Arterial stiffness measurements in pregnancy as a predictive tool for hypertensive disorders of pregnancy and preeclampsia: Protocol for a systematic review and meta-analysis.

Hypertensive disorders of pregnancy (HDPs) are a leading cause of maternal morbidity and mortality worldwide. Unfortunately, accurate early clinical screening methods for the development of these disorders are lacking. Arterial stiffness (AS) is an important hemodynamic indicator of vascular health that has shown promising results for the prediction of HDP onset. Past systematic reviews in the field have reported an increase in AS indices in women who develop HDPs and have highlighted the potential of AS measurements as a predictive tool early in pregnancy. The most recent systematic review, including papers up to 2015, assessed the differences in AS parameters between women with and without pregnancy complications. Since then, there has been a substantial influx of published research on the topic and a growing interest in the incorporation of AS measurements into clinical practice. Thus, we propose a systematic review and meta-analysis that is more inclusive to all HDP subsets and various hemodynamic indices of vascular health to provide a comprehensive overview of the current state of evidence. Specifically, we aim to evaluate these measures in women who develop HDPs compared to normotensive pregnancies to determine which measures are most associated with and/or can predict the development of HDPs. Major databases (Medline, Embase, The Cochrane Library, Web of Science, PubMed, and CINAHL), grey literature (Google Scholar) and clinical trials (clinicaltrials.gov) will be searched to identify studies that report AS and hemodynamic measurements in pregnant women with and without HDPs. No restrictions will be made on study type or year. Articles will be independently evaluated by three authors to determine eligibility based on inclusion and exclusion criteria. Methodological quality of included studies will be assessed. Pooled analyses will be conducted using a random-effects model. Publication bias and between-study heterogeneity will also be assessed. Sources of heterogeneity will be explored by sensitivity, subgroup, and/or meta-regression analyses. Results from this study will be shared through scientific conferences and publications in scientific journals. The analysis of potential AS and hemodynamic markers for HDP onset will help inform the development of screening guidelines and clinically relevant cut-off values of AS and hemodynamic markers for HDP risk, guiding future research. There are no applicable ethical considerations to the writing of this protocol.

Anxiety, depression, and quality of life among subgroups of individuals with acquired brain injury: The role of anxiety sensitivity and experiential avoidance.

OBJECTIVES: The objectives of this observational cohort study were to 1) cluster individuals with acquired brain injury (ABI) into subgroups according to their level of anxiety sensitivity (AS) and experiential avoidance (EA), and 2) compare subgroups with respect to anxiety, depression, and quality of life (QoL). METHODS: Individuals were recruited from an ABI outpatient clinic in Ontario, Canada and completed comprehensive psychosocial questionnaires. A two-step cluster analysis was performed to identify unique subgroups based on the clustering variables Anxiety Sensitivity Index (ASI) and Acceptance and Action Questionnaire (AAQ) which measure AS and EA, respectively. Clinical outcome measures were compared between clusters using multivariate analysis of variance: Generalized Anxiety Disorder 7 item (anxiety); Patient Health Questionnaire-9 (depression), and EQ-5D overall health item (QoL). RESULTS: Among 86 participants included for analysis (mean age 47.1±14.2 years, 54.7% female), three unique clusters were produced. ASI and AAQ were significantly different among all groups (p < 0.001). Cluster 1 (n = 26) had the lowest levels of AS and EA whereas Cluster 3 (n = 24) had the highest levels of AS and EA; Cluster 2 (n = 36) had moderate levels of AS and EA. There was no significant difference between groups in age, gender, time since injury, or Glasgow Coma Scale scores. Cluster 3 had significantly higher anxiety and depression scores than Cluster 1 and 2 (p < 0.001 for all). Further, Cluster 2 had significantly higher anxiety and depression scores than Cluster 1 (p < 0.001 for all). There was no significant difference in EQ-5D scores between Clusters 1 and 2 or Cluster 2 and 3; however, Cluster 3 scored significantly lower on EQ-5D than Cluster 1 (p = 0.032). CONCLUSIONS: There exists a subgroup of individuals with ABI that have high levels of AS and EA; this was associated with greater symptoms of anxiety and depression, and poorer QoL. Interventions to address AS and EA may improve mood and QoL in this population.

