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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 SARS-CoV-2 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients., (© 2022. The Author(s).)

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro . Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Syed, Yu, Yang, Xia, Relich, Russell, Zhang, Khalili, Huang, Kacena, Zheng and Yu.)

Background: Systemic vascular injury occurs in coronavirus disease 2019 (COVID-19) patients; however, the underlying mechanisms remain unknown., Methods: To clarify the role of inflammatory factors in COVID-19 vascular injury, we used a multiplex immunoassay to profile 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs)., Results: COVID-19 patients had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only 1 cytokine, macrophage migration inhibitory factor (MIF), was among these altered analytes, while the rest were chemokines/growth factors. Additionally, only matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor A (VEGF-A) were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. We further studied MMP-1 enzymatic activity and multiple endothelial cell (EC) activation markers (soluble forms of CD146, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) and found that they were highly dysregulated in COVID-19 patients., Conclusions: COVID-19 patients have a unique inflammatory profile, and excessive MMP-1 and hyperactivation of ECs are associated with the severity of COVID-19., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: The objective of this study was to determine the feasibility of telementored instruction in bedside ultrasonography (US) using Google Glass. The authors sought to examine whether first-time US users could obtain adequate parasternal long axis (PSLA) views to approximate ejection fraction (EF) using Google Glass telementoring., Methods: This was a prospective, randomized, single-blinded study. Eighteen second-year medical students were randomized into three groups and tasked with obtaining PSLA cardiac imaging. Group A received real-time telementored education through Google Glass via Google Hangout from a remotely located expert. Group B received bedside education from the same expert. Group C represented the control and received no instruction. Each subject was given 3 minutes to obtain a best PSLA cardiac imaging using a portable GE Vscan. Image clips obtained by each subject were stored. A second expert, blinded to instructional mode, evaluated images for adequacy and assigned an image quality rating on a 0 to 10 scale., Results: Group A was able to obtain adequate images six out of six times (100%) with a median image quality rating of 7.5 (interquartile range [IQR] = 6 to 10) out of 10. Group B was also able to obtain adequate views six out of six times (100%), with a median image quality rating of 8 (IQR = 7 to 9). Group C was able to obtain adequate views one out of six times (17%), with a median image quality of 0 (IQR = 0 to 2). There were no statistically significant differences between Group A and Group B in the achievement of adequate images for E-point septal separation measurement or in image quality., Conclusions: In this pilot/feasibility study, novice US users were able to obtain adequate imaging to determine a healthy patient's EF through telementored education using Google Glass. These preliminary data suggest telementoring as an adequate means of medical education in bedside US. This conclusion will need to be validated with larger, more powerful studies including evaluation of pathologic findings and varying body habitus among models., (© 2014 by the Society for Academic Emergency Medicine.)

We assessed the effects of dietary carotenoid pigment supplementation on liver histochemistry in the rainbow trout. One hundred and eight rainbow trout (mean mass 266+/-10 g) were assigned to each of three replicate tanks for each of three dietary treatments; astaxanthin, canthaxanthin, or control at a target dietary inclusion of 100 mg/kg, by top-coating a pigment-free commercially extruded basal diet (Trouw Aquaculture, U.K.). Fish were fed for 3 weeks at a ration of 1.2% body mass/day, in a recirculating freshwater system maintained at 16 degrees C. Frozen liver sections were stained for total lipids, unsaturated lipids, glycogen, mucopolysaccharides, glycogen phosphorylase and aspartate aminotransferase. Relative amounts were measured quantitatively by image analysis. Carotenoid treatment significantly (P<0.05) altered the total lipid profile and hepatic mucopolysaccharide contents of livers of rainbow trout. Results are discussed in relation to the catabolic potential of the liver in carotenoid pigment metabolism.

This study demonstrates the utility and sensitivity of histopathologic biomarkers by recording lesions to the gill, liver and spleen in three spined sticklebacks (Gasterosteus aculeatus) from several rivers in Southern England which broadly comply with the water quality directives to protect fish health. The main study site was the Letcombe Brook system near Wantage, graded 1 (good) to 3 (fair) by the Environment Agency, using the River Ecosystem (RE) Class system. Sites with similar grades on the rivers Erme, Clyst, Exe and Plym were also selected in Devon. A normal condition factor (0.9 +/- 0.02, mean +/- S.E., n = 90), the presence of food in the stomach, and the whole body ionic composition (Na, K, Mg, Ca, Cu, Zn) suggested that fish were generally healthy. All fish showed some minor incidence of gill and liver lesions, even in the best (grade RE1) river water quality. Scoring the percentage of branchial secondary lamellae showing lesions did not reflect water quality because of biotic factors such as parasite load. However, fatness of secondary lamellae (length/width) increased in lower class rivers. Hepatic fatty change and focal necrosis was related to river quality grades with fatty change increasing from 0.8% to 12% of total liver area in grade RE1 and RE2 rivers, respectively. The gross anatomy of the spleen showed normal red and white pulp, and sinusoid space varied between 11% and 34% of the tissue area, but was not correlated with river grade. Overall, we conclude that histopathologic lesions are present in fish even when water quality meets the Freshwater Fisheries Directive. The Directive therefore only partly protects fish health. The incidence of fatty change in the liver, or fatness of secondary lamellae, in adult three spined sticklebacks are suggested as simple but sensitive histopathologic biomarkers which may be used to protect freshwater fishes as a novel alternative approach to water quality based Directives. We propose histopathologic biomarkers of the three spined stickleback for routine monitoring of fish health in EU freshwaters.

