Therapeutics for treating mpox in humans.

BACKGROUND: Mpox was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 23 July 2022, following the identification of thousands of cases in several non-endemic countries in previous months. There are currently no licenced therapeutics for treating mpox; however, some medications may be authorized for use in an outbreak. The efficacy and safety of possible therapeutic options has not been studied in humans with mpox. There is a need to investigate the evidence on safety and effectiveness of treatments for mpox in humans; should any therapeutic option be efficacious and safe, it may be approved for use around the world. OBJECTIVES: There are two parts to this Cochrane Review: a review of evidence from randomized controlled trials (RCTs), and a narrative review of safety data from non-randomized studies. Randomized controlled trials review To systematically review the existing evidence on the effectiveness of therapeutics for mpox infection in humans compared to: a) another different therapeutic for mpox, or b) placebo, or c) supportive care, defined as the treatment of physical and psychological symptoms arising from the disease. Non-randomized studies review To assess the safety of therapeutics for mpox infection from non-randomized studies (NRS). SEARCH METHODS: Randomized controlled trials review We searched the following databases up to 25 January 2023: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of science), and Cochrane CENTRAL (Issue 1 2023). We conducted a search of trial registries (Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP)) on 25 January 2023. There were no date or language limits placed on the search. We undertook a call to experts in the field for relevant studies or ongoing trials to be considered for inclusion in the review. Non-randomized studies review We searched the following databases on 22 September 2022: Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9 of 12, 2022), published in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); and Scopus (Elsevier). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress. SELECTION CRITERIA: For the RCT review and the narrative review, any therapeutic for the treatment of mpox in humans was eligible for inclusion, including tecovirimat, brincidofovir, cidofovir, NIOCH-14, immunomodulators, and vaccine immune globulin. Randomized controlled trials review Studies were eligible for the main review if they were of randomized controlled design and investigated the effectiveness or safety of therapeutics in human mpox infection. Non-randomized studies review Studies were eligible for inclusion in the review of non-randomized studies if they were of non-randomized design and contained data concerning the safety of any therapeutic in human mpox infection. DATA COLLECTION AND ANALYSIS: Randomized controlled trials review Two review authors independently applied study inclusion criteria to identify eligible studies. If we had identified any eligible studies, we planned to assess the risk of bias, and report results with 95% confidence intervals (CI). The critical outcomes were serious adverse events, development of disease-related complications, admission to hospital for non-hospitalized participants, pain as judged by any visual or numerical pain scale, level of virus detected in clinical samples, time to healing of all skin lesions, and mortality. We planned to perform subgroup analysis to explore whether the effect of the therapeutic on the planned outcomes was modified by disease severity and days from symptom onset to therapeutic administration. We also intended to explore the following subgroups of absolute effects: immunosuppression, age, and pre-existing skin disease. Non-randomized studies review One review author applied study inclusion criteria to identify eligible studies and extracted data. Studies of a non-randomized design containing data on the safety of therapeutics could not be meta-analyzed due to the absence of a comparator; we summarized these data narratively in an appendix. MAIN RESULTS: Randomized controlled trials review We did not identify any completed RCTs investigating the effectiveness of therapeutics for treating mpox for the main review. We identified five ongoing trials that plan to assess the effectiveness of one therapeutic option, tecovirimat, for treating mpox in adults and children. One of these ongoing trials intends to include populations with, or at greater risk of, severe disease, which will allow an assessment of safety in more vulnerable populations. Non-randomized studies review Three non-randomized studies met the inclusion criteria for the narrative review, concerning data on the safety of therapeutics in mpox. Very low-certainty evidence from non-randomized studies of small numbers of people indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection, but a possible safety signal for brincidofovir. All three participants who received brincidofovir had raised alanine aminotransferase (ALT), but not bilirubin, suggesting mild liver injury. No study reported severe drug-induced liver injury with brincidofovir. AUTHORS' CONCLUSIONS: Randomized controlled trials review This review found no evidence from randomized controlled trials concerning the efficacy and safety of therapeutics in humans with mpox. Non-randomized studies review Very low-certainty evidence from non-randomized studies indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection. In contrast, very low-certainty evidence raises a safety signal that brincidofovir may cause liver injury. This is also suggested by indirect evidence from brincidofovir use in smallpox. This warrants further investigation and monitoring. This Cochrane Review will be updated as new evidence becomes available to assist policymakers, health professionals, and consumers in making appropriate decisions for the treatment of mpox.

Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody.

BACKGROUND: Individuals with autism spectrum disorder (ASD) have an increased risk of developing epilepsy. Both ASD and epilepsy have been associated with increased levels of immune factors in the blood, including the proinflammatory cytokine interleukin 6 (IL-6). Mice lacking the synapsin 2 gene (Syn2 KO) exhibit ASD-like behavior and develop epileptic seizures. Their brains display neuroinflammatory changes including elevated IL-6 levels. We aimed to investigate the effect of systemic IL-6 receptor antibody (IL-6R ab) treatment on seizure development and frequency in Syn2 KO mice. MATERIAL AND METHODS: Weekly systemic (i.p.) injections of IL-6R ab or saline were given to Syn2 KO mice starting either early in life at 1 month of age, before seizure debut or at 3 months of age, directly after seizure debut and continued for 4 or 2 months, respectively. Seizures were provoked by handling the mice three times per week. The neuroinflammatory response and synaptic protein levels in the brain were determined by ELISA, immunohistochemistry and western blots. In an additional group of Syn2 KO mice, with IL-6R ab treatment early in life, ASD-related behavioral tests including social interaction and repetitive self-grooming, as well as cognitive memory and depressive-/anxiety-like tests, and actigraphy measurements of circadian sleep-awake rhythm were analyzed. RESULTS: The IL-6R ab treatment reduced seizure development and frequency in Syn2 KO mice when initiated before, but not after, seizure debut. However, early treatment did not reverse the neuroinflammatory response or the imbalance in synaptic protein levels in the brain previously reported in Syn2 KO mice. The treatment did not affect social interaction, performance in memory, depressive-/anxiety-like tests or the sleep-awake rhythm of Syn2 KO mice. CONCLUSION: These findings suggest the involvement of IL-6 receptor signaling during epilepsy development in Syn2 KO mice, without significant alterations of the immune reaction in the brain, and independently of cognitive performance, mood and circadian sleep-awake rhythm.

Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma.

BACKGROUND: CD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC. METHODS: Multi-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis. RESULTS: CD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy. CONCLUSIONS: High expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.

Characteristics of pathology and transcriptome profiling reveal features of immune response of acutely infected and asymptomatic infected of carp edema virus in Koi.

Koi sleepy disease (KSD) is a high mortality and infection viral disease caused by carp edema virus (CEV), which was a serious threat to aquaculture of common carp and export trade of Koi worldwide. Asymptomatic infection is an important cause of the difficulty in preventing KSD and its worldwide spread, because asymptomatic infection can be activated under appropriate condition. However, the understanding of the molecular correlates of these infections is still unknown. The purpose of this study was to compare the pathology change, enzyme activity, immunoglobulin activity, host and viral gene expression differences in acutely infected and cohabiting asymptomatic Koi infected with CEV. Healthy Koi were used as a control. The gross pathology, histopathology and ultrastructural pathology showed the difference and characteristics damage to the tissues of Koi under different infection conditions. Periodic Acid-Schiff stain (PAS), enzyme activity and immunoglobulin activity revealed changes in the immune response of gill tissue between acutely infected, asymptomatic infected and healthy Koi. A total of 111 and 2484 upregulated genes and 257 and 4940 downregulated genes were founded in healthy Koi vs asymptomatic infected Koi and healthy Koi vs acutely infected Koi, respectively. Additionally, 878 upregulated genes and 1089 downregulated genes were identified in asymptomatic vs. acutely infected Koi. Immune gene categories and their corresponding genes in different comparison groups were revealed. A total of 3, 59 and 28 immune-related genes were identified in the group of healthy Koi vs asymptomatic infected Koi, healthy Koi vs acutely infected Koi and asymptomatic infected Koi vs acutely infected Koi, respectively. Nineteen immune-related genes have the same expression manner both in healthy Koi vs acutely infected Koi and asymptomatic Koi vs acutely infected Koi, while 9 immune-related genes were differentially expressed only in asymptomatic Koi vs acutely infected Koi, which may play a role in viral reactivation. In addition, 8 differentially expressed genes (DEGs) were validated by quantitative reverse transcription PCR (RT-qPCR), and the results were consistent with the RNA-Seq results. In conclusion, the data obtained in this study provide new evidence for further elucidating CEV-host interactions and the CEV infection mechanism and will facilitate the implementation of integrated strategies for controlling CEV infection and spread.