Implementing Telerehabilitation After Stroke: Lessons Learned from Canadian Trials.

Introduction: Telerehabilitation has been promoted as a more efficient means of delivering rehabilitation services to stroke patients while also providing care options to those unable to attend conventional therapy. However, the application of telerehabilitation interventions in stroke populations has proven to be more challenging than anticipated, with many studies showing mixed results in terms of its efficacy. Six different clinical trials examining stroke telerehabilitation were initiated across Canada as part of the Heart and Stroke Foundation's 2013 Tele-Rehabilitation for Stroke Initiative, with interventions ranging from lifestyle coaching to delivering memory, speech, or physical training. The purpose of this article was to summarize the over-arching findings from this initiative, particularly the facilitators and barriers to the implementation of telerehabilitation services within a research context. Methods: Details of the projects were obtained directly from the study investigators and from materials published by each group. Qualitative open-ended questions were posed to each group for the discussion of lessons learned. Results: Important lessons learned from this initiative included: (1) the efficacy and cost of telerehabilitation is similar to that of traditional face-to-face management; (2) patients are satisfied with telerehabilitation services when trained appropriately and some social interaction occurs; (3) clinicians prefer face-to-face interactions but will use telerehabilitation when face-to-face is not feasible; and (4) technology should be selected based on ease of use and targeted to the skills and abilities of the users. Conclusions: Overall, results from these studies suggest that telerehabilitation services work best to augment face-to-face rehabilitation or when no other options are available.

Evaluating the effectiveness of aquatic therapy on mobility, balance, and level of functional independence in stroke rehabilitation: a systematic review and meta-analysis.

OBJECTIVE: To meta-analyze and systematically review the effectiveness of aquatic therapy in improving mobility, balance, and functional independence after stroke. DATA SOURCES: Articles published in Medline, Embase, CINAHL, PsycINFO, and Scopus up to 20 August 2019. STUDY SELECTION: Studies met the following inclusion criteria: (1) English, (2) adult stroke population, (3) randomized or non-randomized prospectively controlled trial (RCT or PCT, respectively) study design, (4) the experimental group received >1 session of aquatic therapy, and (5) included a clinical outcome measure of mobility, balance, or functional independence. DATA EXTRACTION: Participant characteristics, treatment protocols, between-group outcomes, point measures, and measures of variability were extracted. Methodological quality was assessed using Physiotherapy Evidence Database (PEDro) tool, and pooled mean differences (MD) ± standard error and 95% confidence intervals (CI) were calculated for Functional Reach Test (FRT), Timed Up and Go Test (TUG), gait speed, and Berg Balance Scale (BBS). DATA SYNTHESIS: Nineteen studies (17 RCTs and 2 PCTs) with a mean sample size of 36 participants and mean PEDro score of 5.6 (range 4-8) were included. Aquatic therapy demonstrated statistically significant improvements over land therapy on FRT (MD = 3.511 ± 1.597; 95% CI: 0.381-6.642; P = 0.028), TUG (MD = 2.229 ± 0.513; 95% CI: 1.224-3.234; P < 0.001), gait speed (MD = 0.049 ± 0.023; 95% CI: 0.005-0.094; P = 0.030), and BBS (MD = 2.252 ± 0.552; 95% CI: 1.171-3.334; P < 0.001). CONCLUSIONS: While the effect of aquatic therapy on mobility and balance is statistically significant compared to land-based therapy, the clinical significance is less clear, highly variable, and outcome measure dependent.

Chloroquine Restores Ganglioside Homeostasis and Improves Pathological and Behavioral Outcomes Post-stroke in the Rat.

