The Utility of Echocardiogram in the Workup of Ischemic Stroke Patients.

BACKGROUND: Cardiac sources of emboli can be identified by transthoracic echocardiogram (TTE). The Canadian Best Practice Guidelines recommend routine use of TTE in the initial workup of ischemic stroke when an embolic source is suspected. However, TTEs are commonly ordered for all patients despite insufficient evidence to justify cost-effectiveness. We aim to evaluate the TTE ordering pattern in the initial workup of ischemic stroke at a regional Stroke Center in Central South Ontario and determine the proportion of studies which led to a change in management and affected length of stay (LOS). METHODS: Hospital records of 520 patients with a discharge diagnosis of TIA or ischemic stroke between October 2016 and June 2017 were reviewed to gather information. RESULTS: 477 patients admitted for TIA or ischemic stroke met inclusion criteria. 67.9% received TTE, out of which 6.0% had findings of cardiac sources of emboli including left ventricular thrombus, atrial septal aneurysm, PFO, atrial myxoma, and valvular vegetation. 2.5% of all TTE findings led to change in medical management. The median LOS of patients who underwent TTE was 2 days longer (p < 0.00001). CONCLUSION: TTE in the initial workup of TIA or ischemic stroke remains common practice. The yield of TTEs is low, and the proportion of studies that lead to changes in medical management is minimal. TTE completion was associated with increased LOS and may result in increased healthcare spending; however, additional factors prolonging the LOS could not be excluded.

Effects of delay to stroke unit admission in patients with ischemic and hemorrhagic stroke.

OBJECTIVE: To determine the association between delay in transfer to a central stroke unit from peripheral institutions and outcomes. METHODS: We conducted a retrospective cohort study of all patients with acute stroke, admitted to a comprehensive stroke center (CSC) from three emergency departments (EDs), between 2016 and 2018. The primary outcomes were length of stay, functional status at 3 months, discharge destination, and time to stroke investigations. RESULTS: One thousand four hundred thirty-five patients were included, with a mean age of 72.9 years, and 92.4% ischemic stroke; 663 (46.2%) patients were female. Each additional day of delay was associated with 2.0 days of increase in length of stay (95% confidence interval [CI] 0.8-3.2, p = 0.001), 11.5 h of delay to vascular imaging (95% CI 9.6-13.4, p < 0.0001), 24.2 h of delay to Holter monitoring (95% CI 7.9-40.6, p = 0.004), and reduced odds of nondisabled functional status at 3 months (odds ratio 0.98, 95% CI 0.96-1.00, p = 0.01). Factors affecting delay included stroke onset within 6 h of ED arrival (605.9 min decrease in delay, 95% CI 407.9-803.9, p < 0.0001), delay to brain imaging (59.4 min increase in delay for each additional hour, 95% CI 48.0-71.4, p < 0.0001), admission from an alternative service (3918.7 min increase in delay, 95% CI 3621.2-4079.9, p < 0.0001), and transfer from a primary stroke center (PSC; 740.2 min increase in delay, 95% CI 456.2-1019.9, p < 0.0001). CONCLUSION: Delay to stroke unit admission in a system involving transfer from PSCs to a CSC was associated with longer hospital stay and poorer functional outcomes.

Oral treatment with Lactobacillus rhamnosus attenuates behavioural deficits and immune changes in chronic social stress.

BACKGROUND: Stress-related disorders involve systemic alterations, including disruption of the intestinal microbial community. Given the putative connections between the microbiota, immunity, neural function, and behaviour, we investigated the potential for microbe-induced gut-to-brain signalling to modulate the impact of stress on host behaviour and immunoregulation. METHODS: Male C57BL/6 mice treated orally over 28 days with either Lactobacillus rhamnosus (JB-1) ™ or vehicle were subjected to chronic social defeat and assessed for alterations in behaviour and immune cell phenotype. 16S rRNA sequencing and mass spectrometry were employed to analyse the faecal microbial community and metabolite profile. RESULTS: Treatment with JB-1 decreased stress-induced anxiety-like behaviour and prevented deficits in social interaction with conspecifics. However, JB-1 did not alter development of aggressor avoidance following social defeat. Microbial treatment attenuated stress-related activation of dendritic cells while increasing IL-10+ regulatory T cells. Furthermore, JB-1 modulated the effect of stress on faecal metabolites with neuroactive and immunomodulatory properties. Exposure to social defeat altered faecal microbial community composition and reduced species richness and diversity, none of which was prevented by JB-1. Stress-related microbiota disruptions persisted in vehicle-treated mice for 3 weeks following stressor cessation. CONCLUSIONS: These data demonstrate that despite the complexity of the gut microbiota, exposure to a single microbial strain can protect against certain stress-induced behaviours and systemic immune alterations without preventing dysbiosis. This work supports microbe-based interventions for stress-related disorders.

