Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment. (AU)

Human pluripotent stem cell (hPSC) and organoid models of autism: opportunities and limitations.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by genetic or environmental perturbations during early development. Diagnoses are dependent on the identification of behavioral abnormalities that likely emerge well after the disorder is established, leaving critical developmental windows uncharacterized. This is further complicated by the incredible clinical and genetic heterogeneity of the disorder that is not captured in most mammalian models. In recent years, advancements in stem cell technology have created the opportunity to model ASD in a human context through the use of pluripotent stem cells (hPSCs), which can be used to generate 2D cellular models as well as 3D unguided- and region-specific neural organoids. These models produce profoundly intricate systems, capable of modeling the developing brain spatiotemporally to reproduce key developmental milestones throughout early development. When complemented with multi-omics, genome editing, and electrophysiology analysis, they can be used as a powerful tool to profile the neurobiological mechanisms underlying this complex disorder. In this review, we will explore the recent advancements in hPSC-based modeling, discuss present and future applications of the model to ASD research, and finally consider the limitations and future directions within the field to make this system more robust and broadly applicable.

An Evaluation of Local Implementing Partner Performance During the First 2 Years of the USAID/PEPFAR Transition.

INTRODUCTION: Locally led and owned development is considered the best practice for international aid. As an implementing agency for the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the U.S. Agency for International Development (USAID) supported the goal of transitioning 70% of its portfolio funding directly to local organizations by 2020, including partner country governments. However, limited evidence or evaluation exists on how such a transition can help achieve HIV-related health outcomes. METHODS: We evaluated monitoring, evaluation, and reporting performance; calculated indicators; and quality of service across the HIV/AIDS treatment cascade for local and international partners in the USAID/PEPFAR portfolio implementing similar programs during the U.S. Government fiscal years (FY) 2019 to 2020 (October 1, 2018-September 30, 2020). We compared results aggregated globally, by country, and across individual partners. RESULTS: Globally, local partners met a lower proportion of their treatment targets than international partners and did not meet targets for pre-exposure prophylaxis or voluntary medical male circumcision in FY2020. However, local partners exceeded targets in programs supporting orphans, vulnerable children, and key populations affected by HIV/AIDS. Local partners also had testing positivity, linkage rates, and viral load suppression that were equivalent to or higher than that of international partners. Based on available assessments, local partners displayed quality of service delivery comparable to international partners. CONCLUSION: Local partners faced challenges, including unfamiliarity with USAID funding, increasing targets across several indicators, and the syndemics of HIV/AIDS and COVID-19. A higher percentage of targets and funding led South African local partners to yield an outsized effect on global percent target achievement. While these findings should be interpreted cautiously due to limited sample size and short time horizon, they are a key first step in evaluating the local partner transition support of the long-term goal of sustained epidemic control of HIV/AIDS.

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis.

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment.

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein-protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

TREM2 Promotes Immune Evasion by Mycobacterium tuberculosis in Human Macrophages.

Macrophage surface receptors are critical for pathogen defense, as they are the gatekeepers for pathogen entry and sensing, which trigger robust immune responses. TREM2 (triggering receptor expressed on myeloid cells 2) is a transmembrane surface receptor that mediates anti-inflammatory immune signaling. A recent study showed that TREM2 is a receptor for mycolic acids in the mycobacterial cell wall and inhibits macrophage activation. However, the underlying functional mechanism of how TREM2 regulates the macrophage antimycobacterial response remains unclear. Here, we show that Mycobacterium tuberculosis, the causative agent for tuberculosis, specifically binds to human TREM2 to disable the macrophage antibacterial response. Live but not killed mycobacteria specifically trigger the upregulation of TREM2 during macrophage infection through a mechanism dependent on STING (the stimulator of interferon genes). TREM2 facilitated uptake of M. tuberculosis into macrophages and is responsible for blocking the production of tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and reactive oxygen species (ROS), while enhancing the production of interferon-ß (IFN-ß) and IL-10. TREM2-mediated blockade of ROS production promoted the survival of M. tuberculosis within infected macrophages. Consistent with this, genetic deletion or antibody-mediated neutralization of TREM2 reduced the intracellular survival of M. tuberculosis through enhanced production of ROS. Importantly, inhibition of type I IFN signaling in TREM2-overexpressing macrophages restored the ability of these cells to produce inflammatory cytokines and ROS, resulting in normal levels of intracellular bacteria killing. Collectively, our study identifies TREM2 as an attractive host receptor for host-directed antimycobacterial therapeutics. IMPORTANCE Mycobacterium tuberculosis is one of the most ancient bacterial pathogens and remains the leading cause of death from a single bacterial agent. The success of M. tuberculosis relies greatly on its ability to parasitize and disable its host macrophages. Previous studies have found that M. tuberculosis uses its unique cell wall lipids to manipulate the immune response by binding to specific surface receptors on macrophages. Our study reveals that M. tuberculosis binds to TREM2, an immunomodulatory receptor expressed on macrophages, to facilitate a "silent" mode of entry. Increased levels of TREM2 triggered by intracellular sensing of M. tuberculosis promoted the intracellular survival of M. tuberculosis through type I IFN-driven inhibition of reactive oxygen species (ROS) and proinflammatory cytokine production. Importantly, deletion of TREM2 reversed the effects of "silent" entry and resulted in increased production of inflammatory cytokines, generation of ROS, and cell death. As such, antibody-mediated or pharmacological targeting of TREM2 could be a promising strategy for novel treatments against M. tuberculosis infection.