Perturbations of ganglioside homeostasis have been observed following stroke whereby toxic simple gangliosides GM2 and GM3 accumulate, while protective complex species GM1 and GD1 are reduced. Thus, there is a need for therapeutic interventions which can prevent ganglioside dysregulation after stroke. A pharmacological intervention using chloroquine was selected for its transient lysosomotropic properties which disrupt the activity of catabolic ganglioside enzymes. Chloroquine was administered both in vitro (0.1 µM), to primary cortical neurons exposed to GM3 toxicity, and in vivo (45 mg/kg i.p.), to 3-month-old male Wistar rats that underwent a severe stroke injury. Chloroquine was administered for seven consecutive days beginning 3 days prior to the stroke injury. Gangliosides were examined using MALDI imaging mass spectrometry at 3 and 21 days after the injury, and motor deficits were examined using the ladder task. Chloroquine treatment prevented ganglioside dysregulation 3 days post-stroke and partially prevented complex ganglioside depletion 21 days post-stroke. Exogenous GM3 was found to be toxic to primary cortical neurons which was protected by chloroquine treatment. Motor deficits were prevented in the forelimbs of stroke-injured rats with chloroquine treatment and was associated with decreased inflammation, neurodegeneration, and an increase in cell survival at the site of injury. Chloroquine administration prevents ganglioside dysregulation acutely, protects against GM3 toxicity in neurons, and is associated with long-term functional and pathological improvements after stroke in the rat. Therefore, targeting lipid dysregulation using lysosomotropic agents such as chloroquine may represent a novel therapeutic avenue for stroke injuries.

Membrane-lipid homeostasis in a prodromal rat model of Alzheimer's disease: Characteristic profiles in ganglioside distributions during aging detected using MALDI imaging mass spectrometry.

BACKGROUND: Accumulation of simple gangliosides GM2 and GM3, and gangliosides with longer long-chain bases (d20:1) have been linked to toxicity and the pathogenesis of Alzheimer's disease (AD). Conversely, complex gangliosides, such as GM1, have been shown to be neuroprotective. Recent evidence using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) has demonstrated that a-series gangliosides are differentially altered during normal aging, yet it remains unclear how simple species are shifting relative to complex gangliosides in the prodromal stages of AD. METHODS: Ganglioside profiles in wild-type (Wt) and transgenic APP21 Fischer rats were detected and quantified using MALDI-IMS at P0 (birth), 3, 12, and 20 months of age and each species quantified to allow for individual species comparisons. RESULTS: Tg APP21 rats were found to have a decreased level of complex gangliosides in a number of brain regions as compared to Wt rats and showed higher levels of simple gangliosides. A unique pattern of expression was observed in the white matter as compared to gray matter regions, with an age-dependent decrease in GD1 d18:1 species observed and significantly elevated levels of GM3 in Tg APP21 rats. CONCLUSIONS: These results are indicative of a pathological shift in ganglioside homeostasis during aging that is exacerbated in Tg APP21 rats. GENERAL SIGNIFICANCE: Ganglioside dysregulation may occur in the prodromal stages of neurodegenerative diseases like AD.

Age-dependent and regional heterogeneity in the long-chain base of A-series gangliosides observed in the rat brain using MALDI Imaging.

Alterations in the long chain base of the sphingosine moiety of gangliosides have been shown to play a role in neurodevelopment and neurodegeneration. Indeed, the accumulation of d20:1 sphingosine has been referred to as a metabolic marker of aging in the brain, however, this remains to be shown in simple gangliosides GM2 and GM3. In this study, Matrix-assisted laser desorption/ionization Imaging Mass Spectrometry (MALDI IMS) was used to examine the neuroanatomical distribution of A-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1) in Fisher 344 rats across the lifespan. The ratio of d20:1/d18:1 species was determined across 11 regions of interest in the brain. Interestingly, a decrease in the d20:1/d18:1 ratio for GM2 and GM3 was observed during early development with the exception of the peri-ventricular corpus callosum, where an age-dependent increase was observed for ganglioside GM3. An age-dependent increase in d20:1 species was confirmed for complex gangliosides GM1 and GD1 with the most significant increase during early development and a high degree of anatomical heterogeneity during aging. The unique neuroanatomically-specific responses of d20:1 ganglioside abundance may lead to a better understanding of regional vulnerability to damage in the aging brain.