Prominent dermal accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection.

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin κ and λ light chains. The present case suggests that when inflammatory cell infiltration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection.

EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy.

Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome trafficking/turnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.

Xeno interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes.

Immunological chaperones tapasin and TAP binding protein, related (TAPBPR) play key roles in antigenic peptide optimization and quality control of nascent class I major histocompatibility complex (MHC-I) molecules. The polymorphic nature of MHC-I proteins leads to a range of allelic dependencies on chaperones for assembly and cell-surface expression, limiting chaperone-mediated peptide exchange to a restricted set of human leukocyte antigen (HLA) allotypes. Here, we demonstrate and characterize xeno interactions between a chicken TAPBPR ortholog and a complementary repertoire of HLA allotypes, relative to its human counterpart. We find that TAPBPR orthologs recognize empty MHC-I with broader allele specificity and facilitate peptide exchange by maintaining a reservoir of receptive molecules. Deep mutational scanning of human TAPBPR further identifies gain-of-function mutants, resembling the chicken sequence, which can enhance HLA-A*01:01 expression in situ and promote peptide exchange in vitro. These results highlight that polymorphic sites on MHC-I and chaperone surfaces can be engineered to manipulate their interactions, enabling chaperone-mediated peptide exchange on disease-relevant HLA alleles.

Brain death-like changes: A case report of anti-GQ1b antibody syndrome.

RATIONALE: Anti-GQ1b antibody syndrome originates in the peripheral nervous system or the central nervous system. Various overlapping syndromes and atypical manifestations are also seen in clinic. It is rare to see multiple sites (almost all targets) of central and peripheral damage at the same time, resulting in brain death-like changes in patient. PATIENT CONCERNS: This is a 55-year-old female patient, with a history of prodromal upper respiratory tract infection, began with headache, quickly developed body paralysis, eye paralysis, disturbance of consciousness, apnea, and tested positive for anti-GQ1b antibody. The patient is diagnosed clearly, the disease progresses rapidly, and almost all GQ1b sites in the central nervous system and peripheral nervous system are involved, which is rare. DIAGNOSES: Anti-GQ1b antibody syndrome. INTERVENTIONS AND OUTCOMES: The patient was treated with tracheal intubation, ventilator assisted breathing, and immunoglobulin. The patient recovered quickly and was discharged after about 30 days in hospital. LESSONS: The concept of anti-GQ1b antibody syndrome is not only beneficial for clinical diagnosis, but also beneficial for understanding the continuous disease spectrum with the same etiology and different clinical manifestations. The pathogenesis of each subtype has not been fully defined. There are mild patients with isolated syndromes and severe patients with multiple subtypes overlapping. Encounter severe patients but also active response, the general prognosis is good.

Immunosuppression by Inflammation-Stimulated Amplification of Myeloid-Derived Suppressor Cells and Changes in Expression of Immune Checkpoint HHLA2 in Chronic Obstructive Pulmonary Disease.

