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Highlights • Thioredoxin reductase (TrxR), a seleno enzyme, regulates cellular redox. • Several human cancers are known to overexpress TrxR. • Inhibitors of TrxR have enhanced radiation induced cytotoxicity in multiple cancers. • TrxR could be a potential target during radiotherapy of cancer patients., Novel agents are required to increase the radiosensitivity of cancer and improve the outcome of radiotherapy. Thioredoxin (Trx) and thioredoxin reductase (TrxR) reduce the oxidized cysteine thiols in several proteins, which regulate cellular redox, survival, proliferation, DNA synthesis, transcription factor activity and apoptosis. TrxR is essential for maintaining a conducive redox state for tumor growth, survival and resistance to therapy. Therefore, it is an appealing pharmacological target for the radiosensitization of tumors. Ionizing radiation (IR) is known to cause cytotoxicity through ROS, oxidative stress and DNA damage. Inhibition of thioredoxin system augments IR induced oxidative stress and potentiates cytotoxic effects. However, TrxR also regulates several critical cellular processes in normal cells. Here, we highlight the pre-clinical research and pharmacological studies to surmise possible utility of different TrxR inhibitors for radiosensitization. This review provides a succinct perspective on the role of TrxR inhibitors during the radiotherapy of cancer., Graphical abstract Image, graphical abstract

Background The latest novel corona virus disease (COVID-19) pandemic shows a significant health concern. We aimed to study the prevalence of gastrointestinal symptoms among COVID-19 Egyptian patients. Methods A cross-sectional study was carried out on 860 patients with COVID-19 infection classified according to Ministry of Health Program (MOHP) into three groups (280 patients with mild infection, 258 patients with moderate disease and 322 patients with severe disease). All patients were subjected to medical history, clinical examination, laboratory investigations, high-resolution computed tomography chest (HRCT chest) and other investigations when needed in some patients e.g., upper gastro-intestinal (GI) endoscopy, abdomino-pelvic ultrasound and ECHO. Results Gastro-intestinal symptoms were present in 27.2% of the studied patients. The most common reported GIT symptoms were vomiting, diarrhea, abdominal/gastric pain, followed by nausea. GIT symptoms presence was significantly higher in severe cases in comparison to mild or moderate cases. C-reactive protein (CRP), serum ferritin, Aspartate aminotransferase (AST), bilirubin, and creatinine were significantly associated with the presence of GI symptoms. Conclusions GI symptoms are prevalent among COVID-19 patients, the most common were vomiting and diarrhea and were associated with COVID-19 severity., Highlights • The latest novel corona virus disease pandemic shows a significant health concern. • GI symptoms are prevalent among COVID-19 patients. • The most common were vomiting and diarrhea and were associated with COVID-19 severity. • GI symptoms presence was significantly higher in severe cases rather than mild or moderate cases. • Gastrointestinal symptoms were present in 27.2% of the studied patients.

Various forms of fibrosis, comprising tissue thickening and scarring, are involved in 40% of deaths across the world. Since the discovery of scarless functional healing in fetuses prior to a certain stage of development, scientists have attempted to replicate scarless wound healing in adults with little success. While the extracellular matrix (ECM), fibroblasts, and inflammatory mediators have been historically investigated as separate branches of biology, it has become increasingly necessary to consider them as parts of a complex and tightly regulated system that becomes dysregulated in fibrosis. With this new paradigm, revisiting fetal scarless wound healing provides a unique opportunity to better understand how this highly regulated system operates mechanistically. In the following review, we navigate the four stages of wound healing (hemostasis, inflammation, repair, and remodeling) against the backdrop of adult versus fetal wound healing, while also exploring the relationships between the ECM, effector cells, and signaling molecules. We conclude by singling out recent findings that offer promising leads to alter the dynamics between the ECM, fibroblasts, and inflammation to promote scarless healing. One factor that promises to be significant is fibroblast heterogeneity and how certain fibroblast subpopulations might be predisposed to scarless healing. Altogether, reconsidering fetal wound healing by examining the interplay of the various factors contributing to fibrosis provides new research directions that will hopefully help us better understand and address fibroproliferative diseases, such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.

Immunization against the spike protein of SARS-CoV-2 reduces transmission

Visual Abstract, Highlights • Drug-eluting stents impede neointimal smooth muscle cell hyperplasia but exacerbate endothelial cell dysfunction and thrombogenicity. It has been a challenge to identify a common target to inhibit both. Findings in this study suggest PERK as such a target. • A PERK inhibitor administered either via an endovascular (in biomimetic nanocarriers) or perivascular (in hydrogel) route effectively mitigated neointimal hyperplasia in rats. • Oral gavage of the PERK inhibitor partially preserved the normal blood flow in a mouse model of induced thrombosis. • Dampening PERK activity inhibited STAT3 while activating SRF in smooth muscle cells, and also reduced prothrombogenic tissue factor and growth impairment of endothelial cells., Summary Developing endothelial-protective, nonthrombogenic antirestenotic treatments has been a challenge. A major hurdle to this has been the identification of a common molecular target in both smooth muscle cells and endothelial cells, inhibition of which blocks dysfunction of both cell types. The authors’ findings suggest that the PERK kinase could be such a target. Importantly, PERK inhibition mitigated both restenosis and thrombosis in preclinical models, implicating a low-thrombogenic antirestenotic paradigm.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by inflammatory nodules, abscesses, and fistulae. Severe disease is frequently treated with adalimumab or infliximab, but limited research and insurance coverage confine treatment options. Often, aggressive multifaceted therapeutic regimens fail in severe cases. The Janus kinase (JAK) inhibitor, tofacitinib, acts through the JAK-STAT pathway, suppressing inflammatory cytokines implicated in HS pathogenesis, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.1 JAK inhibitors may benefit HS patients who lack response to targeted biologic therapy. We report on 2 patients with a rare, recalcitrant, ulcerating HS phenotype who, despite not responding to numerous treatments, including biologics (Table I), exhibited prolonged response to a tofacitinib multimodal regimen. Table I Baseline patient characteristics

Tumor necrosis factor (TNF) inhibitor–induced palmoplantar pustulosis (PPP) can present with debilitating, refractory disease that requires changing or stopping anti-TNF agents or adding systemic treatments. Here, we report an update of a previously reported case of severely recalcitrant PPP successfully treated with the Janus kinase (JAK) inhibitor tofacitinib.

