Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors.

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates.

Depression after stoma surgery: a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors. METHODS: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model. REGISTRATION: PROSPERO, CRD42021262345. RESULTS: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2-58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia-Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not. CONCLUSIONS: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period.

The gut microbiome modulates the transformation of microglial subtypes.

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD.

Perturbed gut microbiota is gender-segregated in unipolar and bipolar depression.

OBJECTIVE: This study aimed to explore the gender specificity of gut microbiome in patients with unipolar and bipolar depression disorder by analyzing the data of gut microbiome in this two mental disorders and healthy people. METHODS: A case-control study using 16S ribosomal RNA gene sequencing from fecal samples of MDD (male set, n = 43; female set, n = 77) and BD (male set, n = 82; female set, n = 83) compared with HCs (male set, n = 71; female set, n = 100) was conducted. Linear discriminant analysis was used to identify microbial characteristics. Through cooccurrence analysis, the potential correlations of the differential gut microbiota in different genders was explored. Finally, the gender-specific distinguishing microorganisms were identified as biomaker, and the diagnostic performance was verified by five-fold cross validation. RESULTS: A specific cluster was found enriched only in female MDD set, including 4 Bacteroideae OTUs. Similarly, 3 Lachnospiraceae OTUs was found significantly increased in female BD compared with other groups. In addition, the consistent enrichment of Pseudomonadacea in male and female may be the characteristic disease-related gut microbiota of BD. Besides, the diagnostic potential of gender specific biomarker panel in male (male validation AUC: 0.758-0.874, accurancy: 0.693-0.792; female validation AUC: 0.727-0.883, accurancy: 0.678-0.781) and female (male validation AUC: 0.787-0.883, accurancy: 0.719-0.784; female validation AUC: 0.795-0.898, accurancy: 0.689-0.838) has also been identified and confirmed. CONCLUSIONS: The microbiological changes in both MDD and BD are sex specific, and gender specific biomarker panel has better diagnostic performance, which provide a certain reference in sex difference for future clinical differentiation and microbial intervention.

Professionalism and clinical short answer question marking with machine learning.

Machine learning may assist in medical student evaluation. This study involved scoring short answer questions administered at three centres. Bidirectional encoder representations from transformers were particularly effective for professionalism question scoring (accuracy ranging from 41.6% to 92.5%). In the scoring of 3-mark professionalism questions, as compared with clinical questions, machine learning had a lower classification accuracy (P < 0.05). The role of machine learning in medical professionalism evaluation warrants further investigation.

Achieving health equity in US suicides: a narrative review and commentary.

Suicide rates in the United States (US) reached a peak in 2018 and declined in 2019 and 2020, with substantial and often growing disparities by age, sex, race/ethnicity, geography, veteran status, sexual minority status, socioeconomic status, and method employed (means disparity). In this narrative review and commentary, we highlight these many disparities in US suicide deaths, then examine the possible causes and potential solutions, with the overarching goal of reducing suicide death disparities to achieve health equity.The data implicate untreated, undertreated, or unidentified depression or other mental illness, and access to firearms, as two modifiable risk factors for suicide across all groups. The data also reveal firearm suicides increasing sharply and linearly with increasing county rurality, while suicide rates by falls (e.g., from tall structures) decrease linearly by increasing rurality, and suicide rates by other means remain fairly constant regardless of relative county urbanization. In addition, for all geographies, gun suicides are significantly higher in males than females, and highest in ages 51-85 + years old for both sexes. Of all US suicides from 1999-2019, 55% of male suicides and 29% of female suicides were by gun in metropolitan (metro) areas, versus 65% (Male) and 42% (Female) suicides by gun in non-metro areas. Guns accounted for 89% of suicides in non-metro males aged 71-85 + years old. Guns (i.e., employment of more lethal means) are also thought to be a major reason why males have, on average, 2-4 times higher suicide rates than women, despite having only 1/4-1/2 as many suicide attempts as women. Overall the literature and data strongly implicate firearm access as a risk factor for suicide across all populations, and even more so for male, rural, and older populations.To achieve the most significant results in suicide prevention across all groups, we need 1) more emphasis on policies and universal programs to reduce suicidal behaviors, and 2) enhanced population-based strategies for ameliorating the two most prominent modifiable targets for suicide prevention: depression and firearms.

Changes in gut viral and bacterial species correlate with altered 1,2-diacylglyceride levels and structure in the prefrontal cortex in a depression-like non-human primate model.

Major depressive disorder (MDD) is a debilitating mental disease, but its underlying molecular mechanisms remain obscure. Our previously established model of naturally occurring depression-like (DL) behaviors in Macaca fascicularis, which is characterized by microbiota-gut-brain (MGB) axis disturbances, can be used to interrogate how a disturbed gut ecosystem may impact the molecular pathology of MDD. Here, gut metagenomics were used to characterize how gut virus and bacterial species, and associated metabolites, change in depression-like monkey model. We identified a panel of 33 gut virus and 14 bacterial species that could discriminate the depression-like from control macaques. In addition, using lipidomic analyses of central and peripheral samples obtained from these animals, we found that the DL macaque were characterized by alterations in the relative abundance, carbon-chain length, and unsaturation degree of 1,2-diacylglyceride (DG) in the prefrontal cortex (PFC), in a brain region-specific manner. In addition, lipid-reaction analysis identified more active and inactive lipid pathways in PFC than in amygdala or hippocampus, with DG being a key nodal player in these lipid pathways. Significantly, co-occurrence network analysis showed that the DG levels may be relevant to the onset of negative emotions behaviors in PFC. Together our findings suggest that altered DG levels and structure in the PFC are hallmarks of the DL macaque, thus providing a new framework for understanding the gut microbiome's role in depression.

Medical student knowledge and critical appraisal of machine learning: a multicentre international cross-sectional study.

To utilise effectively tools that employ machine learning (ML) in clinical practice medical students and doctors will require a degree of understanding of ML models. To evaluate current levels of understanding, a formative examination and survey was conducted across three centres in Australia, New Zealand and the United States. Of the 245 individuals who participated in the study (response rate = 45.4%), the majority had difficulty with identifying weaknesses in model performance analysis. Further studies examining educational interventions addressing such ML topics are warranted.

The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression.

Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.

Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders.

Gut microbiome disturbances have been implicated in major depressive disorder (MDD). However, little is known about how the gut virome, microbiome, and fecal metabolome change, and how they interact in MDD. Here, using whole-genome shotgun metagenomic and untargeted metabolomic methods, we identified 3 bacteriophages, 47 bacterial species, and 50 fecal metabolites showing notable differences in abundance between MDD patients and healthy controls (HCs). Patients with MDD were mainly characterized by increased abundance of the genus Bacteroides and decreased abundance of the genera Blautia and Eubacterium These multilevel omics alterations generated a characteristic MDD coexpression network. Disturbed microbial genes and fecal metabolites were consistently mapped to amino acid (γ-aminobutyrate, phenylalanine, and tryptophan) metabolism. Furthermore, we identified a combinatorial marker panel that robustly discriminated MDD from HC individuals in both the discovery and validation sets. Our findings provide a deep insight into understanding of the roles of disturbed gut ecosystem in MDD.

Offensive Behavior, Striatal Glutamate Metabolites, and Limbic-Hypothalamic-Pituitary-Adrenal Responses to Stress in Chronic Anxiety.

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.

Erratum: Perturbed Microbial Ecology in Myasthenia Gravis: Evidence from the Gut Microbiome and Fecal Metabolome.

[This corrects the article DOI: 10.1002/advs.201901441.].

Gut Microbial Signatures Can Discriminate Unipolar from Bipolar Depression.

Discriminating depressive episodes of bipolar disorder (BD) from major depressive disorder (MDD) is a major clinical challenge. Recently, gut microbiome alterations are implicated in these two mood disorders; however, little is known about the shared and distinct microbial characteristics in MDD versus BD. Here, using 16S ribosomal RNA (rRNA) gene sequencing, the microbial compositions of 165 subjects with MDD are compared with 217 BD, and 217 healthy controls (HCs). It is found that the microbial compositions are different between the three groups. Compared to HCs, MDD is characterized by altered covarying operational taxonomic units (OTUs) assigned to the Bacteroidaceae family, and BD shows disturbed covarying OTUs belonging to Lachnospiraceae, Prevotellaceae, and Ruminococcaceae families. Furthermore, a signature of 26 OTUs is identified that can distinguish patients with MDD from those with BD or HCs, with area under the curve (AUC) values ranging from 0.961 to 0.986 in discovery sets, and 0.702 to 0.741 in validation sets. Moreover, 4 of 26 microbial markers correlate with disease severity in MDD or BD. Together, distinct gut microbial compositions are identified in MDD compared to BD and HCs, and a novel marker panel is provided for distinguishing MDD from BD based on gut microbiome signatures.