Background: The interaction between immune checkpoint and myeloid-derived suppressor cells (MDSCs) play a significant role in inflammatory diseases. But their correlation with chronic obstructive pulmonary disease (COPD) remains unclear. Methods: The differentially expressed immune checkpoints and immunocytes in the airway tissues of COPD patients were identified by bioinformatics analysis, followed by correlation analysis and identification of immune-related differential genes for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. The results of bioinformatics analysis were verified by ELISA and Real-Time PCR and transcriptome sequencing of the peripheral blood of both COPD patients and healthy subjects. Results: The results of the bioinformatics analysis showed that the level of MDSCs in airway tissue and peripheral blood of COPD patients was higher than that of healthy controls. The expression of CSF1 in airway tissue and peripheral blood of COPD patients increased, and CYBB was increased in airway tissue and decreased in peripheral blood of COPD patients. The expression of HHLA2 in the airway tissue decreased in COPD patients, and showed a negative correlation with MDSCs, with a correlation coefficient of -0.37. The peripheral blood flow cytometry results indicated that MDSCs and Treg cells of COPD patients were higher than those in the healthy control group. The results of peripheral blood ELISA and RT-PCR showed that the HHLA2 and CSF1 levels in COPD patients were higher than those in the healthy control group. Conclusion: In COPD, the bone marrow is stimulated to produce MDSCs, and a large number of MDSCs migrate to airway tissue through peripheral blood and cooperate with HHLA2 to exert an immunosuppressive effect. Whether MDSCs play an immunosuppressive effect during migration needs to be further confirmed.

[Clinical characteristics and genetic analysis of four patients with central hypothyroidism due to IGSF1 gene variants].

OBJECTIVE: To explore the clinical manifestations and genetic characteristics of patients with congenital central hypothyroidism due to variants of IGSF1 gene. METHODS: Clinical data, results of genetic testing, and follow-up of four patients admitted to Children's Hospital of Soochow University during 2017 to 2021 were retrospectively analyzed. RESULTS: All of the four patients were males. Patient 1 had presented neonatal jaundice, patients 2 and 3 were admitted for growth retardation during childhood, and thyroid function test indicated slightly low free thyroxine (FT4), patient 4 was found to have reduced FT4 in the neonatal period. Genetic testing revealed that all of the four patients have harbored pathogenic variants of the IGSF1 gene, which were all inherited from their mothers. The thyroid functions in all patients were well controlled with oral levothyroxine and regular follow-up. CONCLUSION: Pathogenic variants of the IGSF1 gene probably underlay the congenital central hypothyroidism with a variety of clinical manifestations, and genetic testing can facilitate the diagnosis at an early stage.

IGPred-HDnet: Prediction of Immunoglobulin Proteins Using Graphical Features and the Hierarchal Deep Learning-Based Approach.

Motivation. Immunoglobulin proteins (IGP) (also called antibodies) are glycoproteins that act as B-cell receptors against external or internal antigens like viruses and bacteria. IGPs play a significant role in diverse cellular processes ranging from adhesion to cell recognition. IGP identifications via the in-silico approach are faster and more cost-effective than wet-lab technological methods. Methods. In this study, we developed an intelligent theoretical deep learning framework, "IGPred-HDnet" for the discrimination of IGPs and non-IGPs. Three types of promising descriptors are feature extraction based on graphical and statistical features (FEGS), amphiphilic pseudo-amino acid composition (Amp-PseAAC), and dipeptide composition (DPC) to extract the graphical, physicochemical, and sequential features. Next, the extracted attributes are evaluated through machine learning, i.e., decision tree (DT), support vector machine (SVM), k-nearest neighbour (KNN), and hierarchical deep network (HDnet) classifiers. The proposed predictor IGPred-HDnet was trained and tested using a 10-fold cross-validation and independent test. Results and Conclusion. The success rates in terms of accuracy (ACC) and Matthew's correlation coefficient (MCC) of IGPred-HDnet on training and independent dataset (Dtrain Dtest) are ACC = 98.00%, 99.10%, and MCC = 0.958, and 0.980 points, respectively. The empirical outcomes demonstrate that the IGPred-HDnet model efficacy on both datasets using the novel FEGS feature and HDnet algorithm achieved superior predictions to other existing computational models. We hope this research will provide great insights into the large-scale identification of IGPs and pharmaceutical companies in new drug design.

Characterization of immunoglobulin loci in the gigantic genome of Ambystoma mexicanum.

Background: The axolotl, Ambystoma mexicanum is a unique biological model for complete tissue regeneration. Is a neotenic endangered species and is highly susceptible to environmental stress, including infectious disease. In contrast to other amphibians, the axolotl is particularly vulnerable to certain viral infections. Like other salamanders, the axolotl genome is one of the largest (32 Gb) and the impact of genome size on Ig loci architecture is unknown. To better understand the immune response in axolotl, we aimed to characterize the immunoglobulin loci of A. mexicanum and compare it with other model vertebrates. Methods: The most recently published genome sequence of A. mexicanum (V6) was used for alignment-based annotation and manual curation using previously described axolotl Ig sequences or reference sequences from other vertebrates. Gene models were further curated using A. mexicanum spleen RNA-seq data. Human, Xenopus tropicalis, Danio rerio (zebrafish), and eight tetrapod reference genomes were used for comparison. Results: Canonical A. mexicanum heavy chain (IGH), lambda (IGL), sigma (IGS), and the putative surrogate light chain (SLC) loci were identified. No kappa locus was found. More than half of the IGHV genes and the IGHF gene are pseudogenes and there is no clan I IGHV genes. Although the IGH locus size is proportional to genome size, we found local size restriction in the IGHM gene and the V gene intergenic distances. In addition, there were V genes with abnormally large V-intron sizes, which correlated with loss of gene functionality. Conclusion: The A. mexicanum immunoglobulin loci share the same general genome architecture as most studied tetrapods. Consistent with its large genome, Ig loci are larger; however, local size restrictions indicate evolutionary constraints likely to be imposed by high transcriptional demand of certain Ig genes, as well as the V(D)J recombination over very long genomic distance ranges. The A. mexicanum has undergone an extensive process of Ig gene loss which partially explains a reduced potential repertoire diversity that may contribute to its impaired antibody response.

CD83 Regulates the Immune Responses in Inflammatory Disorders.

Activating the immune system plays an important role in maintaining physiological homeostasis and defending the body against harmful infections. However, abnormalities in the immune response can lead to various immunopathological responses and severe inflammation. The activation of dendritic cells (DCs) can influence immunological responses by promoting the differentiation of T cells into various functional subtypes crucial for the eradication of pathogens. CD83 is a molecule known to be expressed on mature DCs, activated B cells, and T cells. Two isotypes of CD83, a membrane-bound form and a soluble form, are subjects of extensive scientific research. It has been suggested that CD83 is not only a ubiquitous co-stimulatory molecule but also a crucial player in monitoring and resolving inflammatory reactions. Although CD83 has been involved in immunological responses, its functions in autoimmune diseases and effects on pathogen immune evasion remain unclear. Herein, we outline current immunological findings and the proposed function of CD83 in inflammatory disorders.

Use of adjuvant ISA VG 71 to produce neutralizing egg yolk antibodies against bothropic venom.

