PH&GPM residency program, the presence of any preventive medicine residency (public health and general preventive medicine or occupational medicine or aerospace medicine), and the presence of a combined Doctor of Medicine‒Master of Public Health or Doctor of Osteopathic Medicine‒Master of Public Health program. RESULTS: Between 2017 and 2021, there were 385 physicians newly board certified in PH&GPM, 210 medical schools, and 75 preventive medicine residencies. The 385 physicians graduated from 110 of the 210 medical schools. Analyses showed statistically significant associations between medical schools that graduated PH&GPM physicians and the presence of PH&GPM residencies (OR=3.74; 95% CI=1.61, 8.69), all preventive medicine residencies (OR=2.75; 95% CI=1.37, 5.51), and combined degree programs (OR=4.37; 95% CI=2.45, 7.79). CONCLUSIONS: Because PH&GPM residency programs affiliated with medical schools are a significant factor associated with PH&GPM physicians obtaining board certification, such analyses may provide critical guidance in the utilization of resources intended to produce more physicians certified in this specialty.

CRISPR Activation/Interference Screen to Identify Genetic Networks in HDAC-Inhibitor-Resistant Cells.

Epigenetic alterations have been identified in various tumor types. In part, these alterations are mediated via increased histone deacetylase activity. Although preclinical results of monotherapies with histone deacetylase inhibitors (HDACi) are promising, success in clinical trials is limited. Reasons for these limitations may be de novo or acquired resistance to HDAC inhibitors that could be overcome with rational combination therapies. This requires knowledge of resistance mechanism along with the involved genetic networks. One way to identify such genetic networks is the implementation of a CRISPR-based technology allowing transcriptional repression (CRISPRi) and activation (CRISPRa) at a genome-wide scale. We describe a simple approach to amplify and validate sgRNA libraries, generate a myeloid progenitor cell line expressing catalytically dead Cas9 (dCas9) fusion proteins with transcriptional effectors to repress or activate genetic regions of interest and demonstrate a complementary genome-wide HDACi resistance screening approach. Furthermore, we present bioinformatics tools for quality control and analysis of the sequencing data.

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study.

BACKGROUND: Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a. METHODS: REFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVR35 at week 24 from baseline. Secondary endpoints were a 50% or greater reduction in total symptom score (TSS50) at week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (version 4.0), anaemia response assessed according to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to the European consensus grading system; and exploratory endpoints included overall survival and changes in inflammatory cytokines. Exploratory analyses investigated potential prognostic biomarkers of the benefit of navitoclax-based combination treatment, including bone marrow fibrosis and variant allele frequency, in patients with a suboptimal response to ruxolitinib. This study is registered with ClinicalTrials.gov (NCT03222609) and is ongoing. FINDINGS: Between Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVR35 at week 24 in the high molecular risk group, as did four (31%) of 13 in the non-high molecular risk group. Four (36%) of 11 patients in the high molecular risk group had TSS50 at week 24 compared with two (25%) of eight in the non-high molecular risk group; seven (39%) of 18 in the high molecular risk group had an improvement in fibrosis by at least one grade compared with five (36%) of 14 in the non-high molecular risk group; and four (28%) of 14 had reductions in variant allele frequency of 20% or greater in the high molecular risk group compared with two (17%) of 12 in the non-high molecular risk group. Patients with improvements in fibrosis of one grade or more and a reduction of 20% of more in variant allele frequency had improved overall survival (median overall survival not reached) compared with those who did not achieve fibrosis improvement or a reduction in variant allele frequency (median overall survival 28·5 months [95% CI 19·6-not estimable] for both), suggesting potential disease modification. Additionally, changes in concentrations of ß-2-microglobulin (week 12: r=0·57; week 24: r=0·57), TIMP metallopeptidase inhibitor 1 (week 12: r=0·47; week 24: r=0·54), TNF receptor type II (r=0·55; week 24: r=0·40), and vascular cell adhesion molecule-1 (r=0·58; week 24: r=0·50) were positively associated with changes in spleen volume. INTERPRETATION: These biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. FUNDING: AbbVie.

Robust perceptual-load-dependent audiovisual integration in adult ADHD.

We perceive our daily-life surrounded by different senses (e.g., visual, and auditory). For a coherent percept, our brain binds those multiple streams of sensory stimulations, i.e., multisensory integration (MI). Dependent on stimulus complexity, early MI is triggered by bottom-up or late via top-down attentional deployment. Adult attention-deficit/hyperactivity disorder (ADHD) is associated with successful bottom-up MI and deficient top-down MI. In the current study, we investigated the robustness of the bottom-up MI by adding additional task demand varying the perceptual load. We hypothesized diminished bottom-up MI for high perceptual load for patients with ADHD. 18 adult patients with ADHD and 18 age- and gender-matched healthy controls participated in this study. In the visual search paradigm, a target letter was surrounded by uniform distractors (low load) or by different letters (high load). Additionally, either unimodal (visual flash, auditory beep) or multimodal (audiovisual) flanked the visual search. Linear-mixed modeling was used to investigate the influence of load on reaction times. Further, the race model inequality was calculated. Patients with ADHD showed a similar degree of MI performance like healthy controls, irrespective of perceptual load manipulation. ADHD patients violated the race model for the low load but not for the high-load condition. There seems to be robust bottom-up MI independent of perceptual load in ADHD patients. However, the sensory accumulation might be altered when attentional demands are high.

