Absence Of Antibodies Research Articles

Protective role of antibodies in enteric virus infections: Lessons from primary and secondary immune deficiencies.

Enteric viruses are the main cause of acute gastroenteritis worldwide with a significant morbidity and mortality, especially among children and aged adults. Some enteric viruses also cause disseminated infections and severe neurological manifestations such as poliomyelitis. Protective immunity against these viruses is not well understood in humans, with most knowledge coming from animal models, although the development of poliovirus and rotavirus vaccines has extended our knowledge. In a classical view, innate immunity involves the recognition of foreign DNA or RNA by pathogen recognition receptors leading to the production of interferons and other inflammatory cytokines. Antigen uptake and presentation to T cells and B cells then activate adaptive immunity and, in the case of the mucosal immunity, induce the secretion of dimeric IgA, the more potent immunoglobulins in viral neutralization. The study of Inborn errors of immunity (IEIs) offers a natural opportunity to study nonredundant immunity toward pathogens. In the case of enteric viruses, patients with a defective production of antibodies are at risk of developing neurological complications. Moreover, a recent description of patients with low or absent antibody production with protracted enteric viral infections associated with hepatitis reinforces the prominent role of B cells and immunoglobulins in the control of enteric virus.

DF-1-Derived exosomes mediate transmission of reticuloendotheliosis virus and resist REV-specific antibodies

BackgroundReticuloendotheliosis virus (REV), a member of the family Retroviridae, is a hot area of research, and a previous study showed that exosomes purified from REV-positive semen were not blocked by REV-specific neutralizing antibodies and established productive infections.MethodsTo further verify the infectivity of exosomes from REV-infected cells, we isolated and purified exosomes from REV-infected DF-1 cells and identified them using Western blot and a transmission electron microscope. We then inoculated 7-day-old embryonated eggs, 1-day-old chicks and 23-week-old hens with and without antibody treatment. REV was administered simultaneously as a control.ResultsIn the absence of antibodies, the results indicated that REV-exosomes and REV could infect chicks, resulting in viremia and viral shedding, compared with the infection caused by REV, REV-exosomes reduced the hatching rate and increased mortality after hatching, causing severe growth inhibition and immune organ damage in 1-day-old chicks; both REV and REV-exosomes also could infect hens, however, lead to transient infection. In the presence of antibodies, REV-exosomes were not blocked by REV-specific neutralizing antibodies and infected 7-day-old embryonated eggs. However, REV could not infect 1-day-old chicks and 23-week-old hens.ConclusionIn this study, we compared the infectious ability of REV-exosomes and REV, REV-exosomes could escape from REV-specific neutralizing antibodies in embryonated eggs, providing new insights into the immune escape mechanism of REV.

Comparison of the Accuracy of HSV1 and HSV2 Antibody Tests with PCR in the Diagnosis of Recurrent Genital Herpes.

To assess the accuracy of HSV1and HSV2 antibody testing in identifying genital herpes infection. A cohort of 299 patients previously diagnosed with recurrent genital herpes, confirmed via PCR, were tested using ELISA for HSV1 and HSV2 IgM and IgG antibodies. The study compared the accuracy of HSV1 and HSV2 antibody tests in diagnosing genital herpes. Among 299 patients, 14 tested positives for HSV1 DNA. Of these, 9 had HSV1 IgG antibodies, but none had HSV2 IgG antibody. Among 278 patients with HSV2 DNA, 149 had HSV1 IgG, 9 had HSV2 IgG, and 97 had both. Seven patients had both HSV1 and HSV2 DNA; 3 had HSV1 IgG, 1 had HSV2 IgG, and 3 had both. The accuracy of HSV1 IgG for HSV1 infection was 64.2%, and for HSV1 and HSV2 co-infection, 85.7%. The accuracy of HSV2 IgG for HSV2 infection was 38.1%, and for HSV1 and HSV2 co-infection, 57.1%. The combined antibody positivity accuracy was 34.9%. Genital herpes is primarily caused by HSV2 (92.98%). A smaller percentage is HSV1 (4.67%) or co-infection (2.34%). Despite relatively low diagnostic accuracy (34.9-85.7%) for antibody detection, combined antibody testing is necessary. Herpes DNA testing is recommended for accurate diagnosis. Absence of antibodies does not rule out genital herpes and clinical assessment is essential.

The plasticity of immune memory in invertebrates.

Whether specific immune protection after initial pathogen exposure (immune memory) occurs in invertebrates has long been uncertain. The absence of antibodies, B-cells and T-cells, and the short lifespans of invertebrates led to the hypothesis that immune memory does not occur in these organisms. However, research in the past two decades has supported the existence of immune memory in several invertebrate groups, including Ctenophora, Cnidaria, Nematoda, Mollusca and Arthropoda. Interestingly, some studies have demonstrated immune memory that is specific to the parasite strain. Nonetheless, other work does not provide support for immune memory in invertebrates or offers only partial support. Moreover, the expected biphasic immune response, a characteristic of adaptive immune memory in vertebrates, varies within and between invertebrate species. This variation may be attributed to the influence of biotic or abiotic factors, particularly parasites, on the outcome of immune memory. Despite its critical importance for survival, the role of phenotypic plasticity in immune memory has not been systematically examined in the past two decades. Additionally, the features of immune responses occurring in diverse environments have yet to be fully characterized.

Severe Acute Hepatitis of Unknown Etiology in Pediatric Patients: Multidisciplinary Clinical Approach

Introduction: In mid-2022, the World Health Organization (WHO) declared a moderate-risk outbreak due to an increase in severe acute hepatitis cases of unknown etiology in children. Several reports suggested a viral infection link, with the outbreak spanning over 35 countries. By June 2022, Mexico reported 69 probable cases across 5 entities to the WHO. Case Presentation: A 4-year-old boy presented with vomiting, jaundice, choluria, and hepatomegaly. A multidisciplinary approach was employed, using an algorithm developed exclusively for clinical, epidemiological, and biochemical follow-up. Despite the negative identification of any associated microorganism and the absence of antibodies, liver function tests remained elevated. A fine needle liver biopsy was performed for diagnostic support, followed by histopathological study and sequencing and analysis of the complete high-depth transcriptome. Transcriptome analysis identified dysbiosis-related intestinal microbiota, including increased enterogenic and opportunistic pathogenic bacteria of the genus Clostridium, as well as HERV-K113, implicated in autoimmune disease development. Conclusions: The study's findings suggest possible immune-mediated mechanisms involving dysbiosis of the gut microbiota and the potential role of HERV-K113. Management and control of acute liver disease depend on specific causes, with the main challenge being early determination and implementation of optimal management strategies. The exact pathological mechanisms underlying pediatric acute hepatitis of unknown etiology remain elusive, warranting further studies to confirm or refute these hypotheses and elucidate the underlying pathological mechanisms

Prolonged SARS-CoV-2 T Cell Responses in a Vaccinated COVID-19-Naive Population.

Exploring T cell response duration is pivotal for understanding immune protection evolution in natural SARS-CoV-2 infections. The objective of the present study was to analyze the T cell immune response over time in individuals who were both vaccinated and COVID-19-naive and had undetectable levels of SARS-CoV-2 IgG antibodies at the time of testing. We performed a retrospective descriptive analysis using data extracted from the electronic medical records of consecutive adult individuals who underwent COVID-19 immunity screening at a private healthcare center from September 2021 to September 2022. The study participants were divided into three groups according to the post-vaccination time period, as follows: group A (up to 3 months), group B (3-6 months), and group C (>6 months). T cell response was evaluated using the IGRA methodology T-SPOT®.COVID. Of the total number of subjects (n = 165), 60/165 (36.4%) had been vaccinated in the last 3 months (group A), 57/165 (34.5%) between 3 and 6 months (group B), and 48/165 (29.1%) at least 6 months prior to the examination day (group C). T cell positivity was reported in 33/60 (55.0%) of group A, 45/57 (78.9%) of group B, and 36/48 (75%) of group C (p < 0.007). No statistically significant differences were revealed in the spot-forming cell (SFC) count among groups, with mean SFC counts of 75.96 for group A, 89.92 for group B, and 83.58 for group C (Kruskal-Wallis test, p = 0.278). Our findings suggest that cellular immunity following SARS-CoV-2 vaccination may endure for at least six months, even in the presence of declining or absent IgG antibody levels.