The use of egg yolk antibodies-IgY technology-represents an alternative to the production of mammalian immunoglobulins and has several advantages regarding animal welfare and lower costs of production. The use of adjuvants to achieve the hyperimmunization of laying hens plays a key role in the success of the production of high levels of the antibodies. In the present work, two different adjuvant systems (Freund's adjuvants and MontanideTM ISA 71 VG) were compared to produce IgY anti-Bothrops alternatus. For the first immunization, formalin-inactivated Salmonella was added to MontanideTM ISA 71 VG to emulate Freund's complete adjuvant which includes a mycobacteria antigen. After eight immunizations, IgY produced by using either adjuvant was able to neutralize the lethal activity of the venom in a mouse model, but differences were found regarding the recognition of components of the venom between the two adjuvants tested. Overall, MontanideTM adjuvant used in this work could be a good alternative choice to produce antibodies capable of neutralizing the lethality of complex antigens. This adjuvant is commercially available and used in the formulation of several poultry vaccines and could be used for the IgY technology instead of traditional immunomodulators such as Freund's adjuvants. Key points • IgY extracts recognized major components of the venom.• Avidity indexes of the IgY extracts increased after the successive immunizations.• IgY obtained by two adjuvant systems neutralized the lethal activity of the venom.

Convalescent plasma for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma may reduce mortality in patients with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of this intervention is required. OBJECTIVES: To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID-19; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at up to day 28, worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID-19 symptoms resolution (for individuals with mild disease), quality of life, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 participants; high-certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS: For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have low certainty evidence for our primary outcomes. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