Development of a data utility framework to support effective health data curation.

OBJECTIVES: The value of healthcare data is being increasingly recognised, including the need to improve health dataset utility. There is no established mechanism for evaluating healthcare dataset utility making it difficult to evaluate the effectiveness of activities improving the data. To describe the method for generating and involving the user community in developing a proposed framework for evaluation and communication of healthcare dataset utility for given research areas. METHODS: Aninitial version of a matrix to review datasets across a range of dimensions wasdeveloped based on previous published findings regarding healthcare data. Thiswas used to initiate a design process through interviews and surveys with datausers representing a broad range of user types and use cases, to help develop afocused framework for characterising datasets. RESULTS: Following 21 interviews, 31 survey responses and testing on 43 datasets, five major categories and 13 subcategories were identified as useful for a dataset, including Data Model, Completeness and Linkage. Each sub-category was graded to facilitate rapid and reproducible evaluation of dataset utility for specific use-cases. Testing of applicability to >40 existing datasets demonstrated potential usefulness for subsequent evaluation in real-world practice. DISCUSSION: Theresearch has developed an evidenced-based initial approach for a framework tounderstand the utility of a healthcare dataset. It likely to require further refinementfollowing wider application and additional categories may be required. CONCLUSION: The process has resulted in a user-centred designed framework for objectively evaluating the likely utility of specific healthcare datasets, and therefore, should be of value both for potential users of health data, and for data custodians to identify the areas to provide the optimal value for data curation investment.

Historical evidence of glyphosate exposure from a US agricultural cohort.

In response to the recent review by Gillezeau et al., The evidence of human exposure to glyphosate: A review, Environmental Health 1/19/19, here we report additional glyphosate biomonitoring data from a repository of urine samples collected from United States farmers in 1997-98. To determine if glyphosate exposure could be identified historically, we examined urine samples from a biorepository of specimens collected from US dairy farmers between 1997 and 98. We compared samples from farmers who self-reported glyphosate application in the 8 h prior to sample collection to samples from farm applicators who did not report using glyphosate. Of 18 applicator samples tested, 39% showed detectable levels of glyphosate (mean concentration 4.04 µg/kg; range:1.3-12) compared to 0% detections among 17 non glyphosate applicator samples (p-value < 0.01). One of the applicator samples that tested positive for glyphosate also tested positive for AMPA. Concentrations of glyphosate were consistent with levels reported in the prior occupational biomonitoring studies reviewed by Gillezeau et al.Accurately detecting both glyphosate and AMPA in this small sample of Wisconsin farmers demonstrates a) glyphosate exposures among farmers were occurring 20 years ago, which was prior to the widespread planting of genetically engineered glyphosate tolerant crops first approved in 1996; and b) liquid chromatography tandem mass spectrometry (LC-MS/MS) can be used for sensitive characterization in cryopreserved urine samples. These data offer an important historical benchmark to which urinary levels from current and future biomonitoring studies can be compared.

Reoxidation of Chromium(III) Products Formed under Different Biogeochemical Regimes.

Hexavalent chromium, Cr(VI), is a widespread and toxic groundwater contaminant. Reductive immobilization to Cr(III) is a treatment option, but its success depends on the long-term potential for reduced chromium precipitates to remain immobilized under oxidizing conditions. In this unique long-term study, aquifer sediments subjected to reductive Cr(VI) immobilization under different biogeochemical regimes were tested for their susceptibility to reoxidation. After reductive treatment for 1 year, sediments were exposed to oxygenated conditions for another 2 years in flow-through, laboratory columns. Under oxidizing conditions, immobilized chromium reduced under predominantly denitrifying conditions was mobilized at low concentrations (≪1 µM Cr(VI); ∼ 3% of Cr(III) deposited) that declined over time. A conceptual model of a limited pool of more soluble Cr(III), and a larger pool of relatively insoluble Cr(III), is proposed. In contrast, almost no chromium was mobilized from columns reduced under predominantly fermentative conditions, and where reducing conditions persisted for several months after introduction of oxidizing conditions, presumably due to the presence of a reservoir of reduced species generated during reductive treatment. The results from this 3-year study demonstrate that biogeochemical conditions present during reductive treatment, and the potential for buildup of reducing species, will impact the long-term sustainability of the remediation effort.