Sublimation of DAN Matrix for the Detection and Visualization of Gangliosides in Rat Brain Tissue for MALDI Imaging Mass Spectrometry.

Sample preparation is key for optimal detection and visualization of analytes in Matrix-assisted Laser Desorption/Ionization (MALDI) Imaging Mass Spectrometry (IMS) experiments. Determining the appropriate protocol to follow throughout the sample preparation process can be difficult as each step must be optimized to comply with the unique characteristics of the analytes of interest. This process involves not only finding a compatible matrix that can desorb and ionize the molecules of interest efficiently, but also selecting the appropriate matrix deposition technique. For example, a wet matrix deposition technique, which entails dissolving a matrix in solvent, is superior for desorption of most proteins and peptides, whereas dry matrix deposition techniques are particularly effective for ionization of lipids. Sublimation has been reported as a highly efficient method of dry matrix deposition for the detection of lipids in tissue by MALDI IMS due to the homogeneity of matrix crystal deposition and minimal analyte delocalization as compared to many wet deposition methods 1,2. Broadly, it involves placing a sample and powdered matrix in a vacuum-sealed chamber with the samples pressed against a cold surface. The apparatus is then lowered into a heated bath (sand or oil), resulting in sublimation of the powdered matrix onto the cooled tissue sample surface. Here we describe a sublimation protocol using 1,5-diaminonaphthalene (DAN) matrix for the detection and visualization of gangliosides in the rat brain using MALDI IMS.

Differential Anatomical Expression of Ganglioside GM1 Species Containing d18:1 or d20:1 Sphingosine Detected by MALDI Imaging Mass Spectrometry in Mature Rat Brain.

GM1 ganglioside plays a role in essential neuronal processes, including differentiation, survival, and signaling. Yet, little is known about GM1 species with different sphingosine bases, such as the most abundant species containing 18 carbon atoms in the sphingosine chain (GM1d18:1), and the less abundant containing 20 carbon atoms (GM1d20:1). While absent in the early fetal brain, GM1d20:1 continues to increase throughout pre- and postnatal development and into old age, raising questions about the functional relevance of the GM1d18:1 to GM1d20:1 ratio. Matrix-assisted laser desorption/ionization imaging mass spectrometry is a novel technology that allows differentiation between these two GM1 species and quantification of their expression within an anatomical context. Using this technology, we find GM1d18:1/d20:1 expression ratios are highly specific to defined anatomical brain regions in adult rats. Thus, the ratio was significantly different among different thalamic nuclei and between the corpus callosum and internal capsule. Differential GM1d18:1/GM1d20:1 ratios measured in hippocampal subregions in rat brain complement previous studies conducted in mice. Across layers of the sensory cortex, opposing expression gradients were found for GM1d18:1 and GM1d20:1. Superficial layers demonstrated lower GM1d18:1 and higher GM1d20:1 signal than other layers, while in deep layers GM1d18:1 expression was relatively high and GM1d20:1 expression low. By far the highest GM1d18:1/d20:1 ratio was found in the amygdala. Differential expression of GM1 with d18:1- or d20:1-sphingosine bases in the adult rat brain suggests tight regulation of expression and points toward a distinct functional relevance for each of these GM1 species in neuronal processes.

Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of Aß Toxicity and Stroke.

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer's disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain's response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aß) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aß toxicity, rats received intracerebralventricular (i.c.v.) injections of the toxic 25-35 fragment of the Aß peptide (Aß alone group). To model the combination of Aß toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aß25-35 (combined Aß/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aß. By 21 d, GM2 levels only remained elevated in the combined Aß/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aß/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aß/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke.