Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.

Serological response to vaccination in post-acute sequelae of COVID.

BACKGROUND: Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC. METHODS: We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity. RESULTS: Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden. CONCLUSION: We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.

Retrospective Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Symptomatic Patients Prior to Widespread Diagnostic Testing in Southern California.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused one of the worst pandemics in recent history. Few reports have revealed that SARS-CoV-2 was spreading in the United States as early as the end of January. In this study, we aimed to determine if SARS-CoV-2 had been circulating in the Los Angeles (LA) area at a time when access to diagnostic testing for coronavirus disease 2019 (COVID-19) was severely limited. METHODS: We used a pooling strategy to look for SARS-CoV-2 in remnant respiratory samples submitted for regular respiratory pathogen testing from symptomatic patients from November 2019 to early March 2020. We then performed sequencing on the positive samples. RESULTS: We detected SARS-CoV-2 in 7 specimens from 6 patients, dating back to mid-January. The earliest positive patient, with a sample collected on January 13, 2020 had no relevant travel history but did have a sibling with similar symptoms. Sequencing of these SARS-CoV-2 genomes revealed that the virus was introduced into the LA area from both domestic and international sources as early as January. CONCLUSIONS: We present strong evidence of community spread of SARS-CoV-2 in the LA area well before widespread diagnostic testing was being performed in early 2020. These genomic data demonstrate that SARS-CoV-2 was being introduced into Los Angeles County from both international and domestic sources in January 2020.

COVID-19 shines a light on health inequities in communities of color: A youth-driven photovoice inquiry.

This manuscript reports on a youth-driven health assessment engaging youth of color in identifying community health priorities during the coronavirus disease 2019 (COVID-19) pandemic. Photovoice, a participatory visual ethnographic health assessment strategy, was used to explore the question: What does health or healthiness mean to you and/or your community? Youth captured images that represented their priorities. The photos were discussed using the SHOWed framework and analyzed thematically. Four themes related to community health were identified. Additionally, youth captured their narrative of COVID-19 as "a revealing force that highlights systemic inequities, driving individuals and communities to both cultivate their resilience and take healthcare into their own hands in response to government and policy level failures." Youth are acutely aware of the historical and structural inequities that create multi-level barriers to healthcare access. Health inequities existed long before the pandemic, but the current crisis requires us to examine ways to transform the healthcare landscape moving forward.

Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.

Barth syndrome is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is a phospholipid of the inner mitochondrial membrane essential for the function of numerous mitochondrial proteins and processes. However, it is unclear how tafazzin deficiency impacts cardiac mitochondrial metabolism. To address this question while avoiding confounding effects of cardiomyopathy on mitochondrial phenotype, we utilized Taz-shRNA knockdown (TazKD ) mice, which exhibit defective cardiolipin remodeling and respiratory supercomplex instability characteristic of human Barth syndrome but normal cardiac function into adulthood. Consistent with previous reports from other models, mitochondrial H2O2 emission and oxidative damage were greater in TazKD than in wild-type (WT) hearts, but there were no differences in oxidative phosphorylation coupling efficiency or membrane potential. Fatty acid and pyruvate oxidation capacities were 40-60% lower in TazKD mitochondria, but an up-regulation of glutamate oxidation supported respiration rates approximating those with pyruvate and palmitoylcarnitine in WT. Deficiencies in mitochondrial CoA and shifts in the cardiac acyl-CoA profile paralleled changes in fatty acid oxidation enzymes and acyl-CoA thioesterases, suggesting limitations of CoA availability or "trapping" in TazKD mitochondrial metabolism. Incubation of TazKD mitochondria with exogenous CoA partially rescued pyruvate and palmitoylcarnitine oxidation capacities, implicating dysregulation of CoA-dependent intermediary metabolism rather than respiratory chain defects in the bioenergetic impacts of tafazzin deficiency. These findings support links among cardiolipin abnormalities, respiratory supercomplex instability, and mitochondrial oxidant production and shed new light on the distinct metabolic consequences of tafazzin deficiency in the mammalian heart.

Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia.

BACKGROUND: Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. METHODS: We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations <90% on oxygen support with most intubated. We examined clinical and laboratory parameters including oxygen and vasopressor requirements, cytokine profiles, and C-reactive protein (CRP) levels pre- and post-tocilizumab treatment. RESULTS: Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. CONCLUSIONS: Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

Impact of Clinical Decision Support on Antibiotic Prescribing for Acute Respiratory Infections: a Cluster Randomized Implementation Trial.

