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Several authors have mentioned the importance of allowing for the susceptible proportion of the population. Firstly, while we do know local vaccination numbers, accurate estimation of asymptomatic or mildly asymptomatic case-numbers is problematic, even with the availability of data from high-quality randomised prevalence surveys such as the REACT study (Riley et al., [1]). Peter J. Diggle's discussion contribution to the papers in Session 3 of the Royal Statistical Society's Special Topic Meeting on Covid-19 Transmission: 11 June 2021. [Extracted from the article]

In Sri Lanka 2741 people from Matara, an endemic area for Wuchereria bancrofti, were examined in 1996/97 for microfilariae by 60-μL blood smear and for circulating filarial antigens by Og4C3 ELISA using filter paper-absorbed whole blood. The overall prevalence of microfilaraemia was 3 · 4%, and that of antigenaemia 14 · 4%. The prevalence of antigen-positive and microfilaria-negative people was 11 · 3%. Analysed by age-group, antigenaemia prevalence was similar in all groups, and the average number of antigen units was already very high in the age-group < 10 years, indicating that the infection started in early childhood. Among those who were antigen positive, the microfilaria prevalence was lower in females than in males. Diethylcarbamazine treatment eliminated microfilariae in 78% of the positives. However, 17 months after the treatment, antigenaemia was still positive in 76% of those who were parasitologically cured. [Copyright &y& Elsevier]

Epithelial ovarian cancer (EOC) is a prevalent carcinoma in the female population associated with poor prognostic outcomes, in part due to the late stage of the disease at diagnosis. Aiming to identify tumour-associated antigens (TAAs) with the potential to facilitate earlier detection and targeted therapy of EOC, five scientific literature repositories were systemically searched for primary literature sources reporting the expression of a TAA in the tissue or serum of adult females diagnosed with EOC and healthy women. We identified 7120 articles of which 32 met our inclusion criteria and passed the bias-quality assessment. Subsequently, data were collated on 29 TAAs whose expression had been analysed in 2181 patients and 589 healthy individuals. Reports of CA125 and EpCAM expression were numerous while tissue expression data were available for 28 TAAs. Data were segregated into three meta-cohorts for statistical scrutiny and their capacity for diagnostic and treatment targeting was assessed. We showed that CA-125 was expressed homogenously in EOC patients while EpCAM was expressed heterogeneously. CA-125 was the most promising TAA target for both diagnosis and treatment, gaining a priority score of 12 (/12) while EpCAM gained a priority score of seven. Tissue expression of EOC TAAs was homogenous; 90% of the EOC population express any identified TAA while just 20% of healthy individuals will be positive for the same TAA. We suggest TAA profiling should be a fundamental aspect of EOC diagnosis, sitting alongside the FIGO framework, promoting reduced mortality and directing the development of TAA-targeted therapeutics. [ABSTRACT FROM AUTHOR]

The article presents research papers on drug delivery. One research focuses on polymeric microsphere preparation as an ophthalmic drug delivery system for brimonidine tartrate. Another research examines the effects of surfactants on the biological activity and integrity of spray-dried and crystallized proteins. The comparative biodistribution study on cationic liposome selection for a subunit tuberculosis antigen delivery is also provided.

Introduction The Nigeria government, supported by its development partners conducted several vaccination campaigns involving various antigens across the country in 2019. Majority of the states in the North including the Federal Capital Territory (FCT) implemented the Integrated Measles and Men A vaccination campaign (IVC) which itself was an innovation given that both campaigns were initially planned as stand-alone campaigns. The integration of these campaigns came with additional planning, new implementation strategies and challenges. This paper aims to highlight the key drivers of FCT's performance in achieving greater than 90% vaccination coverage for both antigens and the challenges of the integrated campaign in FCT. Methods A baseline review of previous campaign reports, micro plans and tally sheet data was conducted to identify challenges of previous SIAs in FCT, best practices and lessons learnt. A preliminary analysis of available data revealed a shortfall in resources early enough in the planning phase. Notably, was a shortfall of about 300 vaccination teams for the implementation of the Measles vaccination campaign (as a standalone campaign) as well as shortfall in cold chain equipment and logistic funds. We leveraged on the thrice weekly technical coordination meetings to review these challenges to seek ways to mitigate them. Result Strategic efforts to address the identified gaps led to the state sponsoring an additional 354 vaccination teams to support implementation by leveraging on the SOML funds. Staggering the campaign was key to ensuring adequacy of CCEOPs to address the increase in the number required due to the integration. The additional state sponsored team vaccinated 121777 and 123588 children who otherwise would have been missed with the Measles antigen with the Men A antigen respectively. Conclusion Strategic resolution of identified challenges was pivotal to FCT's performance of greater than 90% vaccination coverages for both antigens. Key words Measles, Meningitis A, Integrated, Vaccination, Campaign [ABSTRACT FROM AUTHOR]

The thin layer rapid use epicutaneous test (TRUE-test) is a new patch test, in which the allergens are incorporated in a thin, flexible solid vehicle on a water impermeable backing. The vehicle shows good stability for allergens, which are crystallized, micronized or emulsified into a gel. The TRUE-test produces an exact dosage, even surface spread and high bioavailability for the allergens. This solves the problems of low bioavailability, uncertain dosage and uneven surface distribution which are commonly seen when petrolatum is used as the vehicle. [ABSTRACT FROM AUTHOR]

