Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. METHODS: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. RESULTS: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). CONCLUSION: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk.

MOG CNS Autoimmunity and MOGAD.

At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis.

Life-Threatening MOG Antibody-Associated Hemorrhagic ADEM With Elevated CSF IL-6.

Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.

Citrate cross-feeding by Pseudomonas aeruginosa supports lasR mutant fitness.

Cross-feeding of metabolites between subpopulations can affect cell phenotypes and population-level behaviors. In chronic Pseudomonas aeruginosa lung infections, subpopulations with loss-of-function (LOF) mutations in the lasR gene are common. LasR, a transcription factor often described for its role in virulence factor expression, also impacts metabolism, which, in turn, affects interactions between LasR+ and LasR- genotypes. Prior transcriptomic analyses suggested that citrate, a metabolite secreted by many cell types, induces virulence factor production when both genotypes are together. An unbiased analysis of the intracellular metabolome revealed broad differences including higher levels of citrate in lasR LOF mutants. Citrate consumption by LasR- strains required the CbrAB two-component system, which relieves carbon catabolite repression and is elevated in lasR LOF mutants. Within mixed communities, the citrate-responsive two-component system TctED and its gene targets OpdH (porin) and TctABC (citrate transporter) that are predicted to be under catabolite repression control were induced and required for enhanced RhlR/I-dependent signaling, pyocyanin production, and fitness of LasR- strains. Citrate uptake by LasR- strains markedly increased pyocyanin production in co-culture with Staphylococcus aureus, which also secretes citrate and frequently co-infects with P. aeruginosa. This citrate-induced restoration of virulence factor production by LasR- strains in communities with diverse species or genotypes may offer an explanation for the contrast observed between the markedly deficient virulence factor production of LasR- strains in monocultures and their association with the most severe forms of cystic fibrosis lung infections. These studies highlight the impact of secreted metabolites in mixed microbial communities.IMPORTANCECross-feeding of metabolites can change community composition, structure, and function. Here, we unravel a cross-feeding mechanism between frequently co-observed isolate genotypes in chronic Pseudomonas aeruginosa lung infections. We illustrate an example of how clonally derived diversity in a microbial communication system enables intra- and inter-species cross-feeding. Citrate, a metabolite released by many cells including P. aeruginosa and Staphylococcus aureus, was differentially consumed between genotypes. Since these two pathogens frequently co-occur in the most severe cystic fibrosis lung infections, the cross-feeding-induced virulence factor expression and fitness described here between diverse genotypes exemplify how co-occurrence can facilitate the development of worse disease outcomes.

Estimates of HIV testing at visits to United States emergency departments.

OBJECTIVES: Emergency department-based HIV testing rates are historically low, but recent testing trends surrounding the COVID-19 pandemic and launch of the Ending the HIV Epidemic (EHE) initiative are unknown. The objective of the study is to estimate recent trends in the proportion of emergency department visits that included HIV testing. METHODS: We performed a cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted nationally representative survey of US emergency departments, from 2014 to 2020. Given EHE's focus on several rural Southern jurisdictions as well as populations disproportionately affected by HIV, we stratified by characteristics including US region and visit-listed race and ethnicity. RESULTS: The proportion of emergency department visits that included HIV testing increased from 2014 (0.6%) to 2018 (1.1%) but was lower in 2019 and 2020 (0.8%). Compared with other regions, the South had the lowest rates of testing in both 2019 (0.6%) and 2020 (0.5%); testing rates in the nonmetropolitan South remained 0.1% or less across all years. Testing rates for emergency department visits by persons who identified as Hispanic/Latino were highest in 2018 (2.2%) but were sharply lower in 2019 and 2020 (0.8%). CONCLUSION: After a small but insufficient increase in emergency department-based HIV testing since 2014, rates decreased between 2018 and 2019 and were stable between 2019 and 2020. Overall, very few emergency department visits during our entire study period included an HIV test, and there were persistently low rates of HIV testing for populations prioritized in national efforts and during visits in rural jurisdictions in the South.

Comparison of US emergency departments by HIV priority jurisdiction designation: A case for geographically targeted screening in teaching hospitals.

The Ending the HIV Epidemic (EHE) Initiative targets a subset of United States (US) priority jurisdictions hardest hit by HIV. It remains unclear which emergency departments (EDs) are the most appropriate targets for EHE-related efforts. To explore this, we used the 2001-2019 National Emergency Department Inventories (NEDI)-USA as a framework to characterize all US EDs, focusing on those in priority jurisdictions and those affiliated with a teaching hospital. We then incorporate multivariable regression to explore the association between ED characteristics and location in an HIV priority jurisdiction. Further, to provide context on the communities these EDs serve, demographic and socioeconomic information and sexually transmitted infection case rate data were included. This reflected 2019 US Census Bureau data on age, race, ethnicity, and proportion uninsured and living in poverty along with 2001-2019 Centers for Disease Control and Prevention case rate data on chlamydia, gonorrhea, and syphilis. We found that EDs in priority jurisdictions (compared to EDs not in priority jurisdictions) more often served populations emphasized in HIV-related efforts (i.e., Black or African American or Hispanic or Latino populations), communities with higher proportions uninsured and living in poverty, and counties with higher rates of chlamydia, gonorrhea, and syphilis. Further, of the groups studied, EDs with teaching hospital affiliations had the highest visit volumes and had steady visit volume growth. In regression, ED annual visit volume was associated with an increased odds of an ED being located in a priority jurisdiction. Our results suggest that geographically targeted screening for HIV in a subset of US priority jurisdiction EDs with a teaching hospital affiliation could be an efficient means to reach vulnerable populations and reduce the burden of undiagnosed HIV in the US.

Citrate cross-feeding between Pseudomonas aerguinosa genotypes supports lasR mutant fitness.

Across the tree of life, clonal populations-from cancer to chronic bacterial infections - frequently give rise to subpopulations with different metabolic phenotypes. Metabolic exchange or cross-feeding between subpopulations can have profound effects on both cell phenotypes and population-level behavior. In Pseudomonas aeruginosa, subpopulations with loss-of-function mutations in the lasR gene are common. Though LasR is often described for its role in density-dependent virulence factor expression, interactions between genotypes suggest potential metabolic differences. The specific metabolic pathways and regulatory genetics enabling such interactions were previously undescribed. Here, we performed an unbiased metabolomics analysis that revealed broad differences in intracellular metabolomes, including higher levels of intracellular citrate in LasR- strains. We found that while both strains secreted citrate, only LasR- strains, consumed citrate in rich media. Elevated activity of the CbrAB two component system which relieves carbon catabolite repression enabled citrate uptake. Within mixed genotype communities, we found that the citrate responsive two component system TctED and its gene targets OpdH (porin) and TctABC (transporter) required for citrate uptake were induced and required for enhanced RhlR signalling and virulence factor expression in LasR- strains. Enhanced citrate uptake by LasR- strains eliminates differences in RhlR activity between LasR+ and LasR- strains thereby circumventing the sensitivity of LasR- strains to quorum sensing controlled exoproducts. Citrate cross feeding also induces pyocyanin production in LasR- strains co-cultured with Staphylococcus aureus, another species known to secrete biologically-active concentrations of citrate. Metabolite cross feeding may play unrecognized roles in competitive fitness and virulence outcomes when different cell types are together. IMPORTANCE: Cross-feeding can change community composition, structure and function. Though cross-feeding has predominantly focused on interactions between species, here we unravel a cross-feeding mechanism between frequently co-observed isolate genotypes of Pseudomonas aeruginosa. Here we illustrate an example of how such clonally-derived metabolic diversity enables intraspecies cross-feeding. Citrate, a metabolite released by many cells including P. aeruginosa, was differentially consumed between genotypes, and this cross-feeding induced virulence factor expression and fitness in genotypes associated with worse disease.

Citrate cross-feeding between Pseudomonas aerguinosa genotypes supports lasR mutant fitness.

