Affective neural circuits and inflammatory markers linked to depression and anxiety symptoms in patients with comorbid obesity.

Although we have effective treatments for depression and anxiety, we lack mechanistic understanding or evidence-based strategies to tailor these treatments in the context of major comorbidities such as obesity. The current feasibility study uses functional neuroimaging and biospecimen data to determine if changes in inflammatory markers, fecal short-chain fatty acids, and neural circuit-based targets can predict depression and anxiety outcomes among participants with comorbid obesity. Blood and stool samples and functional magnetic resonance imaging data were obtained at baseline and 2 months, during the parent ENGAGE-2 trial. From 30 participants with both biospecimen and fMRI data, this subsample study explored the relationship among changes in inflammatory markers and fecal short-chain fatty acids and changes in neural targets, and their joint relationship with depression and anxiety symptoms. Bivariate and partial correlation, canonical correlation, and partial least squares analyses were conducted, with adjustments for age, sex, and treatment group. Initial correlation analyses revealed three inflammatory markers (IL-1RA, IL-6, and TNF-α) and five neural targets (in Negative Affect, Positive Affect, and Default Mode Circuits) with significantly associated changes at 2 months. Partial least squares analyses then showed that changes in IL-1RA and TNF-α and changes in three neural targets (in Negative Affect and Positive Affect Circuits) at 2 months were associated with changes in depression and anxiety symptoms at 6 months. This study sheds light on the plausibility of incorporation of inflammatory and gastrointestinal biomarkers with neural targets as predictors of depression and comorbid anxiety outcomes among patients with obesity.

Associations between fecal short-chain fatty acids, plasma inflammatory cytokines, and dietary markers with depression and anxiety: Post hoc analysis of the ENGAGE-2 pilot trial.

BACKGROUND: The microbiome-gut-brain-axis (MGBA) is emerging as an important mechanistic link between diet and mental health. The role of significant modifiers of the MGBA, including gut microbial metabolites and systemic inflammation, in individuals comorbid with obesity and mental disorders, is under-investigated. OBJECTIVES: This exploratory analysis examined associations among microbial metabolites-fecal SCFAs, plasma inflammatory cytokines, and diet with depression and anxiety scores in adults comorbid with obesity and depression. METHODS: Stool and blood were obtained from a subsample (n = 34) of participants enrolled in an integrated behavioral intervention for weight loss and depression. Pearson partial correlation and multivariate analyses determined associations among changes in fecal SCFAs (propionic, butyric, acetic, and isovaleric acids), plasma cytokines [C-reactive protein, interleukin 1 beta, interleukin 1 receptor antagonist (IL-1RA), interleukin 6, and TNF-α], and 35 dietary markers over 2 mo, and changes in SCL-20 (Depression Symptom Checklist 20-item) and GAD-7 (Generalized Anxiety Disorder 7-Item) scores over 6 mo. RESULTS: Changes in the SCFAs and TNF-α at 2 mo were positively associated (standardized coefficients: 0.06-0.40; 0.03-0.34) with changes in depression and anxiety scores at 6 mo, whereas changes in IL-1RA at 2 mo were inversely associated (standardized coefficients: -0.24; -0.05). After 2 mo, changes in 12 dietary markers, including animal protein, were associated with changes in SCFAs, TNF-α, or IL-1RA at 2 mo (standardized coefficients: -0.27 to 0.20). Changes in 11 dietary markers, including animal protein, at 2 mo were associated with changes in depression or anxiety symptom scores at 6 mo (standardized coefficients: -0.24 to 0.20; -0.16 to 0.15). CONCLUSIONS: Gut microbial metabolites and systemic inflammation may be biomarkers of importance within the MGBA, linking dietary markers, such as animal protein intake, to depression and anxiety for individuals with comorbid obesity. These findings are exploratory and warrant replication.

Transition to multiple mini interview (MMI) interviewing for medical school admissions.

INTRODUCTION: The multiple mini interview (MMI) has been incorporated into the holistic review process in the selection of students to US medical schools. The MMI has been used to evaluate interpersonal and intrapersonal attributes which are deemed as necessary for future physicians. We hypothesized that there would be little difference in overall MMI evaluation data compared with traditional interview ratings. METHODS: The University of North Carolina School of Medicine developed an interview process that included a traditional interview and MMI format during the 2019 admissions cycle. Evaluation data along with key demographic variables for 608 MD program applicants were analyzed using descriptive and inferential statistical analyses. RESULTS: The MMI format slightly favored female over male applicants (p = 0.002) but did not select for or against applicants based on age, race/ethnicity, underserved/rural area upbringing, or indicators of disadvantage. Out of 608 applicants, 356 (59%) completed a post-interview survey in which the experience was positively rated. DISCUSSION: Based on our experience, the use of a hybrid model of traditional interviews complemented with MMI stations provided greater details in the assessment of medical school applicants while obtaining equivalent data and acceptability amongst applicants.