Partial purification of soluble products of guinea-pig lymphocyte activation (LAP) was undertaken by fractional precipitation with ammonium sulphate, ion-exchange and Sephadex chromatography, and by immune precipitation of inducing antigen and of contaminating serum protein. During these purification steps the activity of macrophage migration-inhibition factor (MIF) was concentrated up to 1300-fold and separated from inducing antigen and serum protein. An endpoint assay was devised for expressing antigen-induced MIF activity of LAP fractions as weights of material giving 30% inhibition of migration (MI30 doses). MIF activity precipitated between 50% and 80% saturated ammonium sulphate and eluted from DEAE-cellulose at pH 7-9 at intermediate salt concentrations (0-03-0-2 M phosphate). On Sephadex gel filtration MIF activity was concentrated in fractions of molecular weight range 56,000-82,000 with a smaller amount of activity eluting from 20,000-56,000. After immune precipitation of extraneous protein and elution from DEAE-cellulose, LAP material was found to have an MI30 dose of 0-4 /μg. Materials representative of antigen and serum protein-depleted MIF were selected for intralymphatic injection in order to determine whether MIF-rich LAP fractions were able to induce paracortical distension in guinea-pig lymph nodes (see following paper). [ABSTRACT FROM AUTHOR]

The mononuclear cells from. the joint fluid of certain patients with inflammatory arthritis are shown to be more cytotoxic to a polyploid strain of homologous liver cells than were equivalent numbers of peripheral blood lymphocytes From the same donors. The diagnostic categories of these patients are essentially similar to those of a group of patients studied by Hedberg (1967) in whom joint fluid mononuclear cells were cytotoxic to monolayers of human foetal fibroblasts. Evidence is presented to show that this cytotoxic activity is attributable to lymphocytes, as opposed to polymorphonuclear leucocytes or phagocytic mononuclear cells which adhere to glass. It is not excluded that the latter population may also have some cytotoxic potential. It is argued that the target cell damage described in this paper is probably not induced by any antigen on the target cell. The implications of this suggestion are discussed in relation to the pathogenesis of inflammatory joint disease. [ABSTRACT FROM AUTHOR]

In this paper we provide a detailed description of an experimental method for investigating the induction and resolution of recall immune response to antigen in humans in vivo. This involves the injection of tuberculin purified protein derivative ( PPD) into the skin, followed by inducing suction blisters at the site of injection, from which leucocytes and cytokines that are involved in the response can be isolated and characterized. Using this technique we found that although the majority of CD4+ T cells in the skin that are present early in the response express cutaneous lymphocyte antigen ( CLA), the expression of this marker is reduced significantly in later phases. This may enable these cells to leave the skin during immune resolution. Furthermore, interleukin ( IL)-2 production can be detected both in CD4+ T cells and also in the blister fluid at the peak of the response at day 7, indicating that mediators found in the blister fluid are representative of the cytokine microenvironment in vivo. Finally, we found that older humans have defective ability to respond to cutaneous PPD challenge, but this does not reflect a global immune deficit as they have similar numbers of circulating functional PPD-specific CD4+ T cells as young subjects. The use of the blister technology enables further characterization of the skin specific defect in older humans and also general mechanisms that govern immune regulation in vivo. [ABSTRACT FROM AUTHOR]

Although lymphocyte transformation induced by smallpox vaccine is known to occur in lymphocyte cultures from subjects immune to vaccinia virus, the time course of the development of this transformation has not previously been studied. This paper reports the development of lymphocyte transformation in a subject following primary smallpox vaccination. The first signs of lymphocyte transformation in vitro induced by smallpox vaccine were detected twenty days after vaccination, when there was 8 % lymphoblastoid transformation with a mitotic index of 02%. In immunity to smallpox both gammaglobulin antibodies and lymphocytes play a role. Gammaglobulin antibody appears within ten days of vaccination. Immune mechanisms based on lymphocytes and associated with lymphocyte transformation in vitro occur later. [ABSTRACT FROM AUTHOR]

The Tn antigen (GalNAc α-O-Ser/Thr) is heterogeneously synthesized by a variety of tumors and contains an epitope defined by lectins and antibodies as a cluster of αGalNAc carbohydrates synthesized within a peptide sequence, which is rich in serine and/or threonine. The Tn antigen has been utilized as a target in vaccine experiments and also used as a biomarker for prognosis of different cancer forms. In this paper, we present a new monoclonal antibody, GOD3-2C4, with the clear hallmarks of an anti-Tn antibody. It was generated through somatic cell hybridization after immunization of a mouse with a tumor cell line and a Tn carrying mucin. The antibody recognizes synthetic Tn antigen and binds breast, colon, lung, ovarian and pancreas cancer. The GOD3-2C4 antibody has antibody-dependent cellular cytotoxicity activity against Jurkat cells in vitro, and for the first time, it can be shown that an anti-Tn antibody has a significant in vivo effect on a human cancer cell line grown as a xenograft in severe combined immunodeficiency mice. [ABSTRACT FROM AUTHOR]

Limited production capacity and delays inherent in vaccine development are major hurdles to the widespread use of vaccines to mitigate the effects of a new influenza pandemic. Antigen-sparing vaccines have the most potential to increase population coverage but may be less efficacious. The authors explored this trade-off by applying simple models of influenza transmission and dose response to recent clinical trial data. In this paper, these data are used to illustrate an approach to comparing vaccines on the basis of antigen supply and inferred efficacy. The effects of delays in matched vaccine availability and seroconversion on epidemic size during pandemic phase 6 were also studied. The authors infer from trial data that population benefits stem from the use of low-antigen vaccines. Delayed availability of a matched vaccine could be partially alleviated by using a 1-dose vaccination program with increased coverage and reduced time to full protection. Although less immunogenic, an overall attack rate of up to 6% lower than a 2-dose program could be achieved. However, if prevalence at vaccination is above 1%, effectiveness is much reduced, emphasizing the need for other control measures. [ABSTRACT FROM PUBLISHER]

