Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.

Mobile integrated health-community paramedicine programs' effect on emergency department visits: An exploratory meta-analysis.

INTRODUCTION: Mobile Integrated Health Community Paramedicine (MIH-CP) programs are designed to increase access to care and reduce Emergency Department (ED) and Emergency Medical Services (EMS) usage. Previous MIH-CP systematic reviews reported varied interventions, effect sizes, and a high prevalence of biased methods. We aimed to perform a meta-analysis on MIH-CP effect on ED visits, and to evaluate study designs' effect on reported effect sizes. We hypothesized biased methods would produce larger reported effect sizes. METHODS: We searched Pubmed, Embase, CINAHL, and Scopus databases for peer-reviewed MIH-CP literature from January 1, 2000, to July 24, 2021. We included all full-text English studies whose program met the National Associations of Emergency Medical Technicians definition, reported ED visits, and had an MIH-CP related intervention and outcome. We established risk ratios for each included study through interpreting the reported data. We performed a random-effects and cumulative meta-analysis of ED visit data, tests of heterogeneity, and a moderator analysis to assess for factors influencing the magnitude of observed effect. RESULTS: We identified 16 studies that reported ED visit data and included 12 in our meta-analysis. All studies were observational; 3 used matched controls, 6 pre-post controls, and 3 without controls. 7 studies' intervention were diversion/triage while 5 studies intervened with health education/home primary care services. Pooled risk ratio for our data set was 0.56 (95% confidence interval 0.42-0.74). Cumulative meta-analysis revealed that as of 2018 MIH-CP programs began to show consistent reductions in ED visits. Significant heterogeneity was seen among studies, with I-squared >90%. Moderator analysis showed reduced heterogeneity for matched-control studies. CONCLUSION: Our data revealed MIH-CP programs were associated with a reduced risk of ED visits. Study design did not have a statistically significant influence on effect size, though it did influence heterogeneity. We would recommend future studies continue to use high levels of control to produce reliable data with lower heterogeneity.

A Systematic Review of Methodologies and Outcome Measures of Mobile Integrated Health-Community Paramedicine Programs.

INTRODUCTION: Mobile integrated health-community paramedicine (MIH-CP) uses patient-centered, mobile resources in the out-of-hospital environment to increase access to care and reduce unnecessary emergency department (ED) usage. The objective of this systematic review is to characterize the outcomes and methodologies used by MIH-CP programs around the world and assess the validity of the ways programs evaluate their effectiveness. METHODS: The PubMed, Embase, CINAHL, and Scopus databases were searched for peer-reviewed literature related to MIH-CP programs. We included all full-length studies whose programs met the National Association of Emergency Medical Technicians definition, had MIH-CP-related interventions, and measured outcomes. We excluded all non-English papers, abstract-only, and incomplete studies. RESULTS: Our initial literature review identified 6434 titles. We screened 178 full-text studies to assess for eligibility and identified 33 studies to include in this review. These 33 include four randomized controlled trials, 17 cohort studies, eight 8 case series, and four 4 cross-sectional studies. Of the 29 non-randomized trials, five used matched controls, 13 used pre-post, and 11 used no controls. Outcomes measured were hospital usage (24 studies), ED visits (15), EMS usage (23), patient satisfaction (8), health-related outcomes (8), and cost (9). Studies that evaluated hospital usage reported one of several outcome measures: hospital admissions (11), ED length of stay (3), and hospital readmission rate (2). EMS usage was measured by ambulance transports (12) and EMS calls (10). Cost outcomes observed were ambulance transport savings (7), ED visit savings (4), hospital admission savings (3), and cost per quality-adjusted life year (2). CONCLUSION: Most studies assessing MIH-CP programs reported success of their interventions. However, significant heterogeneity of outcome measures and varying quality of study methodologies exist among studies. Future studies designed with adequately matched controls and applying uniform core metrics for cost savings and health care usage are needed to better evaluate the effectiveness of MIH-CP programs.

Post-traumatic stress in healthcare workers during the COVID-19 pandemic: A systematic review and meta-analysis.