Highlights • Clonal hematopoiesis is a common condition in the elderly that can result from the acquisition of somatic mutations in HSPCs that confer a selective advantage and allow for clonal cell expansion. • This clonal population of mutated HSPCs can give rise to leukocytes with altered immune properties, and this condition can adversely impact the cardiovascular system. • Clonal hematopoiesis may represent a new causal risk factor for cardiovascular disease that can add to the predictive value of the traditional risk factors. • Understanding the clonal hematopoiesis status of a patient could aid in the development of personalized strategies for anti-inflammatory therapies for cardiovascular disease., Heart failure is a common disease with poor prognosis that is associated with cardiac immune cell infiltration and dysregulated cytokine expression. Recently, the clonal expansion of hematopoietic cells with acquired (i.e., nonheritable) DNA mutations, a process referred to as clonal hematopoiesis, has been reported to be associated with cardiovascular diseases including heart failure. Mechanistic studies have shown that leukocytes that harbor these somatic mutations display altered inflammatory characteristics that worsen the phenotypes associated with heart failure in experimental models. In this review, we summarize recent epidemiological and experimental evidence that support the hypothesis that clonal hematopoiesis-mediated immune cell dysfunction contributes to heart failure and cardiovascular disease in general., Central Illustration

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions., Graphical abstract In this article, we discuss the physiological, therapeutic and pathophysiological relevance of cytochrome P450 protein degradation. Employing mice with genetic ablation of CHIP and gp78/AMFR E3 ubiquitin-ligases that stabilize hepatic CYP2E1, we document why this stabilization not always leads to non-alcoholic fatty liver disease: It requires concomitantly enhanced hepatic lipogenesis.Image 1

Background & Aims Biotin is a water-soluble vitamin that is indispensable for human health. Biotin deficiency can cause failure-to-thrive, immunodeficiency, alopecia, dermatitis, and conjunctivitis. We previously reported that biotin deficiency also can lead to severe colitis in mice, which is completely reversed with supplementation. Our aim in this study was to determine if high-dose biotin supplementation can provide a therapeutic benefit in a preclinical model for inflammatory bowel disease (IBD) and to identify the molecular mechanism by which this occurs. Methods Mice were challenged with dextran sodium sulfate to induce colitis and were treated with 1 mmol/L biotin to induce or maintain remission. Clinical response was monitored by the Disease Activity Index and fecal calprotectin levels. The colon tissue was investigated for histology, length, as well as expression of inflammatory cytokines (interleukin 6, tumor necrosis factor-α, interleukin 1β), intestinal permeability, tight junctions (zonula occludens-1 and claudin-2), and the transcription factor nuclear factor-κB (NF-κB). Results Biotin therapy led to delayed onset and severity of colitis as well as accelerated healing. There was improvement in the Disease Activity Index, fecal calprotectin levels, colon length, and histology. In addition, biotin-treated mice had reduced expression of inflammatory cytokines, reduced intestinal permeability, and reduced activation of NF-κB. Conclusions Oral supplementation with biotin provides benefit for maintenance and induction of remission in the dextran sodium sulfate preclinical model for IBD. Biotin does this by reducing the activation of NF-κB, which prevents the production of inflammatory cytokines and helps maintain the integrity of the intestinal barrier. Clinically, the NF-κB pathway is important in the development of IBD and this finding suggests that biotin may have therapeutic potential for patients with IBD., Graphical abstract

Background & Aims Interleukin (IL)23 is a major contributor to inflammatory bowel disease (IBD) pathogenesis and is being pursued as a therapeutic target, both through targeting IL23 alone or in combination with IL12. Unexpected trial outcomes highlight the importance of understanding the cell types through which IL23 regulates immune responses, and how IL23 and IL12 compare in these responses. Macrophages are key players in IBD, and IL23 recently was found to promote inflammatory outcomes in human macrophages. This raises the possibility that IL23 may be required for additional essential macrophage functions, in particular microbial clearance, such that either blocking the IL23 pathway or the IL23R–R381Q IBD-protective variant may reduce macrophage-mediated microbial clearance. Methods We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through Western blot, flow cytometry, and gentamicin protection. Results Autocrine/paracrine IL23 was critical for optimal levels of pattern-recognition-receptor (PRR)-induced intracellular bacterial clearance in human macrophages. Mechanisms regulated by IL23 included induction of pyruvate dehydrogenase kinase 1-dependent bacterial uptake, and up-regulation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate oxidase members, nitric oxide synthase 2, and autophagy through ATG5 and ATG16L1. Complementing these pathways in IL23R-deficient macrophages restored PRR-induced bacterial uptake and clearance. Janus kinase 2, TYK2, and STAT3 were required for IL23-induced mechanisms. IL23 and IL12 induced antimicrobial pathways to similar levels in human macrophages. Relative to IL23R–R381, transfected IL23R–Q381, or monocyte-derived macrophages from IL23R–Q381 carriers showed reduced bacterial uptake and clearance. Conclusions We identify that autocrine/paracrine IL23 is required for optimal PRR-enhanced macrophage bacterial uptake and intracellular bacterial clearance, define mechanisms regulating IL23R-induced bacterial clearance, and determine how the IBD-protective IL23R–R381Q variant modulates these processes., Graphical abstract