Best Practices in North American Pre-Clinical Medical Education in Sexual History Taking: Consensus From the Summits in Medical Education in Sexual Health.

INTRODUCTION: This article discusses a blueprint for a sexual health communication curriculum to facilitate undergraduate medical student acquisition of sexual history taking skills and includes recommendations for important elements of a thorough sexual history script for undergraduate medical students. AIM: To outline the fundamentals, objectives, content, timing, and teaching methods of a gold standard curriculum in sexual health communication. METHODS: Consensus expert opinion was documented at the 2012, 2014, and 2016 Summits in Medical Education in Sexual Health. Additionally, the existing literature was reviewed regarding undergraduate medical education in sexual health. MAIN OUTCOME MEASURES: This article reports expert opinion and a review of the literature on the development of a sexual history taking curriculum. RESULTS: First-year curricula should be focused on acquiring satisfactory basic sexual history taking skills, including both assessment of sexual risk via the 5 Ps (partners, practices, protection from sexually transmitted infections, past history of sexually transmitted infections, and prevention of pregnancy) as well as assessment of sexual wellness-described here as a sixth P (plus), which encompasses the assessment of trauma, violence, sexual satisfaction, sexual health concerns/problems, and support for gender identity and sexual orientation. Second-year curricula should be focused on incorporating improved clinical reasoning, emphasizing sexual history taking for diverse populations and practices, and including the impact of illness on sexual health. Teaching methods must include varied formats. Evaluation may be best as a formative objective structured clinical examination in the first year and summative in the second year. Barriers for curriculum development may be reduced by identifying faculty champions of sexual health/medicine. CLINICAL IMPLICATIONS: Medical students will improve their skills in sexual history taking, which will ultimately impact patient satisfaction and clinical outcomes. Future research is needed to validate this proposed curriculum and assess the impact on clinical skills. STRENGTHS & LIMITATIONS: This article assimilates expert consensus and existing clinical guidelines to provide a novel structured approach to curriculum development in sexual health interviewing in the pre-clinical years. CONCLUSION: The blueprint for developing sexual history taking skills includes a spiral curriculum with varied teaching formats, incorporation of a sexual history script that incorporates inquiry about sexual wellness, and longitudinal assessment across the pre-clinical years. Ideally, sexual health communication content should be incorporated into existing clinical interviewing and physical examination courses. Rubin ES, Rullo J, Tsai P, et al. Best Practices in North American Pre-Clinical Medical Education in Sexual History Taking: Consensus From the Summits in Medical Education in Sexual Health. J Sex Med 2018;15:1414-1425.

Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells.

IUHCT of human cord blood-derived CD34+ cells into fetal NSG mice results in systemic multilineage engraftment with human cells.Preconditioning with in utero injection of an anti-c-Kit receptor antibody (ACK2) results in an improved rate of engraftment.

In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a "Block-and-Lock" Strategy for HIV-1 Treatment.

HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4+ T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation. We show that dCA mediates epigenetic silencing by increasing nucleosomal occupancy at Nucleosome-1, restricting RNAPII recruitment to the HIV-1 promoter. The efficacy of dCA was studied in the bone marrow-liver-thymus (BLT) mouse model of HIV latency and persistence. Adding dCA to ART-suppressed mice systemically reduces viral mRNA in tissues. Moreover, dCA significantly delays and reduces viral rebound levels upon treatment interruption. Altogether, this work demonstrates the potential of block-and-lock cure strategies.

Sexual Health Competencies for Undergraduate Medical Education in North America.

INTRODUCTION: The number of hours spent teaching sexual health content and skills in medical education continues to decrease despite the increase in sexual health issues faced by patients across the lifespan. In 2012 and 2014, experts across sexuality disciplines convened for the Summits on Medical School Education and Sexual Health to strategize and recommend approaches to improve sexual health education in medical education systems and practice settings. One of the summit recommendations was to develop sexual health competencies that could be implemented in undergraduate medical education curricula. AIM: To discuss the process of developing sexual health competencies for undergraduate medical education in North America and present the resulting competencies. METHODS: From 2014 to 2016, a summit multidisciplinary subcommittee met through face-to-face, phone conference, and email meetings to review prior competency-based guidelines and then draft and vet general sexual health competencies for integration into undergraduate medical school curricula. The process built off the Association of American Medical Colleges' competency development process for training medical students to care for lesbian, gay, bisexual, transgender, and gender non-conforming patients and individuals born with differences of sex development. MAIN OUTCOME MEASURES: This report presents the final 20 sexual health competencies and 34 qualifiers aligned with the 8 overall domains of competence. RESULTS: Development of a comprehensive set of sexual health competencies is a necessary first step in standardizing learning expectations for medical students upon completion of undergraduate training. CONCLUSIONS: It is hoped that these competencies will guide the development of sexual health curricula and assessment tools that can be shared across medical schools to ensure that all medical school graduates will be adequately trained and comfortable addressing the different sexual health concerns presented by patients across the lifespan. Bayer CR, Eckstrand KL, Knudson G, et al. Sexual Health Competencies for Undergraduate Medical Education in North America. J Sex Med 2017;14:535-540.

In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection.

BACKGROUND: The latent reservoir in resting CD4(+) T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents. RESULTS: Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4(+) T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4(+) T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells. CONCLUSION: We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.

CD19xCD3 DART protein mediates human B-cell depletion in vivo in humanized BLT mice.

Novel therapeutic strategies are needed for the treatment of hematologic malignancies; and bispecific antibody-derived molecules, such as dual-affinity re-targeting (DART) proteins, are being developed to redirect T cells to kill target cells expressing tumor or viral antigens. Here we present our findings of specific and systemic human B-cell depletion by a CD19xCD3 DART protein in humanized BLT mice. Administration of the CD19xCD3 DART protein resulted in a dramatic sustained depletion of human CD19(+) B cells from the peripheral blood, as well as a dramatic systemic reduction of human CD19(+) B-cell levels in all tissues (bone marrow, spleen, liver, lung) analyzed. When human CD8(+) T cells were depleted from the mice, no significant B-cell depletion was observed in response to CD19xCD3 DART protein treatment, confirming that human CD8(+) T cells are the primary effector cells in this in vivo model. These studies validate the use of BLT humanized mice for the in vivo evaluation and preclinical development of bispecific molecules that redirect human T cells to selectively deplete target cells.

Summit on medical school education in sexual health: report of an expert consultation.

INTRODUCTION.: Medical education in sexual health in the United States and Canada is lacking. Medical students and practicing physicians report being underprepared to adequately address their patients' sexual health needs. Recent studies have shown little instruction on sexual health in medical schools and little consensus around the type of material medical students should learn. To address and manage sexual health issues, medical students need improved education and training. AIM.: This meeting report aims to present findings from a summit on the current state of medical school education in sexual health and provides recommended strategies to better train physicians to address sexual health. METHODS.: To catalyze improvements in sexual health education in medical schools, the summit brought together key U.S. and Canadian medical school educators, sexual health educators, and other experts. Attendees reviewed and discussed relevant data and potential recommendations in plenary sessions and then developed key recommendations in smaller breakout groups. RESULTS.: Findings presented at the summit demonstrate that the United States and Canada have high rates of poor sexual health outcomes and that sexual health education in medical schools is variable and in some settings diminished. To address these issues, government, professional, and student organizations are working on efforts to promote sexual health. Several universities already have sexual health curricula in place. Evaluation mechanisms will be essential for developing and refining sexual health education. CONCLUSIONS.: To be effective, sexual health curricula need to be integrated longitudinally throughout medical training. Identifying faculty champions and supporting student efforts are strategies to increase sexual health education. Sexual health requires a multidisciplinary approach, and cross-sector interaction between various public and private entities can help facilitate change. Areas important to address include: core content and placement in the curriculum; interprofessional education and training for integrated care; evaluation mechanisms; faculty development and cooperative strategies. Initial recommendations were drafted for each.

miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements.

miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression are highly enriched for DNA repair and cell-cycle regulatory genes that form a direct interaction network with prominent nodes at genes that enhance (MYC, E2F2, CCNB1, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, is rescued by miR-24-insensitive E2F2. Therefore, E2F2 is a critical miR-24 target. The E2F2 3'UTR lacks a predicted miR-24 recognition element. In fact, miR-24 regulates expression of E2F2, MYC, AURKB, CCNA2, CDC2, CDK4, and FEN1 by recognizing seedless but highly complementary sequences.