ANTECEDENTES: El plasma de convaleciente podría reducir la mortalidad en pacientes con enfermedades respiratorias víricas, y se está investigando como posible tratamiento para la enfermedad por coronavirus 2019 (covid­19). Se requiere un profundo conocimiento del conjunto de evidencia actual sobre los beneficios y riesgos de esta intervención. OBJETIVOS: Evaluar la efectividad y seguridad de la transfusión de plasma de convaleciente en el tratamiento de las personas con covid­19; y mantener la vigencia de la evidencia con un enfoque de revisión sistemática continua. MÉTODOS DE BÚSQUEDA: Para identificar estudios en curso y completados, se realizaron búsquedas en la base de datos COVID­19 de la OMS: literatura global sobre la enfermedad por coronavirus, MEDLINE, Embase, el Registro Cochrane de Estudios de covid­19 y la Plataforma COVID­19 L*OVE de Epistemonikos. Se realizaron búsquedas mensuales hasta el 3 de marzo de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) que evaluaron el plasma de convaleciente para la covid­19, independientemente de la gravedad de la enfermedad, la edad, el sexo o el origen étnico. Se excluyeron los estudios que incluyeron poblaciones con otras enfermedades por coronavirus, como el síndrome respiratorio agudo grave (SARS) o el síndrome respiratorio de Oriente Medio (MERS), así como los estudios que evaluaron la inmunoglobulina estándar. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se siguió la metodología estándar de Cochrane. Para evaluar el sesgo en los estudios incluidos se utilizó la herramienta RoB 2. Se utilizó el método GRADE para evaluar la certeza de la evidencia para los siguientes desenlaces: mortalidad por todas las causas hasta el día 28, empeoramiento y mejoría del estado clínico (para personas con enfermedad moderada a grave), ingreso hospitalario o muerte, resolución de los síntomas de covid­19 (para personas con enfermedad leve), calidad de vida, eventos adversos de grado 3 o 4 y eventos adversos graves. RESULTADOS PRINCIPALES: En esta cuarta versión actualizada de la revisión se incluyeron 33 ECA con 24 861 participantes, de los cuales 11 432 recibieron plasma de convaleciente. De ellos, 9 estudios son unicéntricos y 24 multicéntricos. Se realizaron 14 estudios en América, 8 en Europa, 3 en el Sudeste Asiático, 2 en África, 2 en el Pacífico occidental, 3 en el Mediterráneo oriental y 1 en varias regiones. Se identificaron otros 49 estudios en curso que evaluaron el plasma de convaleciente, y 33 estudios que informaban de que se habían completado. Personas con un diagnóstico confirmado de covid­19 y enfermedad de moderada a grave El uso de plasma de convaleciente se investigó en 29 ECA con 22 728 participantes con enfermedad moderada a grave. En 23 ECA con 22 020 participantes se comparó el plasma de convaleciente con el placebo o la atención habitual sola, en 5 se comparó con plasma estándar y en 1, con inmunoglobulina humana. Se evalúan subgrupos sobre detección de anticuerpos, aparición de síntomas, grupos de ingresos de países y varias comorbilidades en el texto completo. Plasma de convaleciente versus placebo o atención habitual sola El plasma de convaleciente no reduce la mortalidad por todas las causas hasta el día 28 (razón de riesgos [RR] 0,98; intervalo de confianza [IC] del 95%: 0,92 a 1,03; 220 por cada 1000; 21 ECA, 19 021 participantes; evidencia de certeza alta). Tiene poca o ninguna repercusión en la necesidad de ventilación mecánica invasiva o la muerte (RR 1,03; IC del 95%: 0,97 a 1,11; 296 por cada 1000; seis ECA, 14 477 participantes; evidencia de certeza alta) y no tiene ningún efecto en si los participantes reciben el alta hospitalaria (RR 1,00; IC de 95%: 0,97 a 1,02; 665 por cada 1000; seis ECA, 12 721 participantes; evidencia de certeza alta). El plasma de convaleciente podría tener poca o ninguna repercusión en la calidad de vida (DM 1,00; IC del 95%: ­2,14 a 4,14; un ECA, 483 participantes; evidencia de certeza baja). El plasma de convaleciente podría tener poco o ningún efecto en el riesgo de eventos adversos de grado 3 y 4 (RR 1,17; IC del 95%: 0,96 a 1,42; 212 por cada 1000; seis ECA, 2392 participantes; evidencia de certeza baja). Es probable que tenga poco o ningún efecto sobre el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,91 a 1,44; 135 por cada 1000; seis ECA, 3901 participantes; evidencia de certeza moderada). Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce o aumenta la mortalidad por cualquier causa hasta el día 28 (RR 0,73; IC del 95%: 0,45 a 1,19; 129 por cada 1000; cuatro ECA, 484 participantes; evidencia de certeza muy baja). No se sabe si el plasma de convaleciente reduce o aumenta la necesidad de ventilación mecánica invasiva o la muerte (RR 5,59; IC del 95%: 0,29 a 108,38; 311 por cada 1000; un estudio, 34 participantes; evidencia de certeza muy baja) ni si reduce o aumenta el riesgo de eventos adversos graves (RR 0,80; IC 95%: 0,55 a 1,15; 236 por cada 1000; tres ECA, 327 participantes; evidencia de certeza muy baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus inmunoglobulina humana El plasma de convaleciente podría tener poco o ningún efecto sobre la mortalidad por cualquier causa hasta el día 28 (RR 1,07; IC del 95%: 0,76 a 1,50; 464 por cada 1000; un estudio, 190 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Personas con un diagnóstico confirmado de infección por SARS­CoV­2 y enfermedad leve Se identificaron dos ECA, con 536 participantes, que compararon el plasma de convaleciente con placebo o atención habitual sola y dos ECA, con 1597 participantes con enfermedad leve, que compararon el plasma de convaleciente con plasma estándar. Plasma de convaleciente versus placebo o atención habitual sola No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (odds ratio [OR] 0,36; IC del 95%: 0,09 a 1,46; 8 por cada 1000; dos ECA, 536 participantes; evidencia de certeza muy baja). Podría tener poco o ningún efecto en el ingreso hospitalario o la muerte a los 28 días (RR 1,05; IC del 95%: 0,60 a 1,84; 117 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el tiempo hasta la resolución de los síntomas de covid­19 (cociente de riesgos instantáneos [CRI] 1,05; IC del 95%: 0,85 a 1,30; 483 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el riesgo de eventos adversos de grados 3 y 4 (RR 1,29; IC del 95%: 0,75 a 2,19; 144 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja) y en el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,66 a 1,94; 133 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (OR 0,30; IC del 95%: 0,05 a 1,75; 2 por cada 1000; dos ECA, 1597 participantes; evidencia de certeza muy baja). Es probable que reduzca el ingreso hospitalario o la muerte a los 28 días (RR 0,49; IC del 95%: 0,31 a 0,75; 36 por cada 1000; dos ECA, 1595 participantes; evidencia de certeza moderada). El plasma de convaleciente podría tener poco o ningún efecto sobre la resolución inicial de los síntomas hasta el día 28 (RR 1,12; IC del 95%: 0,98 a 1,27; un ECA, 416 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Esta es una revisión sistemática continua. Cada mes se busca nueva evidencia y se actualiza la revisión cuando se identifica evidencia nueva relevante. CONCLUSIONES DE LOS AUTORES: Para la comparación del plasma de convaleciente versus placebo o la atención habitual sola, existe evidencia de certeza alta de que el plasma de convaleciente para personas con enfermedad moderada a grave no reduce la mortalidad y tiene poco o ningún efecto en la mejoría o el empeoramiento clínico. Es probable que tenga poco o ningún efecto en los eventos adversos graves. Para las personas con enfermedad leve, existe evidencia de certeza baja para los desenlaces principales. Hay 49 estudios en curso y 33 estudios que declaran estar completados en un registro de ensayos. La publicación de los estudios en curso podría resolver algunas de las incertidumbres en torno al tratamiento con plasma de convaleciente para personas con enfermedad asintomática o leve.

