Scaling up public mental health care in Sub-Saharan Africa: insights from infectious disease.

IntroductionModels estimate that the disability burden from mental disorders in Sub-Saharan Africa (SSA) will more than double in the next 40 years. Similar to HIV, mental disorders are stigmatized in many SSA settings and addressing them requires community engagement and long-term treatment. Yet, in contrast to HIV, the public mental healthcare cascade has not been sustained, despite robust data on scalable strategies. We draw on findings from our International AIDS Society (IAS) 2020 virtual workshop and make recommendations for next steps in the scale up of the SSA public mental healthcare continuum.DiscussionEarly HIV surveillance and care cascade targets are discussed as important strategies for HIV response in SSA that should be adopted for mental health. Advocacy, including engagement with civil society, and targeted economic arguments to policymakers, are reviewed in the context of HIV success in SSA. Parallel opportunities for mental disorders are identified. Learning from HIV, communication of strategies that advance mental health care needs in SSA must be prioritized for broad global audiences.ConclusionsThe COVID-19 pandemic is setting off a colossal escalation of global mental health care needs, well-publicized across scientific, media, policymaker, and civil society domains. The pandemic highlights disparities in healthcare access and reinvigorates the push for universal coverage. Learning from HIV strategies, we must seize this historical moment to improve the public mental health care cascade in SSA and capitalize on the powerful alliances ready to be forged. As noted by Ambassador Goosby in our AIDS 2020 workshop, 'The time is now'

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya.

BackgroundMental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework.Methods/designWe will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale -up.DiscussionThe results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information - a critical gap for addressing a leading global cause of disability.Trial registrationClinicalTrials.gov NCT03466346, registered March 15, 2018

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya

Abstract Background Mental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. Methods/design We will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale –up. Discussion The results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information – a critical gap for addressing a leading global cause of disability. Trial registration ClinicalTrials.gov NCT03466346 , registered March 15, 2018.http://deepblue.lib.umich.edu/bitstream/2027.42/173667/1/12888_2019_Article_2395.pd

Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression

The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Ptenflox/flox;Amhr2cre/+). The majority of Ptenflox/flox;Amhr2cre/+ mice featured no ovarian anomalies, but occasionally (∼7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Ptenflox/flox;Amhr2cre/+ GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+) resulted in the development of GCT similar to those observed in Ptenflox/flox;Amhr2cre/+ mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT

The Mammalian Ovary from Genesis to Revelation

Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago