Pandemic Superimposed on Epidemic: Covid-19 Disparities in Black Americans

Health and healthcare disparities are variances in the health of a population or the care rendered to a population. Disparities result in a disproportionately higher prevalence of disease or lower standard of care provided to the index group. Multiple theories exist regarding the genesis of this disturbing finding. The COVID-19 pandemic has had the unfortunate effect of amplifying health inequity in vulnerable populations. African Americans, who make up approximately 12% of the US population are reportedly being diagnosed with COVID-19 and dying at disproportionately higher rates. Viewed holistically, multiple factors are contributing to the perfect storm: 1) Limited availability of public testing, 2) A dramatic increase in low wage worker unemployment/health insurance loss especially in the service sector of the economy, 3) High rates of preexisting chronic disease states/reduced access to early healthcare and 4) Individual provider and structural healthcare system bias. Indeed, COVID-19 represents a pandemic superimposed on a historic epidemic of racial health inequity and healthcare disparities. Therapeutic solutions are not expected in the near term. Thus, identifying the genesis and magnitude of COVID-19's impact on African American communities is the requisite first step toward crafting an immediate well designed response. The mid and long term approach should incorporate population health based tactics and strategies.     

Chronic HIV-2 infection protects against total CD4+ cell depletion and rapid disease progression induced by SHIV89.6p challenge

OBJECTIVE: To better understand HIV-1 sexual transmission risk, we have studied the susceptibility of HIV-2-exposed, uninfected (EU) female pig-tailed macaques to intravaginal (IVAG) re-challenge with the homologous HIV-2 strain, followed by heterologous SHIV89.6p. METHODS: Nine female macaques, previously protected by a post-exposure prophylaxis (PEP) regimen, along with one mock-treated EU animal, were re-exposed to HIV-2 by the IVAG route approximately 1.5 years later. A single follow-up challenge was performed approximately 1 year later with SHIV89.6p to assess susceptibility of chronic HIV-2-infected animals to further re-infection and pathogenic effects with a heterologous virus, somewhat mimicking HIV-1. RESULTS: Eight of ten macaques (80%) became infected systemically with HIV-2, and plasma or cervicovaginal vRNA levels did not appreciably differ from prior historic non-PEP control macaques. Interestingly, all eight HIV-2-infected females were susceptible to SHIV89.6p infection by either intravenous (n = 4) or IVAG exposure (n = 4) after one inoculation. Plasma vRNA levels in these groups were controlled by week 8 and there were no decrease in CD4+ T cells > 50%. The remaining two HIV-2 EU macaques, inoculated intrarectally with SHIV89.6p, were unable to control virus replication and succumbed to disease by week 25 or week 61. CONCLUSIONS: Our findings demonstrate that successful PEP regimens to prevent an initial infection do not have any lasting protective effects. The observed lack of cross-protection against SHIV89.6p transmission among chronic HIV-2-infected macaques provides modeling support for limited epidemiologic data indicating that human HIV-2 infection does not protect against HIV-1 infection, but may serve to alter overt clinical outcome.     

Trait anger predicts relative left frontal cortical activation to anger-inducing stimuli.

Building on past research that has suggested that relatively greater left frontal cortical activity is associated with approach-related anger and that individuals who are high in trait anger are more likely to evidence angry responses, the present research tested whether individuals high in trait anger would be more likely to evidence relatively greater left frontal cortical activity in response to anger-eliciting pictorial stimuli. In the experiment, participants were exposed to pictures intended to evoke anger, fear/disgust, positive, or neutral affective reactions. Electroencephalographic (EEG) activity was recorded continuously, and alpha power was derived from the EEG to measure cortical activity. Trait anger was measured using the Buss and Perry Aggression Questionnaire [Buss, A.H., Perry, M., 1992. The aggression questionnaire. Journal of Personality and Social Psychology, 63, 452-459]. Results revealed that trait anger was positively related to greater relative left frontal cortical activity to anger-evoking pictures but not to other types of pictures.     

A Murine Model for Infection with Burkholderia cepacia with Sustained Persistence in the Spleen

Burkholderia cepacia is an opportunistic pathogen that causes severe systemic infections in patients with chronic granulomatous disease (CGD) or with cystic fibrosis (CF), but its mechanisms of virulence are poorly understood. We developed a murine model of systemic infection in wild-type (WT) and gamma interferon knockout (GKO) BALB/c mice to facilitate dissection of components of pathogenicity and host defense. Both WT and GKO mice were susceptible to chronic splenic infection with B. cepacia, but not with Pseudomonas aeruginosa. B. cepacia strains from patients with CGD persisted longer than those from CF patients. C57BL/6 mice were the most susceptible murine strain; bacteria persisted in the spleen for 2 months. DBA/2, BALB/c, and A/J strains of mice were relatively resistant to infection. Certain strains of B. cepacia complex can persist in the murine spleen after systemic infection; this may provide clues to its virulence in compromised hosts, such as those with CGD and CF.     

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to down-regulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94/NKG2A(+)NKG2D(+)ILT2(+) NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94/HLA-E-dependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94/NKG2A(+) NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFNalpha as well as cultured primary NK cell lines showed increased killing against DeltaUL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94(+) cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94(+) NK cells and show that this system functions during a productive infection.     