Across the tree of life, clonal populations-from cancer to chronic bacterial infections - frequently give rise to subpopulations with different metabolic phenotypes. Metabolic exchange or cross-feeding between subpopulations can have profound effects on both cell phenotypes and population-level behavior. In Pseudomonas aeruginosa, subpopulations with loss-of-function mutations in the lasR gene are common. Though LasR is often described for its role in density-dependent virulence factor expression, interactions between genotypes suggest potential metabolic differences. The specific metabolic pathways and regulatory genetics enabling such interactions were previously undescribed. Here, we performed an unbiased metabolomics analysis that revealed broad differences in intracellular metabolomes, including higher levels of intracellular citrate in LasR- strains. We found that while both strains secreted citrate, only LasR- strains, consumed citrate in rich media. Elevated activity of the CbrAB two component system which relieves carbon catabolite repression enabled citrate uptake. Within mixed genotype communities, we found that the citrate responsive two component system TctED and its gene targets OpdH (porin) and TctABC (transporter) required for citrate uptake were induced and required for enhanced RhlR signalling and virulence factor expression in LasR- strains. Enhanced citrate uptake by LasR- strains eliminates differences in RhlR activity between LasR+ and LasR- strains thereby circumventing the sensitivity of LasR- strains to quorum sensing controlled exoproducts. Citrate cross feeding also induces pyocyanin production in LasR- strains co-cultured with Staphylococcus aureus, another species known to secrete biologically-active concentrations of citrate. Metabolite cross feeding may play unrecognized roles in competitive fitness and virulence outcomes when different cell types are together. IMPORTANCE: Cross-feeding can change community composition, structure and function. Though cross-feeding has predominantly focused on interactions between species, here we unravel a cross-feeding mechanism between frequently co-observed isolate genotypes of Pseudomonas aeruginosa. Here we illustrate an example of how such clonally-derived metabolic diversity enables intraspecies cross-feeding. Citrate, a metabolite released by many cells including P. aeruginosa, was differentially consumed between genotypes, and this cross-feeding induced virulence factor expression and fitness in genotypes associated with worse disease.

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/ß usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.

The Overweight and Obese Patient in Oculofacial Plastic Surgery: A Narrative Review.

PURPOSE: The oculofacial plastic surgeon will more frequently encounter challenges related to overweight and obese patients as the incidence rises. There is a paucity of data in the oculofacial plastic surgical literature regarding this topic. The goal of this review is to detail the role obesity plays in the perioperative course and the considerations for a surgeon treating this patient population. METHODS: The authors conducted a computerized search using PubMed, Embase, and Google Scholar. The search terms used were "(obesity OR overweight) AND surgery," "(obesity OR overweight) AND oculoplastic," "(obesity OR overweight) AND oculofacial," "(obesity OR overweight) AND 'facial plastic surgery', " "(obesity OR overweight) AND 'bariatric surgery', " "(obesity OR overweight) AND (pre-operative OR post-operative OR intraoperative," " (obesity OR overweight) AND complications," "(obesity OR overweight) AND (facial plastic surgery) AND complications)," "(obesity OR overweight) AND eyelid," "(obesity OR overweight) AND (nasolacrimal OR 'nasolacrimal duct')," "(obesity OR overweight) AND IIH," "(obesity OR overweight) AND exophthalmos." RESULTS: A total of 127 articles, published from 1952 to 2022 in the English language or with English translations were included. Articles published earlier than 2000 were cited for foundational knowledge. References cited in the identified articles were also used to gather further data for the review. CONCLUSIONS: Overweight and obese patients pose specific challenges that the oculofacial plastic surgeon should be aware of to better optimize patient outcomes. Multiple comorbidities, poor wound healing, and nutritional deficits all contribute to the complications experienced in this patient population. Further investigation on overweight and obese patients is needed.

Characteristics of California Emergency Departments in Centers for Disease Control and Prevention-Designated HIV Priority Counties.

BACKGROUND: Refocused national HIV testing initiatives include a geographic focus. OBJECTIVE: Using a geographic focus, we sought to identify which emergency departments (EDs) might be the most efficient targets for future HIV testing efforts, using California as an example. METHODS: Retrospective analysis of California EDs, emergency physicians, and patients served, along with county-level estimates of HIV prevalence and proportion of the population living in poverty. Emphasis was placed on characterizing EDs affiliated with teaching hospitals and those located in Centers for Disease Control (CDC) and Prevention HIV priority counties. RESULTS: Of the 320 EDs studied, 178 were in priority counties, 29 were affiliated with teaching hospitals, and 24 had both characteristics. Of the 12,869,889 ED visits included, 61.8% occurred in priority counties, 14.7% in EDs affiliated with teaching hospitals, and 12.0% in EDs with both characteristics. The subset of EDs in priority counties with teaching hospital affiliations (compared with priority and nonpriority county ED groups without a teaching hospital affiliation) had higher overall median visit volumes and higher proportions of visits by at-risk and CDC-targeted populations (e.g., individuals who were homeless, those who identified as Black or African American race, and those who identified as Hispanic or Latino ethnicity, all p < 0.01). CONCLUSIONS: EDs in priority counties affiliated with teaching hospitals are major sources of health care in California. These EDs more often serve populations disproportionately impacted by HIV. These departments are efficient targets to direct testing efforts. Increasing testing in these EDs could reduce the burden of undiagnosed HIV in California.