The O-antigen, consisting of many repeats of an oligosaccharide, is an essential component of the lipopolysaccharide on the surface of Gram-negative bacteria. The O-antigen is one of the most variable cell constituents, and different O-antigen forms are almost entirely due to genetic variations in O-antigen gene clusters. In this paper, we present structural and genetic evidence for a close relationship between Escherichia coli O107 and E. coli O117 O antigens. The O-antigen of E. coli O107 has a pentasaccharide repeating unit with the following structure: →4)-β-d-Gal pNAc-(1→3)-α-l-Rha p-(1→4)-α-d-Glc pNAc-(1→4)-β-d-Gal p-(1→3)-α-d-Gal pNAc-(1→, which differs from the known repeating unit of E. coli O117 only in the substitution ofd-GlcNAc ford-Glc. The O-antigen gene clusters of E. coli O107 and O117 share 98.6% overall DNA identity and contain the same set of genes in the same organization. It is proposed that one cluster was evolved from another via mutations, and the substitution of a few amino acids residues in predicted glycosyltransferases resulted in the functional change of one such protein for transferring different sugars in O107 (d-GlcNAc) and O117 (d-Glc), leading to different O-antigen structures. This is an example of the O-antigen alteration caused by nucleotide mutations, which is less commonly reported for O-antigen variations. [ABSTRACT FROM AUTHOR]

The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4--mediated T-cell suppression to enhance the immune response against tumors. Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy, vaccines, or cytokines. Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy. For example, short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients, and objective responses may be of prolonged duration. In some patients clinical improvement manifests as stable disease, which may also extend for months or years. Immune- related adverse events (IRAEs) have been observed in patients after CTLA-4 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system. Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment. This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials, provides a synopsis of current trials, and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab. [ABSTRACT FROM AUTHOR]

The effects of the patch test application of Malassezia pachydermatis extracts were evaluated in seven healthy basset hounds and in seven basset hounds with Malassezia dermatitis. Antigens (4 and 0.4 mg/ml) and saline controls were applied for 48 h using filter paper discs in Finn chambers. One healthy basset hound and five affected hounds showed positive patch test reactivity to the yeast antigens. Positive patch test reactions were characterized histologically by mild epidermal hyperplasia and mild to moderate perivascular, periadnexal and interstitial infiltrates of neutrophils and CD3 + lymphocytes. Immediate intradermal test reactivity to M. pachydermatis antigens was seen in one healthy and one affected hound, whereas delayed intradermal test reactivity was seen in six healthy hounds and five affected hounds. This study indicates that patch test reactivity to M. pachydermatis antigen may occur in healthy basset hounds, and in contrast to delayed intradermal test reactivity, is more frequent in basset hounds with Malassezia dermatitis. [ABSTRACT FROM AUTHOR]

SUMMARY The addition of a foreign antigen to an inoculum completely inhibits the development of collagen-induced arthritis (CIA). However, the mechanism of this phenomenon, antigen -inhibition, is incompletely understood. Previous studies have demonstrated that the inhibition of arthritis is not mediated through suppression of the antibody response to cartilage antigens. In this paper we investigated cytokine mRNA levels in lymph nodes cells recovered 3, 7 or 16 days from animals immunized with either collagen II in IFA or OVA + collagen II in IFA. At day 7, but not at other time-points, IL-4 mRNA was up-regulated in the lymph nodes of OVA-inhibited non-arthritic animals compared to control animals which all developed arthritis. No significant differences between the two groups could be detected when expression of IFN-γ , IL-2, TNF-α , IL-1β or IL-10 mRNA was analysed. Flow cytometry analysis of draining lymph node cells demonstrated that the T cell marker Ox40 was up-regulated in the OVA-inhibited group. Our results indicate that the complete inhibition of CIA caused by addition of OVA to the collagen II inoculum is due to the presence of a TH2 environment resulting from an increased production of IL-4 mRNA and a parallel increase in Ox40+ T cells. [ABSTRACT FROM AUTHOR]

Aims The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)–mediated post-transcriptional regulation in CAVD. Methods and results We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. Conclusion Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment. [ABSTRACT FROM AUTHOR]

Studies have been conducted to characterize M. leprae antigens from purified Ieprae bacilli derived from infected armadillos. First, the proteins of the mycobacterial extracts were fractionated by SDS-PAGE. Subsequently, the proteins in the gel were electrophoretically transferred on a strip of nitrocellulose paper by the technique of 'electrophoretic blotting'. The separated bacterial protein bands, thus immobilized on the nitrocellulose paper were made to react immunologically with sera from the lepromatous patients, infected armadillo sera and other experimental mycobacterial antisera. It was observed that a majority of M. leprae proteins contained antigenic determinants also present on proteins of BCG. In addition, only two specific antigen bands of 33KD and 12KD were conspicuously detected by the patients' sera and the infected armadillo sera. These substances were further identified as polysaccharides or glycoproteins since they could only be stained by Schiff's reagent or alcian blue. Only 12KD glycoprotein band reacted with concanavalin A, whereas wheat germ agglutinin (WGA) did not show any reaction with them. These 33KD and 12KD glycoprotein antigens were found to lose their antigenicity after pepsin treatment and can be considered as glycoproteins. Further, radiolabelling experiments showed that 12KD antigen underwent radioiodination under usual conditions, but 33KD glycoprotein Failed to be similarly radiolabelled. It is suggested that these protein antigens have M. Ieprae specific determinants on a cross-reacting component. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes from 105 subjects with different forms of leprosy and healthy contacts of leprosy patients were stimulated in vitro with different preparations of mycobacterial antigens alone or in combination with a suboptimal dose of phytohaemagglutinin (PHA). In nearly all individuals sonicated leprosy bacilli and PHA together gave a lower 3H-thymidine incorporation than did the same dose of PHA alone. There was no difference in the degree of inhibition seen in the different patient groups or the healthy contacts. High doses of whole, washed Mycobacterium leprae, combined with PHA led to an increased thymidine incorporation in borderline tuberculoid leprosy patients who had experienced a reversal reaction, and in healthy contacts with more than 6 months of exposure, while most lepromatous patients and contacts with less than 6 months exposure did not show an augmentation of the PHA-induced thymidine incorporation. The inhibition exerted by sonicated M. leprae was dose-dependent, seen even with very low doses of antigen, and was not due to direct cytotoxicity. M. bovis, strain BCG, was weakly suppressive in combination with PHA, and sonicated M. duvalii had a very marked suppressive effect. There was no correlation between the suppressive effect of M. leprue antigens and the other mycobacteria neither was there any correlation with the responses to the mycobacterial antigens alone. Many lepromatous leprosy patients showed significant suppression of background incorporation with addition of M. leprae antigens. This paper discusses whether the apparent `non-responsiveness' in lepromatous leprosy could be due to active suppressor mechanisms operative in vivo. [ABSTRACT FROM AUTHOR]