BACKGROUND: Clinical decision support (CDS) is a promising tool for reducing antibiotic prescribing for acute respiratory infections (ARIs). OBJECTIVE: To assess the impact of previously effective CDS on antibiotic-prescribing rates for ARIs when adapted and implemented in diverse primary care settings. DESIGN: Cluster randomized clinical trial (RCT) implementing a CDS tool designed to guide evidence-based evaluation and treatment of streptococcal pharyngitis and pneumonia. SETTING: Two large academic health system primary care networks with a mix of providers. PARTICIPANTS: All primary care practices within each health system were invited. All providers within participating clinic were considered a participant. Practices were randomized selection to a control or intervention group. INTERVENTIONS: Intervention practice providers had access to an integrated clinical prediction rule (iCPR) system designed to determine the risk of bacterial infection from reason for visit of sore throat, cough, or upper respiratory infection and guide evidence-based evaluation and treatment. MAIN OUTCOME(S): Change in overall antibiotic prescription rates. MEASURE(S): Frequency, rates, and type of antibiotics prescribed in intervention and controls groups. RESULTS: 33 primary care practices participated with 541 providers and 100,573 patient visits. Intervention providers completed the tool in 6.9% of eligible visits. Antibiotics were prescribed in 35% and 36% of intervention and control visits, respectively, showing no statistically significant difference. There were also no differences in rates of orders for rapid streptococcal tests (RR, 0.94; P = 0.11) or chest X-rays (RR, 1.01; P = 0.999) between groups. CONCLUSIONS: The iCPR tool was not effective in reducing antibiotic prescription rates for upper respiratory infections in diverse primary care settings. This has implications for the generalizability of CDS tools as they are adapted to heterogeneous clinical contexts. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02534987). Registered August 26, 2015 at https://clinicaltrials.gov.

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation.

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability-the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors-that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.

"Cure" Versus "Clinical Remission": The Impact of a Medication Description on the Willingness of People Living with HIV to Take a Medication.

Many people living with HIV (PLWHIV) state that they would be willing to take significant risks to be "cured" of the virus. However, how they interpret the word "cure" in this context is not clear. We used a randomized survey to examine whether PLWHIV had a different willingness to take a hypothetical HIV medication if it causes flu-like symptoms, but provides: (a) cure, (b) remission that was labeled "cure", or (c) remission. PLWHIV (n = 454) were more willing to take a medication that provided a "cure" versus a "remission" if the side effects lasted less than 1 year. PLWHIV were more willing to take a medication that provided a remission that was labeled "cure" versus a "remission" (p = 0.01) if the side effects lasted 2 weeks. Clinicians and researchers should be aware of the impact of the word "cure" and ensure that PLWHIV fully understand the possible outcomes of their treatment options.

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics.

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

Retrospective Review of Oral Probiotic Therapy.

Purpose: There have been many in vitro studies reporting on the efficacy of probiotic bacteria in inhibiting pathogens, and there have been published studies reporting on the inhibitor effects of probiotic bacteria on the salivary levels of bacterial pathogens. However, there have not been but a few studies on the clinical benefits of oral probiotic therapy. Study design: Dental records of 60 patients that were enrolled in an Institutional Review Board approved study were reviewed as to current caries activity status with measurement of the Decayed Missing Filled Teeth index and by Caries Management By Risk Assessment (CAMBRA) determination. The current oral health status was compared to the prior-to-study enrollment status and then analyzed in respect to published national norms. The data (without any identifiers) had a statistical analysis by a blinded biostatistician. The data was subjected to statistical analysis (Statsgraphic) before and after the probiotic therapy. Results: Of the 53 subjects available for follow up, only 4 had remained caries active with a grand total of 27 carious lesions being detected and subsequently restored in this group. Of the original total of 60 patients with 292 initial carious lesions, after probiotic therapy and dental restoration, 78 total restorations were placed in the subject group over the following three years. Approximately half of these restorations were required in teeth that had initially presented with smaller lesions and had been placed in a "watch" category. Two of the patients that developed further carious lesions had been randomly assigned to the probiotic PerioBalance, while the other two caries active patients were assigned EvoraKids probiotic. Of the original group of caries active patients, 24 did not present with any further carious involvement. Another 25 could be categorized as caries static, as the restorations required were substantially less than before probiotic therapy had been begun. The F-ratio, which in this case equals 51.3313, is a ratio of the between-group estimate to the within-group estimate. Since the P-value of the F-test is less than 0.05, there is a statistically significant difference between the means of the 4 variables at the 95.0% confidence level. Conclusion: The tested probiotic supplements had a statistically significant effect on the caries experience of the enrolled subjects.

Novel bi-allelic splice mutations in CARD9 causing adult-onset Candida endophthalmitis.

CARD9 deficiency (CANDF2; OMIM# 212050) is an autosomal-recessive monogenic inborn error of immunity conferring susceptibility to invasive fungal diseases, including the very distinct syndrome of spontaneous central nervous system candidiasis, in which opportunistic yeast of the genus Candida infect the central nervous system (either brain parenchyma and/or meninges) in the absence of trauma, chemotherapy or underlying systemic disease. We present a patient with spontaneous endophthalmitis of the right eye due to Candida albicans; further investigations revealed concomitant cerebral abscess. She had a history of left endophthalmitis due to the dematiaceous mould, Aureobasidium pullulans, 15 years earlier. Targeted sequencing of the CARD9 gene revealed 2 novel variants (c.184G>A and c.288C>T). Analysis in silico predicted each variant altered splicing, which was confirmed by sequencing of cDNA from proband and carrier offsprings: c.184G>A results in a 4-base pair frameshift deletion with loss of allelic expression; c.288C>T results in an in-frame 36-bp pair deletion with detectable protein. CARD9 deficiency can present with a phenotype of spontaneous candidal endophthalmitis. We report 2 novel mutations in CARD9, both affecting splicing, expanding the range of morbid variants causing CARD9 deficiency, emphasising the importance of both genomic and cDNA sequencing for this condition.

Afebrile Infants Evaluated in the Emergency Department for Serious Bacterial Infection.

OBJECTIVES: Afebrile infants 0 to 60 days of age are sometimes evaluated for serious bacterial infection (SBI). Our objective was to describe the clinical and laboratory findings in this population and compare them to their febrile counterparts. METHODS: We performed a retrospective observational study comparing afebrile infants undergoing an SBI evaluation to those evaluated for fever. RESULTS: We included infants who were admitted to the hospital and had at least 2 of 3 following bacterial cultures: blood, urine, or cerebrospinal fluid. Of the 1184 infants presenting to the emergency department with chief complaints that may prompt an SBI evaluation, 579 patients met our inclusion criteria with 362 in the fever group and 217 in the afebrile group. The most common chief complaints in the afebrile group were respiratory symptoms (27%), seizure (22%), vomiting/diarrhea (21%), and apparent life-threatening event (11%). Rates of true-positive blood, urine, and cerebrospinal fluid cultures were 2%, 2.4%, and 0.9% respectively. All cases of bacterial meningitis were in the fever group antibiotics (P = 0.16). Infants with fever were more likely to receive antibiotics (P < 0.001), although there were no statistical differences between the 2 groups in the rates of positive blood or urine cultures. CONCLUSIONS: Afebrile infants make up a significant percentage of SBI evaluations in the emergency department. Respiratory symptoms, vomiting, and seizure-like activity are common presentations. Although rates of bacteremia and urinary tract infection are higher in the febrile group, this did not reach statistical significance, and therefore afebrile infants should still be considered at risk for SBI.

Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.

High fatty acid oxidation capacity and phosphorylation control despite elevated leak and reduced respiratory capacity in northern elephant seal muscle mitochondria.

Northern elephant seals (Mirounga angustirostris) are extreme, hypoxia-adapted endotherms that rely largely on aerobic metabolism during extended breath-hold dives in near-freezing water temperatures. While many aspects of their physiology have been characterized to account for these remarkable feats, the contribution of adaptations in the aerobic powerhouses of muscle cells, the mitochondria, are unknown. In the present study, the ontogeny and comparative physiology of elephant seal muscle mitochondrial respiratory function was investigated under a variety of substrate conditions and respiratory states. Intact mitochondrial networks were studied by high-resolution respirometry in saponin-permeabilized fiber bundles obtained from primary swimming muscles of pup, juvenile and adult seals, and compared with fibers from adult human vastus lateralis. Results indicate that seal muscle maintains a high capacity for fatty acid oxidation despite a progressive decrease in total respiratory capacity as animals mature from pups to adults. This is explained by a progressive increase in phosphorylation control and fatty acid utilization over pyruvate in adult seals compared with humans and seal pups. Interestingly, despite higher indices of oxidative phosphorylation efficiency, juvenile and adult seals also exhibit a ~50% greater capacity for respiratory 'leak' compared with humans and seal pups. The ontogeny of this phenotype suggests it is an adaptation of muscle to the prolonged breath-hold exercise and highly variable ambient temperatures experienced by mature elephant seals. These studies highlight the remarkable plasticity of mammalian mitochondria to meet the demands for both efficient ATP production and endothermy in a cold, oxygen-limited environment.

Pharmacological targeting of the hyper-inflammatory response to SARS-CoV-2-infected K18-hACE2 mice using a cluster of differentiation 36 receptor modulator.

The scientific and medical community faced an unprecedented global health hazard that led to nearly 7 million deaths attributable to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In spite of the development of efficient vaccines against SARS-CoV-2, many people remain at risk of developing severe symptoms as the virus continues to spread without beneficial patient therapy. The hyper-inflammatory response to SARS-CoV-2 infection progressing to acute respiratory distress syndrome remains an unmet medical need for improving patient care. The viral infection stimulates alveolar macrophages to adopt an inflammatory phenotype regulated, at least in part, by the cluster of differentiation 36 receptor (CD36) to produce unrestrained inflammatory cytokine secretions. We suggest herein that the modulation of the macrophage response using the synthetic CD36 ligand hexarelin offers potential as therapy for halting respiratory failure in SARS-CoV-2-infected patients.

Determine the quality of human embryonic stem colonies with laser light scattering patterns.

BACKGROUND: With the prompt developments of regenerative medicine, the potential clinical applications of human embryonic stem cells have attracted intense attention. However, the labor-intensive and complex manual cell selection processes required during embryonic stem cell culturing have seriously limited large-scale production and broad applications. Thus, availability of a label-free, non-invasive platform to replace the current cumbersome manual selection has become a critical need. RESULTS: A non-invasive, label-free, and time-efficient optical platform for determining the quality of human embryonic stem cell colonies was developed by analyzing the scattering signals from those stem cell colonies. Additionally, confocal microscopy revealed that the cell colony morphology and surface structures were correlated with the resulting characteristic light scattering patterns. Standard immunostaining assay (Oct-4) was also utilized to validate the quality-determination from this light scattering protocol. The platform developed here can therefore provide identification accuracy of up to 87% for colony determination. CONCLUSIONS: Our study here demonstrated that light scattering patterns can serve as a feasible alternative approach to replace conventional manual selection for human embryonic stem cell cultures.

A cyclic azapeptide ligand of the scavenger receptor CD36/SR-B2 reduces the atherosclerotic lesion progression and enhances plaque stability in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease of the arterial walls that develops at predisposed sites. As a major risk factor for adverse cardiovascular pathology, atherosclerosis can progress to myocardial infarction and stroke, due to the rupture of unstable atherosclerotic lesions. Macrophage uptake of modified lipoproteins and metabolic dysfunction contributes significantly to the initiation and development of atherosclerotic lesions. The cluster of differentiation 36 receptor [CD36 (SR-B2)] plays a key role in atherosclerotic lesion progression and acts as an efferocytic molecule in the resolution of advanced plaque. In previous studies, linear azapeptide CD36 ligands were shown to exhibit anti-atherosclerotic properties. In the present study, a novel potent and selective macrocyclic azapeptide CD36 ligand, MPE-298, has proven effective in protecting against atherosclerosis progression. Features of greater plaque stability were observed after 8 weeks of daily injections with the cyclic azapeptide in apolipoprotein E-deficient mice fed a high-fat high-cholesterol diet.

Regulation of human and mouse bystander T cell activation responses by PD-1.

Bystander activation of memory T cells occurs via cytokine signaling alone in the absence of T cell receptor (TCR) signaling and provides a means of amplifying T cell effector responses in an antigen-nonspecific manner. While the role of Programmed Cell Death Protein 1 (PD-1) on antigen-specific T cell responses is extensively characterized, its role in bystander T cell responses is less clear. We examined the role of the PD-1 pathway during human and mouse non-antigen-specific memory T cell bystander activation and observed that PD-1+ T cells demonstrated less activation and proliferation than activated PD-1- populations in vitro. Higher activation and proliferative responses were also observed in the PD-1- memory population in both mice and patients with cancer receiving high-dose IL-2, mirroring the in vitro phenotypes. This inhibitory effect of PD-1 could be reversed by PD-1 blockade in vivo or observed using memory T cells from PD-1-/- mice. Interestingly, increased activation through abrogation of PD-1 signaling in bystander-activated T cells also resulted in increased apoptosis due to activation-induced cell death (AICD) and eventual T cell loss in vivo. These results demonstrate that the PD-1/PD-Ligand 1 (PD-L1) pathway inhibited bystander-activated memory T cell responses but also protected cells from AICD.

Apparent Risks of Postural Orthostatic Tachycardia Syndrome Diagnoses After COVID-19 Vaccination and SARS-Cov-2 Infection.

Postural orthostatic tachycardia syndrome (POTS) has been previously described after SARS-CoV-2 infection; however, limited data is available on the relation of POTS with COVID-19 vaccination. Here we show in a cohort of 284,592 COVID-19 vaccinated individuals using a sequence-symmetry analysis, that the odds of POTS are higher 90 days after vaccine exposure than 90 days prior to exposure, and that the odds for POTS are higher than referent conventional primary care diagnoses, but lower than the odds of new POTS diagnosis after SARS-CoV-2 infection. Our results identify a possible association between COVID-19 vaccination and incidence of POTS. Notwithstanding the probable low incidence of POTS after COVID-19 vaccination, particularly when compared to SARS-Cov-2 post-infection odds which were five times higher, our results suggest that further studies, are needed to investigate the incidence and etiology of POTS occurring after COVID-19 vaccination.