Gut Microbiome Patterns Associated With Treatment Response in Patients With Major Depressive Disorder.

OBJECTIVES: Compelling animal data exists examining the impact of the gut microbiome on the brain, but work is required to translate these findings in a clinical population. We sought to do this by exploring the effects of antidepressant medications on the gut microbiota, and establishing a baseline Major Depressive Disorder (MDD) gut phenotype. METHODS: Participants with a primary diagnosis of MDD (n = 15) who were nonmedicated were recruited and followed over 6 months. Stool samples were collected prior to treatment initiation and 3 and 6 months following treatment. 16S rRNA sequencing was employed in order to analyze the gut microbial community profile. Symptom severity was measured by the Beck Depression Inventory. Alpha diversity metrics revealed no significant difference in the community diversity across any of the time-points. RESULTS: Comparison of within-group versus between-group distances revealed a lack of clustering of samples based on time-point, suggesting no significant change in the microbiota across treatment duration. When analyzed based on treatment response, however, patients in the responder group exhibited greater phylogenetic diversity than non-responders (Mann-Whitney U = 5, p = 0.026). At 3-months, 35 Operational Taxonomic Units (OTUs) were significantly different between groups and at 6-months, 42 OTUs were significantly different between responders and non-responders. CONCLUSIONS: These observations indicate that antidepressant medications alter the gut microbiota of patients with MDD, with disparate effects in responders versus non responders. This supports the concept of a microbiota phenotype associate with treatment response in MDD.

Protocol for a systematic review and meta-analysis assessing conservative versus liberal intravenous fluid administration in patients with sepsis or septic shock at risk of fluid overload.

INTRODUCTION: Intravenous crystalloid fluid resuscitation forms a crucial part of the early intervention bundle for sepsis and septic shock, with the Surviving Sepsis Campaign guidelines recommending a 30 mL/kg fluid bolus within the first hour. Compliance with this suggested target varies in patients with comorbidities such as congestive heart failure, chronic kidney disease and cirrhosis due to concerns regarding iatrogenic fluid overload. However, it remains unclear whether resuscitation with higher fluid volumes puts them at greater risk of adverse outcomes. Thus, this systematic review will synthesise evidence from existing studies to assess the effects of a conservative as compared with a liberal approach to fluid resuscitation in patients at greater perceived risk of fluid overload due to comorbid conditions. METHODS AND ANALYSIS: This protocol was registered on PROSPERO and has been drafted following the checklist of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will search MEDLINE, MEDLINE Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations, Embase, Embase Classic, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, CINAHL Complete and ClinicalTrials.gov. A preliminary search of these databases was performed from their inception to 30 August 2022. The risk of bias and random errors will be assessed using the revised Cochrane risk-of-bias tool for randomised clinical trials and the Newcastle-Ottawa Scale for case-control and cohort studies. If a sufficient number of comparable studies are identified, we will perform a meta-analysis applying random effects model. We will investigate heterogeneity using a combination of visual inspection of the funnel plot as well as the Egger's test. ETHICS AND DISSEMINATION: No ethics approval is required for this study since no original data will be collected. The findings will be disseminated through peer-reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42022348181.

Changes in the gut microbiome associated with infliximab in patients with bipolar disorder.