Effect of very low nicotine content cigarettes on alcohol drinking and smoking among adult smokers who are at-risk alcohol drinkers.

Alcohol and tobacco use are interrelated. This study examined response to very low nicotine content (VLNC) and moderate nicotine content (MNC) cigarettes by problematic drinking. We utilized a double-blind, randomized, within-subjects crossover design of VLNC and MNC cigarettes in two groups of adult cigarette smokers: with at-risk drinking (ARD; n = 23) and without ARD (n = 24). Participants smoked only their assigned experimental cigarette in their home environment for 7 days, and completed laboratory visits, including ad libitum smoking of the assigned experimental cigarette, at the beginning and end of each experimental week. Participants smoked their usual cigarettes for 7 days between conditions. Participants provided daily reports of alcohol and cigarette consumption. Current Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) alcohol use disorder (AUD) was assessed at baseline and the end of each experimental week. Compliance with smoking of experimental cigarettes was good. Adjusting for baseline drinking, there was no significant effect of experimental cigarette or ARD group on drinks per day or alcohol urges. There was no effect of experimental cigarette or ARD group on cigarettes per day, or on any puff topography outcome or postsmoking exhaled carbon monoxide during laboratory smoking. No participant had a change in AUD status or AUD severity. After 7 days of exposure to VLNC cigarettes, adult cigarette smokers with ARD did not show compensatory drinking or compensatory smoking behavior. A future policy change in the United States to reduce nicotine content in cigarettes may not produce unintended compensatory drinking or smoking among this vulnerable and prevalent population of smokers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dissipative Formation of Covalent Basket Cages.

Living systems use chemical fuels to transiently assemble functional structures. As a step toward constructing abiotic mimics of such structures, we herein describe dissipative formation of covalent basket cage CBC 5 by reversible imine condensation of cup-shaped aldehyde 2 (i.e., basket) with trivalent aromatic amine 4. This nanosized [4+4] cage (V=5 nm3 , Mw =6150 Da) has shape of a truncated tetrahedron with four baskets at its vertices and four aromatic amines forming the faces. Importantly, tris-aldehyde basket 2 and aliphatic tris-amine 7 undergo condensation to give small [1+1] cage 6. The imine metathesis of 6 and aromatic tris-amine 4 into CBC 5 was optimized to bias the equilibrium favouring 6. Addition of tribromoacetic acid (TBA) as a chemical fuel perturbs this equilibrium to result in the transient formation of CBC 5, with subsequent consumption of TBA via decarboxylation driving the system back to the starting state.

United States 2020 Emergency Medicine Resident Workforce Analysis.

STUDY OBJECTIVE: To characterize the emergency medicine resident physician workforce and the residency programs training them. METHODS: We identified emergency medicine residents in the 2020 American Medical Association (AMA) Physician Masterfile, analyzed demographic information, mapped both county-level population-adjusted and hospital referral region densities, and compared 2020 versus 2008 resident physician densities. We also analyzed all Accreditation Council for Graduate Medical Education (ACGME)-accredited emergency medicine residency programs from 2013 to 2020, mapped state-level population-adjusted densities, and identified temporal trends in program location and state-level program densities. All population-adjusted densities were calculated using the US Census Bureau resident population estimates. RESULTS: There were 6,993 emergency medicine residents in the 2020 AMA dataset with complete information. Most of them (98%) were in urban areas. Compared with 2008, per 100,000 US population, this represents disproportionate increases in urban areas (total [0.5], urban [0.5], large rural [0.2] and small rural [0.05]). We further identified 160 (2013) to 265 (2020) residency programs using the ACGME data. The new programs were 3-year training programs that were disproportionately added to states with an already higher number of programs (Florida [5 to 19], Michigan [11 to 25], New York [21 to 31], Ohio [9 to 18], Pennsylvania [12 to 21], California [14 to 22]). CONCLUSION: The number of emergency medicine residency programs has increased; most new programs were added to the states that already had emergency medicine residency programs. There is an emergency physician "desert" in the rural United States, lacking both residents and residency training programs. This analysis provides essential context to the ongoing conversation about the future of the emergency physician workforce.

HIV Testing at Visits to US Emergency Departments, 2018.