The absence of antibodies in longitudinally extensive transverse myelitis may predict a more favourable prognosis

Background: Isolated first episodes of longitudinally extensive transverse myelitis (LETM) have typically been associated with neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). However, in some cases, serological testing and screening for other aetiologies are negative, a condition referred to as double seronegative longitudinally extensive transverse myelitis (dsLETM). Objective: The objective of this study was to evaluate comparative outcomes of dsLETM, MOGAD-LETM and NMOSD-LETM. Methods: Cohort study of LETM cases seen in the UK NMOSD Highly Specialised Service between January 2008 and March 2022. Results: LETM = 87 cases were identified (median onset age = 46 years (15–85); median follow-up = 46 months (1–144); 47% NMOSD-LETM = 41 (aquaporin-4 antibodies (AQP4-IgG) positive = 36), 20% MOGAD-LETM = 17 and 33% dsLETM = 29). Despite similar Expanded Disability Status Scale (EDSS) at nadir, last EDSS was higher in AQP4-IgG and seronegative NMOSD-LETM (sNMOSD) (p = 0.006). Relapses were less common in dsLETM compared to AQP4-IgG NMOSD-LETM and sNMOSD-LETM (19% vs 60% vs 100%; p = 0.001). Poor prognosis could be predicted by AQP4-IgG (odds ratio (OR) = 38.86 (95% confidence interval (CI) = 1.36–1112.86); p = 0.03) and EDSS 3 months after onset (OR = 65.85 (95% CI = 3.65–1188.60); p = 0.005). Conclusion: dsLETM remains clinically challenging and difficult to classify with existing nosological terminology. Despite a similar EDSS at nadir, patients with dsLETM relapsed less and had a better long-term prognosis than NMOSD-LETM.

Anti-PF4/Heparin Monoclonal Antibodies Induce Thrombus Formation in an Ex Vivo Endothelialized Microfluidic System

Introduction: Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin. Antibodies against platelet factor 4 (PF4) or a heparin/PF4 complex have been reported to activate platelets, neutrophils and possibly endothelial cells, resulting in thrombocytopenia, hypercoagulability and thromboembolic complications. While the impact of anti-PF4/heparin antibodies on platelet, neutrophil and monocyte activation has been extensively studied, the role of endothelial cells in HIT-associated thrombosis remains underexplored. In particular, the interactions between HIT-induced procoagulancy and endothelial cells under dynamic conditions is not completely analyzed. In this report, we investigated how HIT antibodies induce thrombosis in an endothelialized microfluidic system. Methods: Fibrinogen microfluidic channels were coated with confluent monolayer of human umbilical vein endothelial cells (HUVECs). Cells were primed with low-dose TNF-α to induce a sub-thrombotic endothelial activation, prior to perfusion of whole blood. Recalcified unstimulated or Thrombin Receptor Activator Peptide 6 (TRAP-6) activated whole blood was perfused at a venous flow rate. HIT-thrombosis model was established and tested with monoclonal anti-PF4/heparin antibodies in whole blood. In brief, whole blood was pre-incubated with unfractionated heparin (UFH, 0.2 IU/mL and 100 IU/mL). Next, anti-PF4/heparin antibodies were introduced to the whole blood mixture and incubated for 30 minutes. Whole blood was recalcified and perfused over resting or primed endothelial cells at a venous shear stress. Thrombus formation was recorded over time. Results: The endothelialized microfluidic model successfully captures sub-thrombotic conditions under venous shear. Activated platelets induced a procoagulant shift and three-dimensional thrombi. We applied our thrombosis model to investigate thrombus formation induced by a HIT mimicking monoclonal antibody. We show that the heparin-dependent platelet activation predicts the thrombotic response in the microfluidic system: HIT antibodies in absence of heparin did not exert a pro-thrombotic effect on activated endothelial cells. Co-incubation with 0.2 IU/mL UFH induced thrombosis, embolization of thrombus material and channel occlusion only when endothelial cells were primed with TNF-α. The pro-thrombotic effect of HIT antibodies was fully reversed at the super-therapeutic dose of 100 IU/mL UFH. Conclusions: HIT antibodies induce thrombosis and embolization in a system emulating physiological environment. For the first time, we present a comprehensive thrombosis model that incorporates the established thrombogenicity of HIT-mimicking antibodies. We show that our thrombosis model incorporates both endothelial- and blood-based control of thrombosis. Primed endothelial cells and antibody-induced procoagulancy trigger thrombosis in a concerted fashion, allowing investigation of the underlying mechanisms and possible preclinical evaluation of potential inhibitors of HIT-thrombosis. Figure 1, upper panel: Maximal thrombus surface area coverage of TNF-α primed endothelial cells, perfused with unstimulated, TRAP-6 activated or HIT-like IgG/heparin challenged whole blood. HIT-like IgG did not increase thrombus formation in absence of heparin. Addition of low-dose heparin exerted a strong pro-thrombotic effect, that was fully reversible with a super-therapeutic concentration of heparin. Lower panel: representative images of thrombi formed by HIT-like IgG in absence and under low or high-dose heparin. Platelets: green, Calcein-AM. Scale bar: 200 µm.