OBJECTIVES: Available information exists supporting the gut-brain axis, but additional information is needed to explore how the gut microbiome changes when exposed to mood disorder treatments. We sought to explore the effects of a novel treatment for bipolar disorder (BD), infliximab, on the gut microbiome. METHODS: Participants with a primary diagnosis of BD (n = 15) who participated in a 12-week, randomized placebo-controlled trial evaluating the efficacy of adjunctive infliximab in the treatment of BD were recruited and followed. Stool samples were collected prior to randomization and at 12 weeks. 16S rRNA sequencing was employed in order to analyze the gut microbial community profile. RESULTS: A total of 17 participants were randomized to infliximab (n = 9; mean [SD] age, 47.6 [10.3] years; 8 female) or to placebo (n = 8; mean [SD] age, 45.9 [10.7] years; 7 female) but two participants from the infliximab group were lost to follow-up post randomization. Across all time points, there were no differences in the diversity on either Shannon or Simpson's Diversity indices. Comparison of Aitchison distances revealed a lack of clustering of the microbiota by time point, but did reveal a small overall effect of treatment that was not significantly different at individual time points. There were also no effects of either time or treatment on differential abundance at either the amplicon sequence variant or genus level. CONCLUSIONS: These observations indicate that no community-wide changes in the microbiota diversity and profile were detected after the use of infliximab treatment.

Ingestion of Lactobacillus rhamnosus modulates chronic stress-induced feather pecking in chickens.

Feather pecking (FP) is a stress-induced neuropsychological disorder of birds. Intestinal dysbiosis and inflammation are common traits of these disorders. FP is, therefore, proposed to be a behavioral consequence of dysregulated communication between the gut and the brain. Probiotic bacteria are known to favorably modulate the gut microbiome and hence the neurochemical and immune components of the gut-brain axis. Consequently, probiotic supplementation represents a promising new therapeutic to mitigate widespread FP in domestic chickens. We monitored FP, gut microbiota composition, immune markers, and amino acids related to the production of neurochemicals in chickens supplemented with Lactobacillus rhamnosus or a placebo. Data demonstrate that, when stressed, the incidence of FP increased significantly; however, L. rhamnosus prevented this increase. L. rhamnosus supplementation showed a strong immunological effect by increasing the regulatory T cell population of the spleen and the cecal tonsils, in addition to limiting cecal microbiota dysbiosis. Despite minimal changes in aromatic amino acid levels, data suggest that catecholaminergic circuits may be an interesting target for further studies. Overall, our findings provide the first data supporting the use of a single-strain probiotic to reduce stress-induced FP in chickens and promise to improve domestic birds' welfare.

Increased persistence of avoidance behaviour and social deficits with L.rhamnosus JB-1 or selective serotonin reuptake inhibitor treatment following social defeat.

Chronic social defeat (CSD) in mice has been suggested as a model for studying post-traumatic stress disorder (PTSD). Our previous work indicated that exposure to Lactobacillus rhamnosus JB-1 (JB-1) during CSD can attenuate subsequent behavioural and immune disruption, suggesting a potential for microbe based therapeutic approaches in PTSD. In the current study, we assessed the ability of JB-1 to mitigate the behavioral consequences of CSD when treatment is instigated in the early post-stress period and compared the probiotic effects with those of the selective serotonin reuptake inhibitor (SSRI), sertraline. JB-1 or sertraline were administered orally 48 h following 10-days of CSD in male C57BL/6 mice. Contrary to our hypothesis of a beneficial effect, 30 days of treatment with either JB-1 or sertraline increased the persistence of both aggressor avoidance and reduced sociability in defeated mice. This was accompanied by lower hippocampal mRNA expression for genes related to fear memory. Defeated mice treated with either JB-1 or sertraline also exhibited systemic immune changes, with a decrease in Th1 cells, activated monocytes, and the monocyte chemoattractant CCL2. This study identifies potentially detrimental effects of both JB-1 and sertraline if administered in the early post-trauma period and suggests caution should be applied when considering psychobiotic or SSRI based approaches for early intervention in trauma related psychiatric disorders.

Publisher Correction: Increased persistence of avoidance behaviour and social deficits with L.rhamnosus JB-1 or selective serotonin reuptake inhibitor treatment following social defeat.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The vagus nerve is necessary for the rapid and widespread neuronal activation in the brain following oral administration of psychoactive bacteria.