Background & Aims The inflammatory response to intestinal damage promotes healing through mechanisms that are incompletely understood. Gene expression of cluster of differentiation 74 (CD74), the receptor for cytokine macrophage migration inhibitory factor, is increased in patients with inflammatory bowel disease (IBD), however, the role of CD74 signaling in intestinal inflammation remains poorly understood. The aim of this study was to determine the functional role of CD74 signaling in intestinal inflammation. Methods We studied the characteristics of CD74 protein expression in human IBD and experimental colitis. The functional role of CD74 signaling in the intestine was investigated using cellular models; wild-type, CD74-/-, and bone marrow chimera mice; neutralizing anti-CD74 antibodies; flow cytometry; immunohistochemistry; immunofluorescence; immunoblotting; and clustered regularly interspaced short palindromic repeats and associated protein 9 technology. Results In IBD patients and experimental colitis, CD74-receptor protein expression was increased in inflamed intestinal tissue, prominently in the crypt epithelial cells. By using distinct but complementary chemical and non–chemically induced mouse models of colitis with genetic and antibody neutralization approaches, we found that CD74 signaling was necessary for gut repair. Mechanistically, we found that the macrophage migration inhibitory factor cytokine, which also is increased in colitis, stimulated the CD74 receptor, enhancing intestinal epithelial cell proliferation through activation of the protein kinase B and the extracellular signal-regulated kinase pathways. Our data also suggest that CD74 signaling in immune cells was not essential for mucosal healing. Conclusions CD74 signaling is strongly activated during intestinal inflammation and protects the host by promoting epithelial cell regeneration, healing, and maintaining mucosal barrier integrity. Enhancing the CD74 pathway may represent a unique therapeutic strategy for promoting healing in IBD., Graphical abstract

Background & Aims Psychological stress is a trigger for the development of irritable bowel syndrome and associated symptoms including abdominal pain. Although irritable bowel syndrome patients show increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of the amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are regulated negatively by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator p38 mitogen-activated protein kinases (MAPK). Methods Fisher-344 male rats were exposed to water avoidance stress (WAS) for 1 hour per day for 7 days. Microglia morphology and the expression of phospho-p38 MAPK and GR were analyzed via immunofluorescence. Microglia-mediated synaptic remodeling was investigated by quantifying the number of postsynaptic density protein 95–positive puncta. Cytokine expression levels in the CeA were assessed via quantitative polymerase chain reaction and a Luminex assay (Bio-Rad, Hercules, CA). Stereotaxic infusion into the CeA of minocycline to inhibit, or fractalkine to activate, microglia was followed by colonic sensitivity measurement via a visceromotor behavioral response to isobaric graded pressures of tonic colorectal distension. Results WAS induced microglial deramification in the CeA. Moreover, WAS induced a 3-fold increase in the expression of phospho-p38 and decreased the ratio of nuclear GR in the microglia. The number of microglia-engulfed postsynaptic density protein 95–positive puncta in the CeA was increased 3-fold by WAS, while cytokine levels were unchanged. WAS-induced changes in microglial morphology, microglia-mediated synaptic engulfment in the CeA, and visceral hypersensitivity were reversed by minocycline whereas in stress-naïve rats, fractalkine induced microglial deramification and visceral hypersensitivity. Conclusions Our data show that chronic stress induces visceral hypersensitivity in male rats and is associated with microglial p38 MAPK activation, GR dysfunction, and neuronal remodeling in the CeA., Graphical abstract

Background & Aims Mucosal-associated invariant T (MAIT) cells are depleted from blood in patients with advanced liver disease and show features of immune dysfunction. Because circulating MAIT cells differ from organ-resident MAIT cells, we aimed to investigate the frequency, phenotype, and function of peritoneal MAIT cells from patients with cirrhosis and spontaneous bacterial peritonitis (SBP). Methods MAIT cells in blood and ascitic fluid from patients with cirrhosis were characterized using flow cytometry. Healthy individuals and noncirrhotic patients undergoing peritoneal dialysis served as controls. MAIT cell migration was studied in transwell assays. Cytokine release in response to infected ascitic fluid and bacterial products was assessed in vitro. Results Peritoneal CD3+ CD161hi Vα7.2+ T cells had an inflammatory, tissue retention phenotype, expressing the alpha E integrin, the chemokine receptors CCR5 and CXCR3, and the activation marker CD69 at higher levels than their circulating equivalents. Seventy-seven percent bound to MR1 tetramers loaded with the pyrimidine intermediate 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. The ratio of peritoneal to blood MAIT cell frequency increased from 1.3 in the absence of SBP to 2.6 at diagnosis and decreased by day 3. MAIT cells migrated toward infected ascitic fluid containing CCL5 and CCL20 and released cytokines in an MR1-restricted fashion. Whereas the depleted circulating MAIT cell pool displayed features of immune exhaustion, peritoneal MAIT cells remained competent producers of inflammatory cytokines in response to bacterial products. Peritoneal MAIT activation correlated with systemic inflammation, suggesting a possible link between peritoneal and systemic immunity. Conclusions Peritoneal MAIT cells phenotypically and functionally differ from circulating MAIT cells in decompensated cirrhosis and redistribute to the peritoneum during SBP., Graphical abstract

Defective epithelial barrier function is present in maladies including epidermal burn injury, environmental lung damage, renal tubular disease, and a range of immune-mediated and infectious intestinal disorders. When the epithelial surface is intact, the paracellular pathway between cells is sealed by the tight junction. However, permeability of tight junctions varies widely across tissues and can be markedly impacted by disease. For example, tight junctions within the skin and urinary bladder are largely impermeant and their permeability is not regulated. In contrast, tight junctions of the proximal renal tubule and intestine are selectively permeable to water and solutes on the basis of their biophysical characteristics and, in the gut, can be regulated by the immune system with remarkable specificity. Conversely, modulation of tight junction barrier conductance, especially within the gastrointestinal tract, can impact immune homeostasis and diverse pathologies. Thus, tight junctions are both effectors and targets of immune regulation. Using the gastrointestinal tract as an example, this review explores current understanding of this complex interplay between tight junctions and immunity.

Introduction Macrophages play an important role in regulating inflammation and tissue regeneration. It is known that anti-inflammatory macrophages play an important role for tissue regeneration. The objective of this study is to modify macrophages phenotypes for anti-inflammatory function by utilizing drug delivery technology. Method In this study, 4 types of poly (L-lactic-co-glycolic acid) (PLGA) microspheres incorporating pioglitazone of an anti-inflammatory modifier (pio-MS) with different sizes were prepared. In vitro release test of pio-MS was performed in phosphate buffered-saline solution (PBS) containing 1 wt% of sodium lauryl sulfate. The arginase activity and the secretion of interleukin (IL)−10 as anti-inflammatory macrophage markers of mouse bone marrow derived-macrophages (BMDM) cultured with the pio-MS were evaluated. Results The sustained release of pioglitazone was observed from all types of pio-MS in vitro. When BMDM were cultured with the pio-MS with an average diameter of 40 μm (pio-MS40), the arginase activity and the secretion of IL-10 increased to a significant extent compared with other pio-MS. Conclusions The pio-MS40 with an diameter of 40 μm had a potential to induce the anti-inflammatory modification of BMDM in this culture system. The sustained release of pioglitazone is promoting to modify the macrophage function., Highlights • Microspheres incorporating pioglitazone with different sizes were prepared. • Sustained release of pioglitazone from the microspheres were observed. • The effect of pioglitazone on macrophages was enhanced by the sustained release.

Abstarct: Plant specific miRNAs (Novel miRNAs) are well known to perform distinctive functions in biological processes. Identification of new miRNAs is necessary to understand their gene regulation. Degradome provides an opportunity to explore the miRNA functions by comparing the miRNA population and their degraded products. In the present study, Small RNA sequencing data was used to identify novel miRNAs. Further, degradome sequencing was carried out to identify miRNAs targets in the plant, Chlorophytum borivilianum. The present study supplemented 40 more novel miRNAs correlating degradome data with smallRNAome. Novel miRNAs, complementary to mRNA partial sequences obtained from degradome sequencing were actually targeting the later. A big pool of miRNA was established by using Oryza sativa, Arabidopsis thaliana, Populus trichocarpa, Ricinus communis, and Vitis vinifera genomic data. Targets were identified for novel miRNAs and total 109 targets were predicted. BLAST2GO analysis elaborate about localization of novel miRNAs’ targets and their corresponding KEGG (Kyoto Encyclopedia for Genes and Genomes) pathways. Identified targets were annotated and were found to be involved in significant biological processes like Nitrogen metabolism, Pyruvate metabolism, Citrate cycle (TCA cycle), photosynthesis, and Glycolysis/Gluconeogenesis. The present study provides an overall view of the miRNA regulation in multiple metabolic pathways that are involved in plant growth, pathogen resistance and secondary metabolism of C. borivilianum. Keywords: Degradome, Chlorophytum borivilianum, microRNAs, Illumina sequencing, SRA

Highlights • The authors discuss the concept of atrial myopathy; its relationship to aging, electrophysiological remodeling, and autonomic remodeling; the interplay between atrial myopathy, AF, and stroke; and suggest how to identify patients with atrial myopathy and how to incorporate atrial myopathy into decisions about anticoagulation. • Atrial myopathy seen in animal models of AF and in patients with AF is the result of a combination of factors that lead to electrical and structural remodeling in the atrium. Although AF may lead to the initiation and/or progression of this myopathy, the presence of AF is by no means essential to the development or the maintenance of the atrial myopathic state. • Methods to identify atrial myopathy include atrial electrograms, tissue biopsy, cardiac imaging, and certain serum biomarkers. A promising modality is 4-dimensional flow cardiac magnetic resonance. The concept of atrial myopathy may help guide oral anticoagulant therapy in selected groups of patients with AF, particularly those with low to intermediate risk of strokes and those who have undergone successful AF ablation. This review highlights the need for prospective randomized trials to test these hypotheses., Summary This paper discusses the evolving concept of atrial myopathy by presenting how it develops and how it affects the properties of the atria. It also reviews the complex relationships among atrial myopathy, atrial fibrillation (AF), and stroke. Finally, it discusses how to apply the concept of atrial myopathy in the clinical setting—to identify patients with atrial myopathy and to be more selective in anticoagulation in a subset of patients with AF. An apparent lack of a temporal relationship between episodes of paroxysmal AF and stroke in patients with cardiac implantable electronic devices has led investigators to search for additional factors that are responsible for AF-related strokes. Multiple animal models and human studies have revealed a close interplay of atrial myopathy, AF, and stroke via various mechanisms (e.g., aging, inflammation, oxidative stress, and stretch), which, in turn, lead to fibrosis, electrical and autonomic remodeling, and a pro-thrombotic state. The complex interplay among these mechanisms creates a vicious cycle of ever-worsening atrial myopathy and a higher risk of more sustained AF and strokes. By highlighting the importance of atrial myopathy and the risk of strokes independent of AF, this paper reviews the methods to identify patients with atrial myopathy and proposes a way to incorporate the concept of atrial myopathy to guide anticoagulation in patients with AF., Central Illustration

Visual Abstract, Highlights • MDA conjugated with HSA activates T cells from human atherosclerotic plaques through a direct mechanism. • MDA-HSA also induces maturation and activation of human dendritic cells, which in turn promote activation of autologous T cells from the same donor's plaques, although this effect appears somewhat weaker than the direct activation. • M1 polarization of macrophages, potentially an atherogenic effect, were also induced by MDA-HSA. • Heat shock protein 60 was induced in T cells by MDA-HSA, is atherogenic, and could promote dendritic cell/T cell activation. • Two peptide modifications of serum albumin in atherosclerotic patients’ HSA were similar to those generated by treatment of HSA with MDA in vitro., Summary Human dendritic cells were differentiated from blood monocytes and treated with malondialdehyde (MDA) conjugated with human serum albumin (HSA). Autologous T cells from human plaques or blood were co-cultured with the pre-treated dendritic cells or treated directly. MDA modifications were studied by mass spectrometry. MDA-HSA induced a pro-inflammatory DC-mediated T-cell activation and also a strong direct effect on T cells, inhibited by an inhibitor of oxidative stress and antibodies against MDA. Atherogenic heat shock protein-60 was strongly induced in T cells activated by MDA-HSA. Two peptide modifications in atherosclerotic patients' HSA were similar to those present in in vitro MDA-modified HSA.

Highlights • RNA adjuvant was developed from the CrPV intergenic region IRES. • The RNA adjuvant functioned as an adjuvant with protein-based vaccines. • The RNA adjuvant increased vaccine efficacy and induced balanced Th1/Th2 response. • The RNA adjuvant enhanced APC chemotaxis., An ideal adjuvant should increase vaccine efficacy through balanced Th1/Th2 responses and be safe to use. Recombinant protein-based vaccines are usually formulated with aluminum (alum)-based adjuvants to ensure an adequate immune response. However, use of alum triggers a Th2-biased immune induction, and hence is not optimal. Although the adjuvanticity of RNA has been reported, a systematic and overall investigation on its efficacy is lacking. We found that single strand RNA (termed RNA adjuvant) derived from cricket paralysis virus intergenic region internal ribosome entry site induced the expression of various adjuvant-function-related genes, such as type 1 and 2 interferon (IFN) and toll-like receptor (TLR), T cell activation, and leukocyte chemotaxis in human peripheral blood mononuclear cells; furthermore, its innate and IFN transcriptome profile patterns were similar to those of a live-attenuated yellow fever vaccine. This suggests that protein-based vaccines formulated using RNA adjuvant function as live-attenuated vaccines. Application of the RNA adjuvant in mouse enhanced the efficacy of Middle East respiratory syndrome spike protein, a protein-subunit vaccine and human papillomavirus L1 protein, a virus-like particle vaccine, by activating innate immune response through TLR7 and enhancing pAPC chemotaxis, leading to a balanced Th1/Th2 responses. Moreover, the combination of alum and the RNA adjuvant synergistically induced humoral and cellular immune responses and endowed long-term immunity. Therefore, RNA adjuvants have broad applicability and can be used with all conventional vaccines to improve vaccine efficacy qualitatively and quantitively.

Keloids are a recurrent benign neoplastic condition that result from a traumatic injury to the skin in susceptible individuals. Keloid tissue extends beyond the margins of the injured site; this characteristic distinguishes it from hypertrophic scars. Individuals of African, Hispanic, or Asian descent appear to be at increased risk for keloids.1 Keloids tend to be asymptomatic but may cause pain or itching and have functional, aesthetic, or psychosocial impact on patients.2 The extent of scar formation is influenced by the duration and extent of the inflammatory phase of wound healing, which is longer in patients with hidradenitis suppurativa (HS). The prevalence of keloids among African-American and biracial individuals in the US population is higher than that among white patients.3 Some cutaneous areas are more prone to keloid scar development, likely caused by the vulnerability to trauma such as ear lobes. Other types of direct skin causes include body piercings, burns, lacerations, and surgical wounds. Keloids can also result from inflammatory processes including acne and folliculitis.4 HS is a chronic inflammatory skin disease characterized by persistent or recurrent flares of inflamed painful nodules, sinus tracts, and scars in the intertriginous areas.5 The prevalence of HS is estimated at 1% worldwide with a female/male ratio of 3:1.6 The pathogenesis of HS is not completely understood. Follicular occlusion is believed to initiate the process, trapping commensal bacteria within the follicle. The rupture of the pilosebaceous unit and activation of the innate immune system leads to a chronic tissue inflammation that is difficult to extinguish.7 Characteristic HS lesions commonly heal with different types of scars. Atrophic scars are shallow and, in some cases, cribriform, whereas hypertrophic scars can present as firm plaques or rope-like scars. In individuals prone to keloid, chronic inflammatory HS lesions may lead to keloid formation that may contain both mixed of inflammatory lesions and scars. Two reported cases exist in the literature of keloids in HS and successful treatment with adalimumab.8, 9 We present a case series of 10 more patients with keloid formation in HS wounds and discuss the clinical presentation and therapeutic options.

Background & Aims Crohn’s disease (CD) is a debilitating inflammatory disorder that affects more than 1.6 million people in North America alone. Members of the tumor necrosis factor superfamily are key regulators of intestinal inflammation; specifically, tumor necrosis factor–like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor–inducible 14 (Fn14), are involved in normal and pathologic tissue remodeling. Our aim was to determine the role of TWEAK/Fn14 in CD and a murine model of CD-like ileitis (ie, SAMP1/YitFc [SAMP] strain). Methods SAMP mice deficient in Fn14 (SAMP × Fn14-/-) were developed and a detailed time-course study was performed evaluating ileal tissues by histology and stereomicroscopy, as well as quantitative polymerase chain reaction and NanoString technology (Seattle, WA). Reciprocal bone marrow chimeras were generated to assess the relevance of Fn14 in hematopoietic vs nonhematopoietic compartments. Surgically resected intestinal tissues and mucosal biopsy specimens from patients with CD, ulcerative colitis, and healthy controls were analyzed for the expression of TWEAK/Fn14 by quantitative polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. Results SAMP × Fn14-/- showed a marked decrease in ileitis severity at 20 weeks of age compared with SAMP WT controls. Bone marrow chimeras showed that Fn14 was required in both hematopoietic and nonhematopoietic compartments for ileitis to develop. Transcriptome data showed multiple cellular pathways regulated by Fn14 signaling. Finally, increased expression of TWEAK and Fn14 was observed in tissue lesions from CD patients compared with ulcerative colitis and healthy controls. Conclusions TWEAK/Fn14 are up-regulated in CD, and also mediate experimental CD-like ileitis, by regulation of multiple innate and adaptive cellular pathways. Therefore, TWEAK/Fn14 may represent a novel therapeutic target for the treatment of small intestinal inflammation in CD., Graphical abstract

Acne fulminans (AF) and hidradenitis suppurativa (HS) are 2 severe conditions with no consensus on medical treatment and no clear pathophysiology.1, 2 We report the remission of long-lasting and severe AF with HS that was unresponsive to many previous treatments.

Visual Abstract, Highlights • PKA-phosphorylation of Hsp20 is elevated in human failing hearts. • Increases in phosphorylated Hsp20 in vivo are associated with fibrotic remodeling and reduced left ventricular function. • The phosphorylated Hsp20 in cardiomyocyte promotes upregulation of IL-6 and its subsequent paracrine actions on the cardiac fibroblast. • Blockade of IL-6 effects ex vivo and in vivo reduces the pro-fibrotic effects of phosphorylated Hsp20. • Targeting phosphorylated Hsp20 in the cardiomyocyte may represent a potential therapeutic strategy to mitigate fibrotic remodeling and preserve function in the failing heart., Summary Cardiomyocyte-specific increases in phosphorylated Hsp20 (S16D-Hsp20) to levels similar to those observed in human failing hearts are associated with early fibrotic remodeling and depressed left ventricular function, symptoms which progress to heart failure and early death. The underlying mechanisms appear to involve translocation of phosphorylated Hsp20 to the nucleus and upregulation of interleukin (IL)-6, which subsequently activates cardiac fibroblasts in a paracrine fashion through transcription factor STAT3 signaling. Accordingly, treatment of S16D-Hsp20 mice with a rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) attenuated interstitial fibrosis and preserved cardiac function. These findings suggest that phosphorylated Hsp20 may be a potential therapeutic target in heart failure.

OBJETIVO: Evaluar el resultado del cribado de hepatitis B y C en pacientes ingresados con COVID-19. PACIENTES Y MÉTODOS: Estudio transversal, prospectivo, realizado en dos hospitales españoles de tercer nivel. Se estudiaron marcadores de hepatitis B (HBsAg, anti-HBc) y C (anti-VHC, ARN VHC) a todos los pacientes hospitalizados con COVID-19 del 1 de marzo al 31 de diciembre de 2020. RESULTADOS: En este periodo ingresaron 4662 pacientes con COVID-19: 56,3% fueron varones, la edad mediana fue 76 (0-104) años. Se realizó serología de hepatitis B a 2915 (62,5%) pacientes; 253 (8,75%) presentaban anti-HBc+ y 11 (0,38%) HBsAg+. De los 11 pacientes, 4 desconocían el diagnóstico, 7 recibieron esteroides y uno recibió profilaxis. Hubo un caso de reactivación del VHB. Se determinaron anticuerpos anti-VHC a 2895 (62%) pacientes; 24 (0,83%) fueron positivos. De ellos, 13 pacientes estaban diagnosticados: 10 habían recibido tratamiento, uno se había curado espontáneamente y dos no habían sido tratados. De los 11 restantes, 10 tenían ARN VHC indetectable. En total, sólo 3 (0,10%) pacientes tenían carga viral detectable. Sin embargo, ninguno recibió tratamiento (2 > 90 años con comorbilidades, 1 falleció por COVID-19). CONCLUSIONES: El cribado de hepatitis C en pacientes ingresados por COVID-19 en nuestro medio ha mostrado menor utilidad de la esperada. La baja prevalencia de infección activa tras los tratamientos antivirales y la alta edad mediana de nuestra población limitan la detección de potenciales candidatos a tratamiento. El cribado de hepatitis B debería dirigirse a prevenir la reactivación en pacientes que precisen tratamientos inmunosupresores.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly caused pneumonia and pulmonary fibrosis through upper respiratory tract infection, which resulted in acute respiratory distress syndrome (ARDS) and multiorgan damage of cardiovascular, nervous, digestive, and genitourinary systems. Although the virus test turned negative after the patient recovered, the damage to multiorgan which caused by SARS-CoV-2 may irreversible. Therefore, the health status of the recovered patients has gradually become the focus of people's attention. Whether coronavirus disease 2019 (COVID-19) patients can receive exercise rehabilitation training after discharge? and what's the basis? We try to analyze and answer these questions, will provide some ideas about the patients to develop a reasonable and effective exercise rehabilitation program.

Background & Aims We previously showed that abundance of Candida tropicalis is significantly greater in Crohn’s disease patients compared with first-degree relatives without Crohn’s disease. The aim of this study was to determine the effects and mechanisms of action of C tropicalis infection on intestinal inflammation and injury in mice. Methods C57BL/6 mice were inoculated with C tropicalis, and colitis was induced by administration of dextran sodium sulfate in drinking water. Disease severity and intestinal permeability subsequently were evaluated by endoscopy, histology, quantitative reverse-transcription polymerase chain reaction, as well as 16S ribosomal RNA and NanoString analyses (NanoString Technologies, Seattle, WA). Results Infected mice showed more severe colitis, with alterations in gut mucosal helper T cells (Th)1 and Th17 cytokine expression, and an increased frequency of mesenteric lymph node–derived group 2 innate lymphoid cells compared with uninfected controls. Gut microbiome composition, including changes in the mucin-degrading bacteria, Akkermansia muciniphila and Ruminococcus gnavus, was altered significantly, as was expression of several genes affecting intestinal epithelial homeostasis in isolated colonoids, after C tropicalis infection compared with uninfected controls. In line with these findings, fecal microbiome transplantation of germ-free recipient mice using infected vs uninfected donors showed altered expression of several tight-junction proteins and increased susceptibility to dextran sodium sulfate–induced colitis. Conclusions C tropicalis induces dysbiosis that involves changes in the presence of mucin-degrading bacteria, leading to altered tight junction protein expression with increased intestinal permeability and followed by induction of robust Th1/Th17 responses, which ultimately lead to an accelerated proinflammatory phenotype in experimental colitic mice., Graphical abstract

Visual Abstract, Highlights • A first-of-a-kind systems biology computational model is presented that describes multiscale regulation of perfusion recovery in experimental peripheral arterial disease. • Multilevel model calibration and validation enable high-resolution model simulations for experimental peripheral arterial disease (mouse HLI). • An integrative model-based mechanistic characterization of the intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion following different patterns of occlusion-induced ischemia in HLI is described. • Using a model-based virtual HLI mouse population, pharmacologic inhibition of cell necrosis is predicted as a strategy with high therapeutic potential to improve perfusion recovery; in real HLI mice, the positive impact of this new strategy is then experimentally studied and confirmed., Summary In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion after occlusion-induced ischemia. The computational model was specifically formulated for a preclinical animal model of PAD (mouse hindlimb ischemia [HLI]), and it has gone through multilevel model calibration and validation against a comprehensive set of experimental data so that it accurately captures the complex cellular signaling, cell–cell communication, and function during post-HLI perfusion recovery. As an example, our model simulations generated a highly detailed description of the time-dependent spectrum-like macrophage phenotypes in HLI, and through model sensitivity analysis we identified key cellular processes with potential therapeutic significance in the pathophysiology of PAD. Furthermore, we computationally evaluated the in vivo effects of different targeted interventions on post-HLI tissue perfusion recovery in a model-based, data-driven, virtual mouse population and experimentally confirmed the therapeutic effect of a novel model-predicted intervention in real HLI mice. This novel multiscale model opens up a new avenue to use integrative systems biology modeling to facilitate translational research in PAD.

The mechanistic target of rapamycin (mTOR) pathway integrates metabolic cues into cell fate decisions. A particularly fateful event during the adaptive immune response is the engagement of a T cell receptor by its cognate antigen presented by an antigen-presenting cell (APC). Here, the induction of adequate T cell activation and lineage specification is critical to mount protective immunity; at the same time, inadequate activation, which could lead to autoimmunity, must be avoided. mTOR forms highly conserved protein complexes 1 and 2 that shape lineage specification by integrating signals originating from TCR engagement, co-stimulatory or co-inhibitory receptors and cytokines and availability of nutrients. If one considers autoimmunity as the result of aberrant lineage specification in response to such signals, the importance of this pathway becomes evident; this provides the conceptual basis for mTOR inhibition in the treatment of systemic autoimmunity, such as systemic lupus erythematosus (SLE). Clinical trials in SLE patients have provided preliminary evidence that mTOR blockade by sirolimus (rapamycin) can reverse pro-inflammatory lineage skewing, including the expansion of Th17 and double-negative T cells and plasma cells and the contraction of regulatory T cells. Moreover, sirolimus has shown promising efficacy in the treatment of refractory idiopathic multicentric Castleman disease, newly characterized by systemic autoimmunity due to mTOR overactivation. Alternatively, mTOR blockade enhances responsiveness to vaccination and reduces infections by influenza virus in healthy elderly subjects. Such seemingly contradictory findings highlight the importance to further evaluate the clinical effects of mTOR manipulation, including its potential role in treatment of COVID-19 infection. mTOR blockade may extend healthy lifespan by abrogating inflammation induced by viral infections and autoimmunity. This review provides a mechanistic assessment of mTOR pathway activation in lineage specification within the adaptive and innate immune systems and its role in health and autoimmunity. We then discuss some of the recent experimental and clinical discoveries implicating mTOR in viral pathogensis and aging.

Type 2 diabetes mellitus, obesity, hypertension, and other associated metabolic complications have been demonstrated as a crucial contributor to the enhanced morbidity and mortality of patients with coronavirus disease 2019 (COVID-19). Data on the interplay between metabolic comorbidities and the outcomes in patients with COVID-19 have been emerging and rapidly increasing. This implies a mechanistic link between metabolic diseases and COVID-19 resulting in the exacerbation of the condition. Nonetheless, new evidences are emerging to support insulin-mediated aggressive glucose-lowering treatment as a possible trigger of high mortality rate in diabetic COVID-19 patients, putting the clinician in a confounding and difficult dilemma for the treatment of COVID-19 patients with metabolic comorbidities. Thus, this review discusses the pathophysiological link among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), metabolic complications, and severe inflammation in COVID-19 development, especially in those with multi-organ injuries. We discuss the influence of several routinely used drugs in COVID-19 patients, including anti-inflammatory and anti-coagulant drugs, antidiabetic drugs, renin-angiotensin-aldosterone system inhibitors. Especially, we provide a balanced overview on the clinical application of glucose-lowering drugs (insulin and metformin), angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers. Although there is insufficient evidence from clinical or basic research to comprehensively reveal the mechanistic link between adverse outcomes in COVID-19 and metabolic comorbidities, it is hoped that the update in the current review may help to better outline the optimal strategies for clinical management of COVID-19 patients with metabolic comorbidities.

Graphical abstract SARS-CoV-2 infected alveoli and the different types of the two antibody-based treatments discussed in this review. Can antibodies be used to protect against COVID-19 and neutralize autoantibodies?, Coronavirus disease 2019 (COVID-19) has been declared by the World Health Organization (WHO) as a pandemic since March 2020. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The only available tools to avoid contamination and transmission of this virus are physical distancing, the use of N95 and surgical masks, and hand hygiene. Vaccines are another essential tool to reduce the impact of the pandemic, though these present challenges in terms of production and logistics, particularly in underdeveloped and developing countries. One of the critical early research findings is the interaction of the spike virus protein with the angiotensin-converting enzyme 2 (ACE2) human receptor. Developing strategies to block this interaction has therefore been identified as a way to treat this infection. Neutralizing antibodies (nAbs) have emerged as a therapeutic approach since the pandemic started. Infected patients may be asymptomatic or present with mild symptoms, and others may evolve to moderate or severe disease, leading to death. An immunological phenomenon known as cytokine storm has been observed in patients with severe disease characterized by a proinflammatory cytokine cascade response that leads to lung injury. Thus, some treatment strategies focus on anti-cytokine storm nAbs. This review summarizes the latest advances in research and clinical trials, challenges, and perspectives on antibody-based treatments (ABT) as therapies against COVID-19.

Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein–protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.

Graphical abstract, Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, −5, −13, −25, –33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, −5, −13, −25, –33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.

Background Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. Methods The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. Results Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. Conclusion An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

Background Markedly elevated levels of pro-inflammatory cytokines and defective type-I interferon responses were reported in COVID-19 patients. Objective This study aimed to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. Methods Cytokine concentrations and SARS-CoV-2 antigen were measured at hospital admission in serum of symptomatic COVID-19 patients (N=115), classified at hospitalization into three respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS) and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N=86). Results At time of hospitalization, ECMO patients presented a dominant pro-inflammatory response with elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8 and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at one month was associated with higher levels of pro-inflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (Risk Ratio 24.3, p, Graphical abstract, Capsule SummaryDistinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality in different oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.

As the world navigates the coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I interferon activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, thus, studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease.

Coronavirus disease 2019 (COVID-19) continues to have a devastating effect on a global scale. COVID-19 variants continue to arise and counteract vaccination efficacy. As such, preventative health measures, such as social distancing and stay at home mandates, will continue for the foreseeable future. Evidence on those at greatest risk for poor outcomes if infected with COVID-19 has rapidly come to light. It has become clear that those with unhealthy lifestyle characteristics, chronic disease risk factors and/or a confirmed diagnosis of one or more chronic conditions are at greatest risk for hospitalization, intensive care unit admission, mechanical ventilation, and death if infected with COVID-19. The cytokine storm is a phenomenon that has been posited as a pathophysiologic response to COVID-19 infection that leads to poor outcomes. The current graphical review illustrates the association between unhealthy lifestyle characteristics and increased vulnerability to the cytokine storm as well as the physiologic mechanisms healthy living behaviors elicit and decrease risk for the cytokine storm. Through this graphical review, we will demonstrate unhealthy lifestyle characteristics, chronic disease risk factors and diagnoses, and COVID-19 outcomes are intricately linked, creating a new global syndemic. It is also clear that a primary way to uncouple this syndemic is through increasing healthy living behaviors, as illustrated in this graphical review. Moving forward, healthy living medicine should be practiced with renewed vigor to improve human resiliency to health threats posed by both chronic disease and viral infections.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

Obesity and the metabolic syndrome (MetS), which have reached pandemic proportions significantly increase the risk for type 2 diabetes, cardiovascular disease, and other serious conditions. Recent data with COVID-19 patients indicate that obesity also is a significant risk factor for this novel viral disease and poor outcome of associated critical illness. These findings considerably change the view of obesity as a driver of serious, but slowly-progressing chronic diseases, and emphasize the urgency to explore new therapeutic approaches. Inflammation is a recognized driver of metabolic derangements in obesity and MetS, and a core feature of COVID-19 pathobiology. Recent advances in our understanding of inflammatory regulation have highlighted the role of the nervous system and the vagus nerve-based inflammatory reflex. Current bioelectronic and pharmacological therapeutic explorations centered on the inflammatory reflex offer new approaches for conditions characterized by immune and metabolic dysregulation and for ameliorating the escalating burden of obesity, MetS, and COVID-19.