The SARS-CoV-2 (COVID-19) pandemic has increased healthcare worker (HCW) susceptibility to mental illness. We conducted a meta-analysis to investigate the prevalence and possible factors associated with post-traumatic stress disorder (PTSD) symptoms among HCW during the COVID-19 pandemic. We searched PubMed, SCOPUS and EMBASE databases up to May 4th, 2022. We performed random effects meta-analysis and moderator analyses for the prevalence of PTSD-relevant symptoms and severe PTSD symptoms. We identified 1276 studies, reviewed 209 full-text articles, and included 119 studies (117,143 participants) with a total of 121 data points in our final analysis. 34 studies (24,541 participants) reported prevalence of severe PTSD symptoms. Approximately 25.2% of participants were physicians, 42.8% nurses, 12.4% allied health professionals, 8.9% auxiliary health professionals, and 10.8% "other". The pooled prevalence of PTSD symptoms among HCWs was 34% (95% CI, 0.30-0.39, I2 >90%), and 14% for severe PTSD (95% CI, 0.11 - 0.17, I2 >90%). The introduction of COVID vaccines was associated with a sharp decline in the prevalence of PTSD, and new virus variants were associated with small increases in PTSD rates. It is important that policies work towards allocating adequate resources towards protecting the well-being of healthcare workers to minimize adverse consequences of PTSD.

Delayed cognitive processing and treatment status quo bias in early-stage multiple sclerosis.

BACKGROUND: The evolving therapeutic landscape requires more participation of patients with relapsing remitting multiple sclerosis (RRMS) in treatment decisions. The aim of this study was to assess the association between patient's self-perception, cognitive impairment and behavioral factors in treatment choices in a cohort of patients at an early stage of RRMS. METHODS: We conducted a multicenter, non-interventional study including adult patients with a diagnosis of RRMS, a disease duration ≤18 months and receiving care at one of the 21 participating MS centers from across Spain. We used patient-reported measures to gather information on fatigue, mood, quality of life, and perception of severity of their MS. Functional metrics (Expanded Disability Status Scale [EDSS], cognitive function by the Symbol Digit Modalities Test [SDMT], 25-foot walk test) and clinical and radiological data were provided by the treating neurologist. The primary outcome of the study was status quo (SQ) bias, defined as participant's tendency to continue taking a previously selected but inferior treatment when intensification was warranted. SQ bias was assessed based on participants treatment preference in six simulated RRMS case scenarios with evidence of clinical relapses and radiological disease progression. RESULTS: Of 189 participants who met the inclusion criteria, 188 (99.5%) fully completed the study. The mean age was 36.6 ± 9.5 years, 70.7% female, mean disease duration: 1.2 ± 0.8 years, median EDSS score: 1.0 [IQR=0.0-2.0]). Overall, 43.1% patients (n = 81/188) had an abnormal SDMT (≤49 correct answers). SQ bias was observed in at least one case scenario in 72.3% (137/188). Participant's perception of their MS severity was associated with higher SQ bias (ß coeff 0.042; 95% CI 0.0074-0.076) among those with delayed cognitive processing. Higher baseline EDSS and number of T2 lesions were predictors of delayed processing speed (OR EDSS=1.57, 95% CI: 1.11-2.21, p = 0.011; OR T2 lesions=1.50, 95% CI: 1.11-2.03, p<0.01). Bayesian multilevel model accounting for clustering showed that delayed cognitive processing (exp coeff 1.06; 95% CI 1.04-1.09) and MS symptoms severity (exp coeff 1.28; 95% CI 1.22-1.33) were associated with SQ bias. CONCLUSION: Over 40% of patients in earlier stages of RRMS experience delays in cognitive processing that might affect their decision-making ability. Our findings suggest that patients' self-perception of disease severity combined with a delay in cognitive processing would affect treatment choices leading to status quo bias early in the course of their disease.

Effect of desire for pregnancy on decisions to escalate treatment in multiple sclerosis care: Differences between MS specialists and non-MS specialists.