This paper reports the properties of purified human F antigen (liver-specific antigen). Homgenates of liver in 0.25 M sucrose were centrifuged at 105,000 g. The supernatants were chromatographed on Sepharose 6-Band tour major peaks were separated. The third peak proved to be predominantly F antigen. This fraction was subsequently subjected to DEAM-cellulose column chromatography and F antigen was eluted at a concentration less than 0.2 M NaCl in 0.01M sodium phosphate huller (pH 7.2). Finally, purified F antigen was obtained alter preparative isoelectric focusing. Purified human F antigen was found to have a mol. wt between 40,000 and 80,000, a pl of 6.5-6.7 and a density of 1.26. It is a protein antigen and contains on detectable carbodhydrate or lipid. No differences were found in purified F-antigen preparations from several species when tested by sodium dodecyl sulphate (DS) disc gel electrophoresis. Immunofluorescent studies showed that F antigen was homogeneously distributed in the cytoplasm of liver cells but was not present on the cell surface. Immunization of guinea-pigs with purified human liver-specific protein did not induce antibody to the F antigenic determinant defined by mouse anti-F antiserum. It did, however, induce antibodies to two human liver antigens. One of these seems to be a human-specific determinant on the F antigen molecule and the other appears to be a separate molecule which is similar in molecular weight and electrophoretic mobility to the F-antigen molecule. [ABSTRACT FROM AUTHOR]

This paper describes immunofluorescence studies on liver cell surface localization of hepatitis B surface antigen (HBsAg) and of IgG in acute and chronic hepatitis and in cirrhosis. In acute hepatitis B, HBsAg was found at the surface of hepatocytes in an early phase of the disease, hut not during the recovery. This finding is consistent with the hypothesis that immune reactions to HBsAg may be responsible for the liver cell lysis. In HBsAg-positive chronic hepatitis and cirrhosis the antigen was found in the cytoplasm, but not on the surface of the hepatocytes, while in HBsAg-negative cases the antigen could not be detected in the liver cells. Both in HBsAg-positive and in HBsAg-negative chronic active hepatitis (CAH) and cryptogenic cirrhosis, IgG bound to the membrane of the hepatoeytes could be detected, suggesting a role of antibodies in the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

This paper describes the application of parallel bioassay to the measurement of lymphocyte mitogenic, inflammatory and macrophage migration inhibitory activities present in guinea-pig lymphokine preparations. Seven lymphokine preparations were made under similar conditions by antigen activation of sensitized guinea-pig peritoneal exudate cells; and one of these was prepared in sufficient quantity as a 'working standard' for the repeated assay of the three lymphokine activities in the other six 'test' preparations. Mean potency ratios of the separate lymphokine activities were calculated for the test preparations by reference to those of the standard preparation (designated as unity). Although the seven preparations were made under operationally similar circumstances, χ² analysis of the assay results revealed that the three separate lymphokine activities occurred in different absolute amounts and relative proportions in the different preparations. This demonstration by parallel bioassay of heterogeneity and dissociation of lymphokine activities implies that these biological activities cannot be ascribed to a single substance. This type of analysis has general application in the characterization and separation of biologically active substances present in preparations exhibiting multiple activities. [ABSTRACT FROM AUTHOR]

In polyacrylamide gel gradient electrophoresis, serum and blister fluid of patients with bullous pemphigoid showed a nearly identical protein distribution pattern except for one more concentrated fraction in the blister fluid. This fraction could be isolated by several gel chromatographic steps and then be characterized as a protein with a molecular weight of 240,000 (BFP 240,000) consisting of several subunits. Two of these subunits could be identified as C3 fragments and two other ones as basement membrane zone antigens (BMZ-Ag) by means of a modified Laurell technique. The molecular weight of the BFP 240,000 may be small enough to allow it to penetrate through the vessel wall into the blood circulation where, with the BMZ-antibodies (BMZ-Ab), BMZ-Ag-BMZ-Ab-complexes can be formed. The occurrence of such immune complexes in the serum has been shown in a previous paper. [ABSTRACT FROM AUTHOR]

The recognition and binding of glycoprotein receptors on lymphocytes to specific antigens present on high endothelial venules (HEV) precedes the egress of lymphocytes from the blood stream into the tissues. In this paper, we report the presence of HEVs with tannic-acid staining material (TASM[SUP+] HEVS) in Stahylococcus aureus-associated erythroderma, which allow the migration of CD8[SUP+] lymphocytes from the bloodstream into the epidermis TASM positivity is also expressed on lymphocytes within the regional lymph nodes, and by intravascular lymphocytes prior to leaving the TASM[SUP+] HEV. It is proposed that TASM positivity may represent a molecule, which may function in binding lymhocytes to HEVs prior to egress from the HEV (TASM is lost from lymphocytes after leaving the HEVS.) The expression of TASM positivity may form an essential part of the CD8[SUP+] lymhocyte-HEV recognition system, and may be the means whereby CD8[SUP+] lymphocytes generated in the regional lymph nodes by various mitogens (in this case by staphylococcal mitogens) may 'home' to specific sites with the epidermis TASM positivity on both the within the epidermis TASM positivity on both the HEVs and lymphocytes may serve as a convenient market of such a system. [ABSTRACT FROM AUTHOR]

The article presents various research papers related to complement deficiencies, published in an earlier issue of the journal "Clinical & Experimental Immunology". One of the abstracts talk about acquired deficiency in C1-inhibitor associated with an undifferentiated gastric adenocarcinoma. Acquired deficiency in C1-inhibitor (C1-INH) clinically manifests similar to hereditary angioedema and is usually associated with a B cell malignancy or is sometimes characterized by an autoantibody towards the C1-INH molecule.