New insight of human-IgH 3'regulatory regions in immunoglobulins switch.

BACKGROUND: Several studies in animal models have demonstrated the role of the 3' Regulatory Region (3'RR) in the B cell maturation in mammals. In healthy humans, the concentration of each class of circulating immunoglobulins (Igs) has stable but different levels, due to several control mechanisms that also involve a duplicated version of the 3'RR on the chromosome 14 (chr14). The classes' equilibrium can be altered during infections and in other pathological conditions. MATERIAL AND METHODS: We studied the concentrations of IgA, IgM, IgG classes and IgG subclasses in a cohort of 1235 people having immunoglobulin concentrations within normal range to determine the presence of any correlation between the Igs serum concentrations, age and ratio among Ig classes and IgG subclasses in healthy humans. Furthermore, we assessed the concentrations of IgE and the allelic frequency of 3'RR1 hs1.2 enhancer in a group of 115 subjects with high levels of circulating IgE due to acute exacerbation of allergic asthma and in a control group of 118 healthy subjects. RESULTS: In both children and adult subjects, the concentrations of the four IgG subclasses decreased from IgG1 to IgG4. Furthermore, the 3'RR1 enhancer hs1.2 alleles contribute to the control of the IgG subclasses levels, but it does not affect the IgE levels. CONCLUSION: The 3'RR1 controls IgG and IgE through different mechanisms, only in the IgG case involving the hs1.2 alleles. Thus, considering the IgH constant genes loci on the chromosome 14 and the multiple steps of switch that rearrange the whole region, we found that in humans the classes of Igs are modulated by mechanisms involving a complex interaction and transition between 3'RR1 and 3'RR2, also in physiological conditions.

Genome-wide identification and skin expression of immunoglobulin superfamily in discus fish (Symphysodon aequifasciatus) reveal common genes associated with vertebrate lactation.

Discus Symphysodon spp. employs an unusual parental care behavior where fry feed on parental skin mucus after hatching. Studies on discus immunoglobulin superfamily (IgSF) especially during parental care are scarce. Here, a total of 518 IgSF members were identified based on discus genome and clustered into 12 groups, unevenly distributing on 30 linkage groups. A total of 92 pairs of tandem duplication and 40 pairs of segmental duplication that underwent purifying selection were identified. IgSF genes expressed differentially in discus skin during different care stages and between male and female parents. Specifically, the transcription of btn1a1, similar with mammalian lactation, increased after spawning, reached a peak when fry started biting on parents' skin mucus, and then decreased. The expression of btn2a1 and other immune members, e.g., nect4, fcl5 and cd22, were up-regulated when fry stopped biting on mucus. These results suggest the expression differentiation of IgSF genes in skin of discus fish during parental care.