BACKGROUND: Therapeutic inertia (TI) is a worldwide phenomenon that affects 60 to 90% of neurologists and up to 25% of daily treatment decisions during management of multiple sclerosis (MS) patients. A large volume of MS patients are women of childbearing age, and desire for pregnancy is a complex variable often affecting MS care. The objective of this study was to determine the effect of desire for pregnancy on decisions to escalate treatment during management of MS patients. METHODS: 300 neurologists with expertise in MS from 20 countries were invited to participate in the study. Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. Disaggregated discrete choice experiments were used to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. An excel calculator that provides estimates as the percentage of participants that would escalate treatment for a simulated case-scenario was constructed. RESULTS: 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per month by each neurologist was 18 (±16). Non-MS specialists were significantly less likely to escalate treatment than MS specialists across mild, moderate, and severe patient cases. These differences were accentuated when case scenarios introduced a desire for pregnancy. The findings were consistent when MRI-lesions, severity of symptoms, and number of relapses were included. CONCLUSIONS: Desire for pregnancy differentially influences decisions to escalate treatment, suggesting knowledge-to-action gaps between MS and non-MS specialists. Our findings indicate the need for educational strategies to overcome these gaps and improve clinical outcomes for MS patients who desire pregnancy.

Prevalence of myocardial infarction among patients with chest pain and cocaine use: A systematic review and meta-analysis.

BACKGROUND: Cocaine abuse is a public health burden. Cocaine is known to cause vasospasm and acute myocardial infarction (AMI). The prevalence of AMI in patients presenting with chest pain and concurrent cocaine use (CPCC) varies among studies. We performed a systemic review and meta-analysis to assess the current literature for the prevalence of AMI in patients with CPCC. METHODS: We performed a literature search of PubMed, EMBASE, and Scopus from its beginning to May 18, 2020 and updated this search on February 18, 2021. Full-text studies that assessed the primary outcome (AMI) specifically among patients with CPCC who presented to the emergency department (ED) were included. We excluded studies that were not in English, did not take place in the ED, and case reports, which only reported positive cases and not incidence of AMI. Random effect meta-analysis was performed to assess the prevalence of primary outcome and to examine correlations between risk factors and AMI. Heterogeneity was assessed by I-square value. We also performed subgroup analysis to identify potential sources of heterogeneity. RESULTS: We identified 2178 studies and screened 102 full-text studies to include 16 studies (3269 patients) in our final analysis. The pooled prevalence of AMI was 4.7% (95% CI 0.8-23), I-square of 84%. However, rates among studies of low risk patients were lower (1.1% 95% CI 0.2-5) compared to studies of mixed risk patients (7.7%, 95% 5-11). A meta-regression was used to look at correlation between risk factors and AMI and found that AMI was positively correlated in patients with a history of CAD (correlation coefficient [Corr. Coeff.] 5.6, 96% CI 2.3-8.7), HTN (Corr. Coeff. 2.9, 95% CI 0.9-4.9), DM (Corr. Coeff. 8.0, 95% CI 2.4-14), HLD (Corr. Coeff. 5.9, 95% CI 2.4, 9). Sources of potential heterogeneity included patients' risk as defined by the authors, study designs, publication year, and study sample size. CONCLUSION: The overall prevalence of AMI and death among patients with cocaine-associated chest pain was relatively low, although high risk patients were still associated with high prevalence of AMI. Clinicians should consider risk-stratify these patients and treat them accordingly.

7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder.

The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.

Safety Matters: A Meta-analysis of Interhospital Transport Adverse Events in Critically Ill Patients.

OBJECTIVE: Interhospital transport (IHT) is common among critically ill patients. Our meta-analysis investigated the prevalence and possible factors associated with adverse events (AEs) during IHT. METHODS: Searching PubMed, Embase, and Scopus databases until February 12, 2021, we included studies that a priori defined AEs for adult medical patients. We excluded case reports, non-full-text, and non-English language studies. We performed a random effects meta-analysis and moderator analyses. RESULTS: We identified 554 studies and included 19 studies (14,969 patients) in our final analysis. The mean patients' (standard deviation) age was 60 (13.7). The pooled medical AEs for IHT was 1,059 (11%, 95% confidence interval, 7.5%-16%). The most common AE (n, %) was hypotension (424, 2.8%). Moderator analyses and meta-regressions suggested that conditions (P < .001) such as respiratory failure from coronavirus infection (88%), stroke (19%), and the need for extracorporeal membrane oxygenation (40%) were associated with higher AE prevalence. Transport by nurses (31%) and physicians (11%) was associated with a higher AE prevalence, whereas transport type did not influence AE prevalence. CONCLUSION: Our study suggests the prevalence of AEs of critically ill patients during IHT is low and likely due to patients' disease severity. Further studies should focus on interventions to mitigate AEs to improve patients' outcomes.

SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury.

BACKGROUND: Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. METHODS: Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. RESULTS: Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. CONCLUSION: SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

Complication of vasopressor infusion through peripheral venous catheter: A systematic review and meta-analysis.

BACKGROUND: Vasopressors are mainstay treatment for patients in shock and are usually infused through central venous catheters (CVCs). However, CVCs are associated with risk of infection or delay from the needs of confirmation of placement. Infusing vasopressor through peripheral venous catheter (PIVs) could be an alternative in the Emergency Departments (ED) but data regarding complications is inconclusive. We performed a random-effects meta-analysis to assess literature involving prevalence of complications from infusing vasopressors via PIVs. METHODS: We searched PubMed, EMBASE and Scopus databases from beginnings to 02/02/2020 to identify relevant randomized control trials, cohort, case-control studies. We excluded case reports. Authors assessed studies' quality with Newcastle-Ottawa Scale and Cochrane Risk of Bias tool. Kappa score was used to assess interrater agreement. Outcome was complications as direct results from infusing vasopressors through PIVs. RESULTS: We identified 325 articles and included 9 studies after reviewing 16 full text articles. Our analysis included 1835 patients whose mean age was 63 (Standard Deviation 12) years and 48% was female. There were 122 (7%) complications, of which 117 (96%) were minor. The meta-analysis with random effects showed the pooled prevalence of complications as 0.086 (95%CI 0.031-0.21). Studies reporting infusion safety guidelines had significantly lower prevalence of complications (0.029, 95%CI 0.018-0.045), compared to those not reporting a safety guideline (0.12, 95%CI 0.038-0.30, p = 0.024). CONCLUSION: There was low prevalence of complications as a direct result from infusing vasopressors through PIVs. Studies with safety guidelines were associated with significantly lower prevalence of complications. Further studies are needed to confirm our observations.

Intersecting roles of ER stress, mitochondrial dysfunction, autophagy, and calcium homeostasis in HIV-associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) is a collective term describing the spectrum of neurocognitive deficits that arise from HIV infection. Although the introduction to highly active antiretroviral therapy (HAART) has prolonged the lifespan of HIV patients, neurocognitive impairments remain prevalent, as patients are left perpetually with HIV. Currently, physicians face a challenge in treating HAND patients, so a greater understanding of the mechanisms underlying HAND pathology has been a growing focus in HIV research. Recent research has revealed the role disrupted calcium homeostasis in HIV-mediated neurotoxicity. Calcium plays a well-established role in the crosstalk between the mitochondrion and ER as well as in regulating autophagy, and ER stress, mitochondrial dysfunction, and impaired autophagic activity are considered hallmarks in several neurodegenerative and neurocognitive disorders. Therefore, it is paramount that the intricate inter-organelle signaling in relation to calcium homeostasis during HIV infection and the development of HAND is elucidated. This review consolidates current knowledge regarding the neuropathology of neurocognitive disorders and HIV infection with a focus on the underlying role of calcium during ER stress, mitochondrial dysfunction, and autophagy associated with the progression of HAND. The details of this intricate crosstalk during HAND remain relatively unknown; further research in this field can potentially aid in the development of improved therapy for patients suffering from HAND.

Interplay between ER stress and autophagy: A possible mechanism in multiple sclerosis pathology.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system that results in demyelination, neurodegeneration, and axonal loss. During MS pathology, autoreactive T cells specific for self-antigens migrate the blood-brain-barrier and are responsible for the axonal and neuronal damage. ER stress, a disruption in cellular homeostasis due to the accumulation of misfolded proteins, is a hallmark of MS pathology. In response to the homeostatic imbalance, ER stress activates the unfolded protein response, an intricate system of signaling pathways that aims to restore cellular balance. During the UPR, various autophagy pathways are also activated. Autophagy is a diverse network of regulatory catabolic processes which direct the clearance of damaged and unnecessary organelles and proteins while recycling necessary cellular components. In respect to its role in the health of the immune system, autophagy is critical to the survival and proliferation of T cells. This review consolidates current knowledge and recent literature about ER stress, UPR, and autophagy in MS and implicate their crosstalk as a characteristic feature of MS, potentially aiding in the development of novel therapeutic strategies for MS research.

HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy.

Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.