The use of fibre-reinforced polymer matrix composite materials is growing at a faster rate than the gross domestic product (GDP) in many countries. An improved understanding of their processing and mechanical behaviour would extend the potential applications of these materials. For unidirectional composites, it is predicted that localized absence of fibres is related to longitudinal compression failure. The use of woven reinforcements permits more effective manufacture than for unidirectional fibres. It has been demonstrated experimentally that compression strengths of woven composites are reduced when fibres are clustered. Summerscales predicted that clustering of fibres would increase the permeability of the reinforcement and hence expedite the processing of these materials. Commercial fabrics are available which employ this concept using flow-enhancing bound tows. The net effect of clustering fibres is to enhance processability whilst reducing the mechanical properties. The effects reported above were qualitative correlations. To improve the design tools for reinforcement fabrics we have sought to quantify the changes in the micro/meso-structure of woven reinforcement fabrics. Gross differences in the appearance of laminate sections are apparent for different weave styles. The use of automated image analysis is essential for the quantification of subtle changes in fabric architecture. This paper considers Voronoi tessellation and fractal dimensions for the quantification of the microstructures of woven fibre-reinforced composites. It reviews our studies in the last decade of the process-property-structure relationships for commercial and experimental fabric reinforcements in an attempt to resolve the processing vs. properties dilemma. A new flow-enhancement concept has been developed which has a reduced impact on laminate mechanical properties.

In the course of evaluating the hypothesis that tryptophan or tryptophan metabolites mediate some of the physiological or pathological aspects of the inflammatory response, we assessed the bioavailability of tryptophan and kynurenine in renal allograft recipients during periods of stable graft function, acute rejection and OKT3 therapy. In normal controls and patients with stable function, approximately 8% of the tryptophan and less than 5% of the kynurenine in serum were present in the freely diffusable form. The free tryptophan concentration was significantly increased during acute rejection, while free tryptophan as well as total and free kynurenine concentrations were significantly increased during OKT3 therapy. In each case the ratio of free indole to the sum of the plasma concentrations of large neutral amino acids was also increased. In vitro studies of indole binding to human serum proteins demonstrated the parallel displacement of bound tryptophan and kynurenine by physiological changes in pH, serum albumin concentration and free fatty acid concentration. The results suggest that inflammation associated increases in the oxidative metabolism of tryptophan are accompanied by the increased availability of serum indoles for intracellular metabolism in the tissues.

Serum concentrations of tryptophan (TRP) and kynurenine (KYN) were determined in renal allograft recipients (RAR) as an index of interferon-gamma-induced, indoleamine-dioxygenase-catalysed TRP degradation. Serum TRP and KYN in RAR during periods of stable graft function were typically within the normal range, however, the median values for serum KYN demonstrated significant increases 5-7 days prior to biopsy-confirmed acute rejection (1.6-fold, P less than 0.01) and on the day of biopsy (1.7-fold, P less than 0.001). Serum KYN was also markedly elevated in patients who contracted viral or Gram-negative bacterial infections in the absence of graft rejection. Serum KYN was not correlated with serum creatinine in RAR nor were serum TRP or KYN affected by antirejection therapy with high dose steroids. Retrospective analysis of intra-patient changes in serum KYN demonstrated that KYN monitoring was a useful adjunct to serum creatinine in the early detection of first acute rejection episodes. The first course of OKT3 therapy was associated with low serum TRP and significant increases in serum KYN (two- to three-fold) following the first three doses. The time course of these abnormalities corresponded to that over which many of the side effects of the OKT3 'first dose reaction' have been reported to occur. Significant changes in serum KYN were not observed in patients receiving repeat courses of OKT3 therapy. Significant decreases in serum TRP and significant increases in serum KYN were both prevalent and frequent in RAR during the first two postoperative months.(ABSTRACT TRUNCATED AT 250 WORDS)