Recently, we reported on the importance of food antigens on the pathogenesis of an experimentally-induced model of, and some patients with, IgA nephropathy. In this paper, the glomerular deposition of food antigens (casein, lactalbumin, peanut protein, soy bean protein, rice protein, ovalbumin) was investigated by an immunofluorescence technique in 28 patients with IgA nephropathy and 32 controls (ten with lupus nephritis, three with Henoch-Schoenlein purpura nephritis and 19 with other glomerulonephritis). Glomerular IgA deposition was demonstrated in all IgA nephropathy and Henoch-Schoenlein purpura nephritis, and in four lupus nephritis. Positive findings of food antigens, observed as mesangial pattern, were obtained in eleven cases (39.3%) with casein, 21 (75.0%) with soy bean protein and one (3.6%) with rice protein in IgA nephropathy, even though no such findings were seen in the control group. Eleven of 28 patients with IgA nephropathy were positive with soy bean protein alone, nine were positive with soy bean protein+casein, one was positive with soy bean protein + casein + rice protein, and one was positive with casein alone. The deposition of food antigens was not observed in six cases only. Furthermore, no correlation was noted between the deposition of food antigens and the deposition of IgA1, IgA2 or J chain, in vitro binding of the secretory component, or histopathological grades. These results suggest that the exact meanings of glomerular deposition are unclear. Food antigens are postulated, however, as possibly participating strongly in the pathogenesis and as being localized in the glomerular mesangium as an antigen in some patients with IgA nephropathy. [ABSTRACT FROM AUTHOR]

The binding of EPF to lymphocytes stimulates the release of soluble mediators, active in T cell dependent reactions, namely the rosette inhibition test and the adoptive transfer of contact sensitivity. On the basis of their ability to inhibit the delayed type hypersensitivity reaction in this latter assay, they have been classified as suppressor factors. This paper describes the identification of two EPF-induced suppressor factors. Unlike EPF which is neither species-restricted nor strain-restricted, these factors are genetically restricted in their action in the rosette inhibition test EPF-S1 (estimated Mr 14,000) is restricted to the I region of the mouse MHC, while EPF-S2 (estimated Mr 55,000) is restricted to a locus (or loci) outside the MHC. Like other antigen non-specific factors, release of these suppressor factors can be stimulated also by Con A. [ABSTRACT FROM AUTHOR]

Freshly isolated B cells from chronic lymphocytic leukaemia patients (B-CLL) have been previously shown to induce a strong proliferative response and high levels of NK-like activity in lymphocytes from healthy donors. The present paper deals with the origin, mitotic state, target spectrum and cell surface phenotype of the NK-like effectors generated after stimulation with B-CLL. Experiments using large granular lymphocytes (LGL) and T cells as responders demonstrated that most of the precursors of the newly generated NK-like effectors express the CD3 antigen. The induction of NK-like activity paralleled cell activation, as judged by blast transformation, thymidine uptake and appearance of cell surface activation markers. The newly generated NK-like effectors displayed a T cell phenotype and a broader target repertoire than native NK cells. [ABSTRACT FROM AUTHOR]

Patients with the S. aureus hyper IgE syndrome (SAHIGES) have an abnormal IgE response to cell wall and surface antigens of S. aureus. In this paper we describe the detection of IgE antibodies to soluble antigens of staphylococci (S. aureus and S. epidermidis) and qualitative abnormalities of the IgG response lo soluble S. aureus antigens in patients with SAHIGES. These findings may be of pathogenetic importance and help to delineate SAHIGES from other diseases. [ABSTRACT FROM AUTHOR]

Prolonged exposure to antigens may result in high IgG4 antibody titres as was shown in a previous paper (Aalberse et al., 1983b). In novice bee keepers, a shift in the IgGI/IgG4 ratio of the response against phospholipase-A (PLA; a major component of bee venom) occurred. This resulted in an IgG4-dominated response after approximately 2 years of bee-keeping experience. Subject of the present study was the influence of relatively high concentrations of IgG4 antibodies on the biological activity of immune complexes. In the PLA antigen model, it was demonstrated (a) that IgG4-containing immune complexes do not activate complement and (b) that lgG4 antibodies effectively inhibit immune precipitation and complement activation by IgG1 antibodies. Evidence is provided that lgG4 antibodies inhibit binding of Clq to IgG1 in mixed, IgG1- and lgG4-containing complexes. It is proposed that IgG4 antibodies protect against the biological effects of the complement-fixing IgG subclasses. For this reason, determination of the total IgG response or just determination of antibody activity in the complement-fixing isotypes is insufficient in immune-complex diseases. The modulating effect of the non-complement-fixing isotypes should be taken into account to predict the biological activity of the immune complexes. [ABSTRACT FROM AUTHOR]

The antigen-induced DNA synthesis in vitro in lymphocytes from patients with acute Plasmodium falciparum malaria was investigated. The patients and healthy controls from Sweden or Colombia were the same as those studied in the accompanying paper (Troye-Blomberg el al., 1983). The malarial antigens used were sonicated membrane preparations or purified and concentrated supernatants from in vitro cultures of P. facliparum, similar preparations derived from normal human erythrocytes served as control antigen. In the patients' lymphocytes P. falciparum antigens induced a weak or moderate but significant stimulation of DNA synthesis, peaking after 3-4 days of incubation. This early response was specific for P. faleiparum since it was not obtained with lymphocytes from healthy donors nor with those from patients with acute P. vivax or P. ovale malaria. No antigen-induced response was seen in about half of the P.falciparum patients. However in a few negative eases, available for consecutive testing, positive reactions were seen with lymphocytes taken 2 weeks after infection when the blood of these patients was free of parasites. The early response induced in patients' lymphocytes to the P. falciparum antigens was not obtained with RBC antigen, however, these preparations frequently induced a response rising to significant levels later during incubation (day 5-6)- Similar delayed responses were obtained when either- patients' or control donors' lymphocytes were exposed to the P. falciparum antigens. This indicates that both the RBC and the parasite preparations contained mitogenic substances affecting human lymphocytes in general and easily obscuring the P, falciparum specific responses seen only in the patients. This latter response was relatively low and short lived, suggesting that it reflected a secondary in vitro stimulation of in vivo primed lymphocytes and that it was regulated by suppressor mechanisms. [ABSTRACT FROM AUTHOR]