Modulation of protein phosphatase 2A activity alters androgen-independent growth of prostate cancer cells: therapeutic implications

Earlier we identified PPP2CA, which encodes for the α-isoform of protein phosphatase 2A (PP2A) catalytic subunit, as one of the downregulated genes in androgen-independent prostate cancer. PP2A is a serine/threonine phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in prostate cancer has not yet been determined. Here, we have investigated the effect of PP2A activity modulation on the androgen-independent growth of prostate cancer cells. Our data show that the PPP2CA expression and PP2A activity is downregulated in androgen-independent (C4-2) prostate cancer cells as compared with androgen-dependent (LNCaP) cells. Downregulation of PP2A activity by pharmacologic inhibition or short interfering RNA-mediated PPP2CA silencing sustains the growth of LNCaP cells under an androgen-deprived condition by relieving the androgen deprivation-induced cell-cycle arrest and preventing apoptosis. Immunoblot analyses reveal enhanced phosphorylation of Akt, extracellular signal-regulated kinase (ERK), BAD, increased expression of cyclins (A1/D1), and decreased expression of cyclin inhibitor (p27) on PP2A downregulation. Furthermore, our data show that androgen receptor (AR) signaling is partially maintained in PP2A-inhibited cells through increased AR expression and ligand-independent phosphorylation. Pharmacologic inhibition of Akt, ERK, and AR suggest a role of these signaling pathways in facilitating the androgen-independent growth of LNCaP cells. These observations are supported by the effect of ceramide, a PP2A activator, on androgen-independent C4-2 cells. Ceramide inhibited the growth of C4-2 cells on androgen deprivation, an effect that could be abrogated by PP2A downregulation. Altogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer.     

Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review

This review provides a detailed overview of the current state of knowledge about the ultrastructure and dynamics of liver sinusoidal endothelial fenestrae. Various aspects of liver sinusoidal endothelial fenestrae regarding their structure, origin, species specificity, dynamics and formation will be explored. In addition, the role of liver sinusoidal endothelial fenestrae in relation to lipoprotein metabolism, fibrosis and cancer will be approached.     

Emotion differentiation in early recovery from alcohol use disorder: Associations with in-the-moment affect and 3-month drinking outcomes

Background

Early recovery from alcohol use disorder (AUD) is commonly associated with high levels of negative affect, stress, and emotional vulnerability, which confer significant relapse risk. Emotion differentiation—the ability to distinguish between discrete emotions—has been shown to predict relapse after treatment for a drug use disorder, but this relationship has not been explored in individuals recovering from AUD.

Methods

The current study used thrice daily random and up to thrice daily self-initiated ecological momentary assessment surveys (N = 42, observations = 915) to examine whether 1) moments of high affective arousal are characterized by momentary differences in emotion differentiation among individuals in the first year of a current AUD recovery attempt, and 2) individuals’ average emotion differentiation would predict subsequent alcohol use measured by the timeline follow-back over a 3-month follow-up period.

Results

Multilevel models showed that moments (Level 1) of higher-than-average negative affect (p < 0.001) and/or stress (p = 0.033) were characterized by less negative emotion differentiation, while moments of higher-than-average positive affect were characterized by greater positive emotion differentiation (p < 0.001). At the between-person level (Level 2), participants with higher stress overall had lower negative emotion differentiation (p = 0.009). Linear regression showed that average negative, but not positive, emotion differentiation was inversely associated with percent drinking days over the subsequent 3-month follow-up period (p = 0.042). Neither form of average emotion differentiation was associated with drinking quantity.

Conclusions

We found that for individuals in early AUD recovery, affective states are associated with acute shifts in the capacity for emotion differentiation. Further, we found that average negative emotion differentiation prospectively predicts subsequent alcohol use.

     

Combinatorial detection of autoreactive CD8<Superscript>+</Superscript> T cells with HLA-A2 multimers: a multi-centre study by the Immunology of Diabetes Society T Cell Workshop

Aims/hypothesis

Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8⁺ T cell populations. Here, we set out to evaluate the performance of a combinatorial HLA-A2 multimer assay in a multi-centre setting.

Methods

The combinatorial HLA-A2 multimer assay was applied in five participating centres using centralised reagents and blinded replicate samples. In preliminary experiments, samples from healthy donors were analysed using recall antigen multimers. In subsequent experiments, samples from healthy donors and individuals with type 1 diabetes were analysed using beta cell antigen and recall antigen multimers.

Results

The combinatorial assay was successfully implemented in each participating centre, with CVs between replicate samples that indicated good reproducibility for viral epitopes (mean %CV = 33.8). For beta cell epitopes, the assay was very effective in a single-centre setting (mean %CV = 18.4), but showed sixfold greater variability across multi-centre replicates (mean %CV = 119). In general, beta cell antigen-specific CD8⁺ T cells were detected more commonly in individuals with type 1 diabetes than in healthy donors. Furthermore, CD8⁺ T cells recognising HLA-A2-restricted insulin and glutamate decarboxylase epitopes were found to occur at higher frequencies in individuals with type 1 diabetes than in healthy donors.

Conclusions/interpretation

Our results suggest that, although combinatorial multimer assays are challenging, they can be implemented in multiple laboratories, providing relevant T cell frequency measurements. Assay reproducibility was notably higher in the single-centre setting, suggesting that biomarker analysis of clinical trial samples would be most successful when assays are performed in a single laboratory. Technical improvements, including further standardisation of cytometry platforms, will likely be necessary to reduce assay variability in the multi-centre setting.