Uncertainty in geospatial health: challenges and opportunities ahead.

PURPOSE: Uncertainty is not always well captured, understood, or modeled properly, and can bias the robustness of complex relationships, such as the association between the environment and public health through exposure, estimates of geographic accessibility and cluster detection, to name a few. METHODS: We review current challenges and future opportunities as geospatial data and analyses are applied to the field of public health. We are particularly interested in the sources of uncertainty in geospatial data and how this uncertainty may propagate in spatial analysis. RESULTS: We present opportunities to reduce the magnitude and impact of uncertainty. Specifically, we focus on (1) the use of multiple reference data sources to reduce geocoding errors, (2) the validity of online geocoders and how confidentiality (e.g., HIPAA) may be breached, (3) use of multiple reference data sources to reduce geocoding errors, (4) the impact of geoimputation techniques on travel estimates, (5) residential mobility and how it affects accessibility metrics and clustering, and (6) modeling errors in the American Community Survey. Our paper discusses how to communicate spatial and spatiotemporal uncertainty, and high-performance computing to conduct large amounts of simulations to ultimately increase statistical robustness for studies in public health. CONCLUSIONS: Our paper contributes to recent efforts to fill in knowledge gaps at the intersection of spatial uncertainty and public health.

Financing Preventive Medicine Graduate Medical Education.

Financing US preventive medicine residency programs has been a persistently difficult issue. The unique nature of preventive medicine renders training more burdensome and costly than other specialties. This article describes the numerous and varied federal sources of Graduate Medical Education funding to outline available residency financing options for the specialty of preventive medicine. This information could be utilized by various preventive medicine organizations in their efforts to strengthen the specialty.

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs.

Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.

NRF2 activator A-1396076 ameliorates inflammation in autoimmune disease models by inhibiting antigen dependent T cell activation.

Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We have identified A-1396076, a potent and selective NRF2 activator with demonstrated KEAP1 binding and modulation of cellular NRF2 mediated effects. In vivo administration of A-1396076 inhibits inflammation across several rodent models of autoimmunity when administered at or before the time of antigen challenge while also inducing NRF2 modulated gene transcription in the liver of the animals. It was not effective when administered after the time of antigen challenge or in a T cell independent model of arthritis induced by passive transfer of anti-collagen antibodies. A-1396076 inhibited antigen dependent T cell activation as measured by IFN-γ production in an ex vivo re-stimulation assay and following anti-CD3 challenge of MOG-sensitized mice. A-1396076 reduced costimulatory molecule expression on dendritic cells in the lungs of OVA LPS challenged mice suggesting that the mechanism of T cell inhibition was mediated at least partially by interfering with antigen presentation. These data suggest that NRF2 activation may be an effective strategy to dampen inflammation for treatment of autoimmune disease.

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

Outcomes from the Health Resources and Services Administration's Dental Faculty Development Program.

PURPOSE/OBJECTIVES: While the Commission on Dental Accreditation (CODA) requires programs to conduct faculty development, implementation of faculty development activities vary widely. Faculty development programs can enhance teaching, research, and leadership skills needed to transition from clinical practice to teaching. In 2012, the Health Resources and Services Administration (HRSA) funded 6 institutions to plan, develop, and operate programs for training oral healthcare providers who plan to teach in general, pediatric, public health dentistry, or dental hygiene. This performance study examines the results of the dental faculty development programs. METHODS: After the 5-year grant program (2012-2017), we used descriptive analysis to examine annual performance data including trainee demographics, faculty development activities, post-completion intentions, and course development activities. RESULTS: Nearly 300 trainees participated across 6 funded grantees; the majority were female, aged 30-49 years, and non-Hispanic White. For those who completed, 80% intended to teach. Common faculty development activities included community-based training, curriculum enhancements, Web-based training, and interprofessional education methods. Faculty development modalities included faculty seminars, Master's degrees, and mentoring. Pipeline activities, online resources, and continuing education supported dental students and providers moving into academics. CONCLUSIONS: Faculty development better prepares individuals to compete in academic environments and develop faculty. Community-based programs may utilize faculty development to recruit community preceptors and achieve calibration. HRSA investment in faculty development programs builds resources and infrastructure to promote continuing engagement in clinical education, research, and administrative skills. Future research is needed to establish the impact of faculty development initiatives on practice change and patient outcomes.