In the present paper we demonstrate that there is an antigenic determinant common to two different types of human teukaemia-associated antigens. i.e. human thymus Ieukaemia-associated (HTL) antigens and common acute lymphoblastic leukuemia (cALL) antigen. In addition, there are distinct antigenic determinants which are unique to the HTL antigens or to the cALL antigen. The new, common antigenic determinant will be useful as a new differentiation marker of human haematopoietic cells as well as a new Ieukaemia-associated marker. In the present study. we used several different anti-human leukaemia antisera which include those prepared by immunizing rabbits (Nos. 7549 and 7550) with purified HTL antigens. The antisera 7549 and 7550, without any absorption1 showed strong specificity as well as strong antibody activity toward Ieukaemia cells. These are the first anti-human leukaemia antisera, except for the monoclonas hybridoma antibodies, that show good specificity for leukaemia cells without prior absorption. [ABSTRACT FROM AUTHOR]

In this paper we use a sensitive, 125I-anti-immunoglobulin-binding assay, recently adapted for use with tissue homogenates as targets, to demonstrate autoantibodies to brain, liver and heart in the sera of normal persons. Quantitative absorption analyses demonstrated that the autoantigens detected were in each case organ-specific, and the brain autoantigen was shown to be present In equal amounts on cerebral cortex, cerebral white matter and cerebellar cortex. The autoantibodies were shown to be IgM in nature by gel filtration studies and experiments where IgM was reduced to monomers, and were found to bind equally well at 4, 20 and 37 C. Cross-reactions with brain, liver and heart of rat and dog were unpredictable and usually weak. Parallel studies with kidney homogenates failed to detect anti-kidney autoantibodies, but immunofluorescence studies on frozen sections revealed large amounts of immunoglobulin in normal kidneys, mainly on glomerular and tubular basement membranes, raising the possibility that autoantibodies to kidney are present but that the autoantigen sites are saturated in vivo. Sera from patients with multiple sclerosis were indistinguishable from normal sera in their binding to brain homogenate, and CSF from five patients with multiple sclerosis did not bind at all to brain homogenate. The theoretical and practical significance of multiple IgM autoantibodies in normal persons, and the organ specificity of the autoantibodies, is discussed. [ABSTRACT FROM AUTHOR]

We have previously shown that the 180 kDa bullous pemphigoid antigen (BPAG2) is distributed on the lateral-apical (as a pool) and ventral (as hemidesmosomes) cell membranes of monolayer cultured keratinocytes and that addition of IgG purified from bullous pemphigoid (BP) patients (BP-IgG) causes the internalization of immune complexes of BPAG2 and BP-IgG from the lateral-apical cell membrane. This internalization of BPAG2 is believed to inhibit the Ca2+ induced reformation of hemidesmosomes on the ventral cell membrane, possibly by inhibiting the supply of the antigen from the lateral-apical to the ventral membranes to form hemidesmosomes. The purpose of this paper is to examine, by using biopsy specimens from BP patients (12 cases), whether or not this internalization of BPAG2 is generated in situ. The fates of BPAG2, 230 kDa BPA (BPAG1) and bound BP-IgG were traced by immunofluorescence microscopy using monoclonal antibodies to BPAG1, BPAG2 and human IgG. In more than half of the lesional and perilesional biopsy specimens, internalization of BPAG2 into the basal cells was observed, while in normal skin BPAG2 was detected on the whole surface of the basal cells without its internalization. No internalization of BPAG1 was detected in BP and normal epidermis. These results suggest that binding of BP-IgG on the lateral-apical cell surface of basal cells causes internalization of BPAG2 in situ in the epidermis of BP patients similar to that seen in cultured cell systems, and that this internalization of immune complexes of BPAG2 and BP-IgG may play an important part in blister formation in BP. [ABSTRACT FROM AUTHOR]

Two liver-specific antigens are known: a water soluble protein (LP-2) and a water insoluble macromolecular low density lipoprotein (LP-1). In this paper the relative role of the two antigens in the development of experimental immune hepatitis has been investigated. Immunization of rabbits with a human preparation containing both antigens, led in all animals to lesions characteristic of an immune hepatitis. Immunization of the animals with a purified water soluble liver protein proved less efficient: only two out of six animals developed characteristic lesions which were less severe than those in the first group. It was deduced that although not a prerequisite, the liver-specific lipoprotein plays an important supportive role in the development of immune hepatitis, [ABSTRACT FROM AUTHOR]

Target cell killing by lymphocytes can be induced by appropriate antibody complexed to target cell antigens. In this paper it is shown that this form of lymphocyte mediated cytotoxicity is susceptible to inhibition by third party immune complexes which compete with target cell bound antibody for receptors for immunoglobulin on the cytotoxic lymphocytes. The physical state of the complexes is investigated in relation to their inhibitory efficiency. Evidence is presented to show that soluble complexes which exist in antigen-antibody equilibrium or slight antigen excess are the most effective inhibitors. No evidence could be obtained to support the hypothesis that soluble immune complexes can induce indiscriminate cytotoxic activity in lymphocytes. The biological significance of this effect is discussed in relation to chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Phytohaemagglutinin has been observed consistently to stimulate mitosis in epithelial cells of normal human adult skin maintained in organ culture for 4 days. This finding is considered to support the view that PHA acts as a direct mitotic stimulant and not as a specific antigen. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) class II molecules play a pivotal role in antigen presentation and CD4+ T cell response. Accurate prediction of the immunogenicity of MHC class II-associated antigens is critical for vaccine design and cancer immunotherapies. However, current computational methods are limited by insufficient training data and algorithmic constraints, and the rules that govern which peptides are truly recognized by existing T cell receptors remain poorly understood. Here, we build a transfer learning-based, long short-term memory model named 'TLimmuno2' to predict whether epitope-MHC class II complex can elicit T cell response. Through leveraging binding affinity data, TLimmuno2 shows superior performance compared with existing models on independent validation datasets. TLimmuno2 can find real immunogenic neoantigen in real-world cancer immunotherapy data. The identification of significant MHC class II neoantigen-mediated immunoediting signal in the cancer genome atlas pan-cancer dataset further suggests the robustness of TLimmuno2 in identifying really immunogenic neoantigens that are undergoing negative selection during cancer evolution. Overall, TLimmuno2 is a powerful tool for the immunogenicity prediction of MHC class II presented epitopes and could promote the development of personalized immunotherapies. [ABSTRACT FROM AUTHOR]