BACKGROUND: An early HIV diagnosis improves patient outcomes, reduces the burden of undiagnosed HIV, and limits transmission. There is a need for an updated assessment of HIV testing rates in the emergency department (ED). SETTING: The National Hospital Ambulatory Medical Care Survey sampling ED visits were weighted to give an estimate of ED visits across all US states in 2018. METHODS: We analyzed patients aged 13-64 years without known HIV and estimated ED visits with HIV testing and then stratified by race, ethnicity, and region. Descriptive statistics and mapping were used to illustrate and compare patient, visit, and hospital characteristics for visits with HIV testing. RESULTS: Of 83.0 million weighted visits to EDs in 2018 by patients aged 13-64 years without a known HIV infection (based on 13,237 National Hospital Ambulatory Medical Care Survey sample visits), HIV testing was performed in 1.05% of visits. HIV testing was more frequent for patients aged 13-34 years compared with that for patients aged 35-64 years (1.32% vs. 0.82%, P = 0.056), Black patients compared with that for White and other patients (1.73% vs. 0.79% and 0.41%, P = 0.002), Hispanic or Latino patients compared with that for non-Hispanic or Latino patients (2.18% vs. 0.84%, P = 0.001), and patients insured by Medicaid compared with that for patients insured by private or other insurance (1.71% vs. 0.64% and 0.96%, P = 0.003). HIV testing rates were the highest in the Northeast (1.72%), followed by the South (1.05%). CONCLUSIONS: HIV testing occurred in a minority of ED visits. There are differences in rates of HIV testing by race, ethnicity, and location. Although rates of testing have increased, rates of ED-based HIV testing remain low.

Ocular surface disease in thyroid eye disease: A narrative review.

Ocular surface disease (OSD) in the setting of thyroid eye disease (TED) is traditionally thought of as a natural consequence of anatomical changes such as proptosis and corneal exposure. However, a growing body of research suggests that ocular surface inflammation and multi-factorial changes to the homeostasis of the ocular surface contribute substantially to the OSD seen in TED patients. In this paper we review the existing literature which highlights the work and existing theories underlying this new paradigm shift.

Age-related immune alterations and cerebrovascular inflammation.

Aging is associated with chronic systemic inflammation, which contributes to the development of many age-related diseases, including vascular disease. The world's population is aging, leading to an increasing prevalence of both stroke and vascular dementia. The inflammatory response to ischemic stroke is critical to both stroke pathophysiology and recovery. Age is a predictor of poor outcomes after stroke. The immune response to stroke is altered in aged individuals, which contributes to the disparate outcomes between young and aged patients. In this review, we describe the current knowledge of the effects of aging on the immune system and the cerebral vasculature and how these changes alter the immune response to stroke and vascular dementia in animal and human studies. Potential implications of these age-related immune alterations on chronic inflammation in vascular disease outcome are highlighted.

Sex differences in the immune response to acute COVID-19 respiratory tract infection.

BACKGROUND: Sex differences in COVID-19 are increasingly recognized globally. Although infection rates are similar between the sexes, men have more severe illness. The mechanism underlying these sex differences is unknown, but a differential immune response to COVID-19 has been implicated in several recent studies. However, how sex differences shape the immune response to COVID-19 remains understudied. METHODS: We collected demographics and blood samples from over 600 hospitalized patients diagnosed with COVID-19 from May 24th 2020 to April 28th, 2021. These patients were divided into two cohorts: Cohort 1 was further classified into three groups based on the severity of the disease (mild, moderate and severe); Cohort 2 patients were longitudinally followed at three time points from hospital admission (1 day, 7 days, and 14 days). MultiPlex and conventional ELISA were used to examine inflammatory mediator levels in the plasma in both cohorts. Flow cytometry was conducted to examine leukocyte responses in Cohort 2. RESULTS: There were more COVID+ males in the total cohort, and the mortality rate was higher in males vs. females. More male patients were seen in most age groups (in 10-year increments), and in most ethnic groups. Males with severe disease had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) than females; levels of IL-8, GRO, sCD40L, MIP-1ß, MCP-1 were also significantly higher in severe vs. mild or control patients in males but not in females. Females had significantly higher anti-inflammatory cytokine IL-10 levels at 14 days compared to males, and the level of IL-10 significantly increased in moderate vs. the control group in females but not in males. At 7 days and 14 days, males had significantly more circulating neutrophils and monocytes than females; however, B cell numbers were significantly higher in females vs. males. CONCLUSION: Sex differences exist in hospitalized patients with acute COVID-19 respiratory tract infection. Exacerbated inflammatory responses were seen in male vs. female patients, even when matched for disease severity. Males appear to have a more robust innate immune response, and females mount a stronger adaptive immune response to COVID-19 respiratory tract infection.