There is accumulating evidence that certain gut microbes modulate brain chemistry and have antidepressant-like behavioural effects. However, it is unclear which brain regions respond to bacteria-derived signals or how signals are transmitted to distinct regions. We investigated the role of the vagus in mediating neuronal activation following oral treatment with Lactobacillus rhamnosus (JB-1). Male Balb/c mice were orally administered a single dose of saline or a live or heat-killed preparation of a physiologically active bacterial strain, Lactobacillus rhamnosus (JB-1). 165 min later, c-Fos immunoreactivity in the brain was mapped, and mesenteric vagal afferent fibre firing was recorded. Mice also underwent sub-diaphragmatic vagotomy to investigate whether severing the vagus prevented JB-1-induced c-Fos expression. Finally, we examined the ΔFosB response following acute versus chronic bacterial treatment. While a single exposure to live and heat-killed bacteria altered vagal activity, only live treatment induced rapid neural activation in widespread but distinct brain regions, as assessed by c-Fos expression. Sub-diaphragmatic vagotomy abolished c-Fos immunoreactivity in most, but not all, previously responsive regions. Chronic, but not acute treatment induced a distinct pattern of ΔFosB expression, including in previously unresponsive brain regions. These data identify that specific brain regions respond rapidly to gut microbes via vagal-dependent and independent pathways, and demonstrate that acute versus long-term exposure is associated with differential responses in distinct brain regions.

Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling.

The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.

Reverse Engineering the Febrile System.

Fever, the elevation of core body temperature by behavioral or physiological means, is one of the most salient aspects of human sickness, yet there is debate regarding its functional role. In this paper, we demonstrate that the febrile system is an evolved adaptation shaped by natural selection to coordinate the immune system to fight pathogens. First, we show that previous arguments in favor of fever being an adaptation are epistemologically inadequate, and we describe how an adaptationist strategy addresses this issue more effectively. Second, we argue that the mechanisms producing fever provide clear indications of adaptation. Third, we demonstrate that there are many beneficial immune system responses activated during fever and that these responses are not mere byproducts of heat on chemical reactions. Rather, we show that natural selection appears to have modified several immune system effects to be coordinated by fever. Fourth, we argue that there are some adaptations that coordinate the febrile system with other important fitness components, particularly growth and reproduction. Finally, we discuss evidence that the febrile system may also have evolved an antitumor function, providing suggestions for future research into this area. This research informs the debate on the functional value of fever and antipyretic use.

Structural & functional consequences of chronic psychosocial stress on the microbiome & host.

INTRODUCTION: Given the lasting impact of psychological distress on behavior, along with the role of the microbiome in neurobehavioral development, we sought to examine the relationship between the microbiota and stress-induced behavioral deficits. METHODS: Male C57BL/6 mice exposed to chronic social defeat were subjected to behavioral analysis and profiling of the intestinal microbiome. Mice were also analyzed for phenotypic and functional immune changes. A computational approach on 16S rRNA marker gene sequences was used to predict functional changes in the metagenome as a consequence of structural shifts in the microbiota. RESULTS: Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community, along with distinct shifts at the level of operational taxonomic units (OTU) across phyla. The degree of deficits in social, but not exploratory behavior was correlated with group differences between the microbial community profile. In silico analysis predicted a shift in the functional profile of the microbiome: defeated mice exhibited reduced functional diversity and a lower prevalence of pathways involved in the synthesis and metabolism of neurotransmitter precursors and short-chain fatty acids. Defeated mice also exhibited sustained alterations in dendritic cell activation, and transiently elevated levels of IL-10+ T regulatory cells that were suppressed over time. CONCLUSIONS: This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses and complex OTU-level shifts in the microbiota. It is thus suggested that a dysbiotic state, along with specific changes in microbial markers, may predict the onset of adverse neurocognitive deficits commonly observed following exposure to severe stressors. The data also predict novel pathways that might underlie microbiota-mediated effects on brain and behavior, thus presenting targets for investigations into mechanisms and potential therapy.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.