Motivation: While growing numbers of T cell receptor (TCR) repertoires are being mapped by high-throughput sequencing, existing methods do not allow for computationally connecting a given TCR sequence to its target antigen, or relating it to a specific pathology. As an alternative, a manually-curated database can relate TCR sequences with their cognate antigens and associated pathologies based on published experimental data. Results: We present McPAS-TCR, a manually curated database of TCR sequences associated with various pathologies and antigens based on published literature. Our database currently contains more than 5000 sequences of TCRs associated with various pathologic conditions (including pathogen infections, cancer and autoimmunity) and their respective antigens in humans and in mice. A web-based tool allows for searching the database based on different criteria, and for finding annotated sequences from the database in users' data. The McPAS-TCR website assembles information from a large number of studies that is very hard to dissect otherwise. Initial analyses of the data provide interesting insights on pathology-associated TCR sequences. [ABSTRACT FROM AUTHOR]

The Vitamin D Standardization Program (VDSP) has collaborated with numerous groups and agencies to assemble a set of tools, i.e., a reference measurement system, that can be used to establish the traceability of 25-hydroxyvitamin D [25(OH)D] assays to relevant reference measurement procedures and reference materials. This is done with the goal of verifying end-user laboratory performance using precise statistical criteria to determine whether a specific assay is standardized. The purpose of this paper was to outline a set of steps that routine clinical and research laboratories can use to standardize their 25(OH)D assays using these tools. These steps apply to laboratories using commercially developed immunoassay measurement systems as well as in-house assays, usually based on high HPLC or LC tandem MS measurement systems. The steps are (1) initial calibration, (2) initial assessment of accuracy and bias, (3) assessment of total percent CV and mean bias, (4) use of trueness controls, and (5) participation in accuracy-based performance testing and/or external quality assessment schemes. The goal of each laboratory assay is to have a total CV of ≤10% and mean bias of ≤5%. Rigorous and less rigorous but low-cost options for meeting these statistical criteria are provided. Research laboratories who infrequently measure 25(OH)D are advised to repeat steps 1–4 for every measurement cycle. For users of commercial immunoassays who have relatively little control over standardization, we present an option for using trueness controls to develop a master equation that can be used to standardize results to the reference methods. [ABSTRACT FROM AUTHOR]

Background Increasing the availability of antigen rapid diagnostic tests (Ag-RDTs) in low- and middle-income countries (LMICs) is key to alleviating global SARS-CoV-2 testing inequity (median testing rate in December 2021–March 2022 when the Omicron variant was spreading in multiple countries: high-income countries = 600 tests/100 000 people/day; LMICs = 14 tests/100 000 people/day). However, target testing levels and effectiveness of asymptomatic community screening to impact SARS-CoV-2 transmission in LMICs are unclear. Methods We used Propelling Action for Testing and Treating (PATAT), an LMIC-focused agent-based model to simulate coronavirus disease 2019 (COVID-19) epidemics, varying the amount of Ag-RDTs available for symptomatic testing at healthcare facilities and asymptomatic community testing in different social settings. We assumed that testing was a function of access to healthcare facilities and availability of Ag-RDTs. We explicitly modelled symptomatic testing demand from individuals without SARS-CoV-2 and measured impact based on the number of infections averted due to test-and-isolate. Results Testing symptomatic individuals yields greater benefits than any asymptomatic community testing strategy until most symptomatic individuals who sought testing have been tested. Meeting symptomatic testing demand likely requires at least 200–400 tests/100 000 people/day, on average, as symptomatic testing demand is highly influenced by individuals without SARS-CoV-2. After symptomatic testing demand is satisfied, excess tests to proactively screen for asymptomatic infections among household members yield the largest additional infections averted. Conclusions Testing strategies aimed at reducing transmission should prioritize symptomatic testing and incentivizing test-positive individuals to adhere to isolation to maximize effectiveness. [ABSTRACT FROM AUTHOR]

Background Rotavirus vaccine performance appears worse in countries with high rotavirus genotype diversity. Evidence suggests diminished vaccine efficacy (VE) against G2P[4], which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive. Methods We pooled individual-level data from 10 Phase II and III clinical trials of rotavirus vaccine containing G1 and P[8] antigens (RV1) conducted between 2000 and 2012. We estimated VE against both any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for non-specific VE against any RVGE, genotype-specific VE, and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with RV1 antigens. We adjusted models for concomitant oral poliovirus and RV1 vaccination and the country's designated child mortality stratum. Results Analysis included 87 644 infants from 22 countries in the Americas, Europe, Africa, and Asia. For VE against severe RVGE, non-specific VE was 91% (95% confidence interval [CI]: 87–94%). Genotype-specific VE ranged from 96% (95% CI: 89–98%) against G1P[8] to 71% (43–85%) against G2P[4]. RV1-typic VE was 92% (95% CI: 84–96%) against partially heterotypic genotypes but 83% (67–91%) against fully heterotypic genotypes. For VE against any-severity RVGE, non-specific VE was 82% (95% CI: 75–87%). Genotype-specific VE ranged from 94% (95% CI: 86–97%) against G1P[8] to 63% (41–77%) against G2P[4]. RV1-typic VE was 83% (95% CI: 72–90%) against partially heterotypic genotypes but 63% (40–77%) against fully heterotypic genotypes. Conclusions RV1 VE is comparatively diminished against fully heterotypic genotypes including G2P[4]. [ABSTRACT FROM AUTHOR]