Pilot trial of a group cognitive behavioural therapy program for comorbid depression and obesity.

BACKGROUND: Depression and obesity are significant global health concerns that commonly occur together. An integrated group cognitive behavioural therapy program was therefore developed to simultaneously address comorbid depression and obesity. METHODS: Twenty-four participants (63% women, mean age 46 years) who screened positively for depression with a body mass index ≥25 were recruited from a self-referred general population sample. The group therapy program (10 two-hour weekly sessions) was examined in a single-arm, before-after pilot trial, conducted in a behavioural health clinic in Adelaide, Australia. Primary outcomes included survey and assessment-based analyses of depression, anxiety, body image, self-esteem, and weight (kg), assessed at four time-points: baseline, post-intervention, three-months and 12-months post program. Eighteen participants (75%) completed the program and all assessments. RESULTS: Significant improvements in depression, anxiety, self-esteem and body shape concern scores, several quality of life domains, eating behaviours and total physical activity (among others) - but not weight - were observed over the course of the trial. CONCLUSIONS: Results from this pilot trial suggest that combining interventions for depression and obesity may be useful. Further development of the program, particularly regarding the potential for physical health benefits, and a randomised controlled trial, are warranted. TRIAL REGISTRATION: Trial registration: ANZCTR, ACTRN12617001079336, 13 July 2017. Retrospectively registered after date of the first consent (6 July 2017), but before the date of the first intervention session (20 July 2017).

Perturbed Microbial Ecology in Myasthenia Gravis: Evidence from the Gut Microbiome and Fecal Metabolome.

Myasthenia gravis (MG) is a devastating acquired autoimmune disease. Emerging evidence indicates that the gut microbiome plays a key role in maintaining immune system homeostasis. This work reports that MG is characterized by decreased α-phylogenetic diversity, and significantly disturbed gut microbiome and fecal metabolome. The altered gut microbial composition is associated with fecal metabolome changes, with 38.75% of altered bacterial operational taxonomic units showing significant correlations with a range of metabolite biomarkers. Some microbes are particularly linked with MG severity. Moreover, a combination of microbial makers and their correlated metabolites enable discriminating MG from healthy controls (HCs) with 100% accuracy. To investigate whether disturbed gut mcirobiome might contribute to the onset of MG, germ-free (GF) mice are initially colonized with MG microbiota (MMb) or healthy microbiota (HMb), and then immunized in a classic mouse model of MG. The MMb mice demonstrate substantially impaired locomotion ability compared with the HMb mice. This effect could be reversed by cocolonizing GF mice with both MMb and HMb. The MMb mice also exhibit similar disturbances of fecal metabolic pathways as found in MG. Together these data demonstrate disturbances in microbiome composition and activity that are likely to be relevant to the pathogenesis of MG.

Effect of medical student debt on mental health, academic performance and specialty choice: a systematic review.

OBJECTIVES: With the high and rising total cost of medical school, medical student debt is an increasing concern for medical students and graduates, with significant potential to impact the well-being of physicians and their patients. We hypothesised that medical student debt levels would be negatively correlated with mental health and academic performance, and would influence career direction (ie, medical specialty choice). DESIGN: We performed a systematic literature review to identify articles that assessed associations between medical student mental health, academic performance, specialty choice and debt. The databases PubMed, Medline, Embase, Scopus and PsycINFO were searched on 12 April 2017, for combinations of the medical subject headings Medical Student and Debt as search terms. Updates were incorporated on 24 April 2019. RESULTS: 678 articles were identified, of which 52 met the inclusion criteria after being reviewed in full text. The majority of studies were conducted in the USA with some from Canada, New Zealand, Scotland and Australia. The most heavily researched aspect was the association between medical student debt and specialty choice, with the majority of studies finding that medical student debt was associated with pursuit of higher paying specialties. In addition, reported levels of financial stress were high among medical students, and correlated with debt. Finally, debt was also shown to be associated with poorer academic performance. CONCLUSIONS: Medical student debt levels are negatively associated with mental well-being and academic outcomes, and high debt is likely to drive students towards choosing higher paying specialties. Additional prospective studies may be warranted, to better understand how educational debt loads are affecting the well-being, career preparation and career choices of physicians-in-training, which may in turn impact the quality of care provided to their current and future patients.