Background: A new variant of endemic pemphigus foliaceus (EPF) has been documented, El Bagre-EPF. We aimed to study antinuclear antibodies (ANAs) in these patients. Methods: We performed a case-control study, testing 57 patients affected by this disease and 57 controls from the endemic area matched by work activity and demographics. The participants were evaluated clinically as well as by detection of ANAs utilizing HEp-2 cells. We utilized Triton-induced partial permeabilization of the cell membranes, allowing for the visualization of intracellular and intranuclear antigens. We also immunoadsorbed the ANAs using synthetic peptides to elucidate the nature of the ANA. Results: We detected the presence of a new pattern of ANAs. The new pattern of ANAs was seen in 24% of the El Bagre-EPF patients, compared to our controls (P < 0.001). The new ANA pattern consisted of a thin nuclear and nucleolar rim, finely speckled nucleolar, nuclear membrane pores stains, and a positive intranuclear stain directed against small nuclear components, as well as cytoplasmic deposits of autoantibodies were also observed. The new ANAs pattern perfectly colocalized with commercial antibodies to miocardium-enriched zonula occlusans-1 associated protein (MIZAP), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), p0071 and desmoplakins I–II (all from Progen Biotechnik). Additionally in 14% of patients with El Bagre-EPF forme fruste and hyperpigmented clinical presentations, a classic homogeneous ANA pattern was observed with autoantibodies specific for Ro, La, Sm, and double-stranded DNA antigens. Immunoadsorption with peptide-based sequences from MIZAP, ARVCF, p0071 and desmoplakins I–II removed the new ANA pattern. Conclusions: We describe a new pattern of ANAs in El Bagre-EPF, colocalizing with autoantibodies directed against MIZAP, ARVCF, p0071, and desmoplakins I–II. [ABSTRACT FROM AUTHOR]

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. [ABSTRACT FROM AUTHOR]

The article presents information on the research paper "Cutaneous Anergy and Hodgkin's Disease," by H.W. Schier, published in the 1954 issue of the New England Journal of Medicine. Cutaneous anergy was found in 33 cases of Hodgkin's disease to the antigens of mumps virus, canclida albicans, trichophyton gypseum and purified protein derivative of tuberculin. The study suggested that patients with hodgkin's disease fail to produce demonstrable antibodies in normal quantities.

Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8-9 mice per group, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti-PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure. [ABSTRACT FROM AUTHOR]

Antigen-combining sites of the camelid heavy-chain antibody variable domain (VHH) are constructed by three complementarity-determining regions (CDR1, CDR2 and CDR3). We prepared cDNA using mRNA extracted from peripheral lymphocytes of alpacas that had been non-immunized or immunized with human serum albumin (HSA). The VHH gene fragments encoding the amino-terminal half-containing CDR1 as well as CDR2 and the carboxy-terminal half-containing CDR3 were amplified independently by PCR, and then full-length VHH gene fragments were generated by overlap extension PCR and cloned into the phagemid vector. This protocol, referred to as CDR shuffling, allowed us to construct an alpaca VHH phage display library possessing repertoires different from those naturally occurring in animals. We asked, first, whether this library was able to provide the functional VHH fragments against HSA, an immunized antigen, and obtained 29 anti-HSA VHH clones, 41% possessed K D values of lower than 10−8 M, 5 of which had K D values of 10−10 M. We also obtained VHH clones against non-immunized protein antigens such as cardiac troponin T and I, Ebola virus glycoprotein 1 and human immunoglobulin G by biopanning. We compared the amino acid sequences and affinities and found that 43% of VHHs had K D values of less than 10−8 M, although those having K D values of 10−10 M were unavailable. These results suggested that the CDR-shuffled VHH phage display library could potentially provide VHHs against non-immunized protein antigens with similar levels of affinities to those against immunized antigens. [ABSTRACT FROM AUTHOR]

Background For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. Methods In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. Results All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. Conclusion Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy. Clinical Trials Registration NCT02613871. [ABSTRACT FROM AUTHOR]

Background Cryptococcosis is a serious opportunistic fungal disease, and the proportion of cases among patients with immunosuppressive conditions other than HIV or organ transplant has increased. Understanding laboratory testing patterns for cryptococcosis is useful for estimating its true burden and developing testing guidance. Methods We identified cryptococcosis tests (cryptococcal antigen [CrAg], cryptococcal antibody, and fungal cultures) performed at a major national commercial laboratory ordered during March 1, 2019–October 1, 2021, and analyzed test results, patient and provider features, reasons for testing, geography, and temporal trends. Results Among 29 180 serum CrAg tests, 4422 (15.2%) were positive, and among 10 724 cerebrospinal fluid (CSF) CrAg tests, 492 (4.6%) were positive. Frequent reasons for serum CrAg testing in nonhospital settings (10 882 tests) were HIV (44.6%) and cryptococcosis (17.0%); other underlying conditions were uncommonly listed (<10% total). Serum CrAg positivity declined from 25.6% in October 2019 to 11.3% in September 2021. The South had the highest positivity for serum CrAg tests (16.6%), CSF CrAg tests (4.7%), and fungal cultures (0.15%). Among 5009 cryptococcal antibody tests, 5 (0.1%) were positive. Conclusions Few outpatient serum CrAg tests were performed for patients with immunocompromising conditions other than HIV, suggesting potential missed opportunities for early detection. Given the high positive predictive value of CrAg testing, research is needed to improve early diagnosis, particularly in patients without HIV. Conversely, the low yield of antibody testing suggests that it may be of low value. The decline in CrAg positivity during the COVID-19 pandemic warrants further investigation. [ABSTRACT FROM AUTHOR]