Insertion of a FLAG-tag sequence at the end of exon 9 of the TBX5 gene in three induced pluripotent stem cell lines (DHMi004-A-4, DHMi004-A-5, DHMi004-A-6) by CRISPR/Cas9 technology

The identification of TBX5-related regulatory sequences in genes essential for heart development is hampered by the absence of antibodies which allow precipitation of TBX5:DNA complexes. Employing CRISPR/Cas9 technology, we have inserted a FLAG-tag sequence at the end of exon 9 of the TBX5 gene prior to the stop codon by homologous recombination. The translated TBX5-FLAG fusion protein of the three iPSC lines can effectively be precipitated by anti-FLAG antibodies and, thus, allow the detection of specific TBX5-binding sites and their associated genes.

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery

AbstractEncapsulins, self‐assembling protein nanocages derived from prokaryotes, are promising nanoparticle‐based drug delivery systems (NDDS). However, the in vivo behavior and fate of encapsulins are poorly understood. In this study, the interactions between the model encapsulin from Thermotoga maritima (TmEnc) and key biological barriers encountered by NDDS are probed. Here, a purified TmEnc formulation that exhibits colloidal stability, storability, and blood compatibility is intravenously injected into BALB/c mice. TmEnc has an excellent nanosafety profile, with no abnormal weight loss or gross pathology observed, and only temporary alterations in toxicity biomarkers are detected. Notably, TmEnc demonstrates immunogenic properties, inducing the generation of nanocage‐specific IgM and IgG antibodies, but without any prolonged pro‐inflammatory effects. An absence of antibody cross‐reactivity also suggests immune‐orthogonality among encapsulin systems. Moreover, TmEnc forms a serum‐derived protein corona on its surface which changes dynamically and appears to play a role in immune recognition. TmEnc's biodistribution profile further reveals its sequestration from the blood circulation by the liver and then biodegrades within Kupffer cells, thus indicating clearance via the mononuclear phagocyte system. Collectively, these findings provide critical insights into how encapsulins behave in vivo, thereby informing their future design, modification, and application in targeted drug delivery.

Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils.

Hepatitis E virus (HEV) causes self-limited acute hepatitis in immunocompetent individuals and can establish chronic infection in solid organ transplant recipients taking immunosuppressive drugs. A well characterized small animal model is needed to understand HEV pathogenesis. In this study, we established a robust model to study acute and persistent HEV infection using Mongolian gerbils (Meriones unguiculatus) with or without immunosuppression. Gerbils were implanted subcutaneously with continuous release tacrolimus pellet to induce immunosuppression. Gerbils with or without tacrolimus treatment were inoculated with HEV intraperitoneally. Viremia, fecal virus shedding, serum antibody and ALT levels, liver histopathological lesions, hepatocyte apoptosis, and liver macrophage distribution were assessed. Mild to moderate self-limited hepatitis and IgM and IgG antibody responses against HEV ORF2 were observed in immunocompetent gerbils. Levels of HEV-specific IgM responses were higher and lasted longer in immunocompetent gerbils with higher peak viremia. Persistent viremia and fecal virus shedding with either weak, or absent HEV antibody levels were seen in immunosuppressed gerbils. Following HEV infection, serum ALT levels were increased, with lower and delayed peaks observed in immunosuppressed compared to immunocompetent gerbils. In immunocompetent gerbils, foci of apoptotic hepatocytes were detected that were distributed with inflammatory infiltrates containing CD68+ macrophages. However, these foci were absent in immunosuppressed gerbils. The immunosuppressed gerbils showed no inflammation with no increase in CD68+ macrophages despite high virus replication in liver. Our findings suggest adaptive immune responses are necessary for inducing hepatocyte apoptosis, CD68+ macrophage recruitment, and inflammatory cell infiltration in response to HEV infection. Our studies show that Mongolian gerbils provide a promising model to study pathogenesis during acute and persistent HEV infection.

Evidence for Microchimerism in Baboon Recipients of Pig Hearts.

Xenotransplantation, like allotransplantation, is usually associated with microchimerism, i.e., the presence of cells from the donor in the recipient. Microchimerism was reported in first xenotransplantation trials in humans, as well as in most preclinical trials in nonhuman primates (for review, see Denner, Viruses 2023, 15, 190). When using pigs as xenotransplantation donors, their cells contain porcine endogenous retroviruses (PERVs) in their genome. This makes it difficult to discriminate between microchimerism and PERV infection of the recipient. Here, we demonstrate the appropriate virological methods to be used for the identification of microchimerism, first by screening for porcine cellular genes, and then how to detect infection of the host. Using porcine short interspersed nuclear sequences (SINEs), which have hundreds of thousands of copies in the pig genome, significantly increased the sensitivity of the screening for pig cells. Second, absence of PERV RNA demonstrated an absence of viral genomic RNA or expression as mRNA. Lastly, absence of antibodies against PERV proteins conclusively demonstrated an absence of a PERV infection. When applying these methods for analyzing baboons after pig heart transplantation, microchimerism could be demonstrated and infection excluded in all animals. These methods can be used in future clinical trials.

Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02.

4113 Background: Gemcitabine, cisplatin and durvalumab followed by maintenance durvalumab is standard of care first-line (1L) therapy for patients (pts) with advanced BTC. In this trial, we investigated the combination of a PARP inhibitor with anti-PD1 antibody in absence of progression after at least 4 months of standard 1L platinum-based chemotherapy. Methods: Pts with advanced BTC, ECOG PS 0-1 and absence of progression on 1L platinum-based therapy were enrolled on a phase 2 trial to receive rucaparib 600 mg PO BID in combination with nivolumab 240 mg IV Q2 weeks every 28 days for up to 2 years. The primary endpoint was 4-month progression-free survival (PFS) rate from the date of first study treatment with an alternative hypothesis of 85%. Secondary endpoints included median PFS and overall survival (OS) from first study treatment (PFS1, OS1) as well as from start date of first-line chemotherapy (PFS2, OS2), best overall response, and safety. Results: 31 pts were enrolled of which 14 (45%) were women, 25 (80.6%) Caucasian and 24 (77.64%) with ECOG 1. Primary disease site was intrahepatic, extrahepatic hilar and distal, and gallbladder cancer in 21 (67.7%), 4 (12.9%), 1 (3.2%) and 4 (12.9%), respectively. 1L platinum-based treatment included gemcitabine/cisplatin based in 26 (83.9%), FOLFOX in 3 (9.7%) and carboplatin/paclitaxel in 1 (3.2%) pts. Mean (range) cycles of rucaparib and nivolumab were 6.75 (1-24) and 5.9 (1-24). The median follow-up time is 28.7 months using reverse censoring methodology. PFS rate at 4 months was 54.8% (95% CI, 36-70.3), comparable to the 63% null estimate based on ABC-02 trial. Median PFS1 and OS1 are estimated to be 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 calculated from date of 1L chemotherapy are estimated as 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) pts had partial response (with IDH R132G and KRAS G12D) as best response with stable disease in an additional 22 (71%) pts. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 15 (48.4%) pts, including 1 patient who died on therapy due to possibly-related immune-related myocarditis. The most common grade 2 or greater TRAEs included fatigue (9, 29.0%), anemia (7, 22.6%), neutropenia (6, 19.3%), elevated AST (5, 16.1%) and elevated ALT (4, 12.9%). Reasons for treatment discontinuation included death (2), progression (27), adverse event (1) while 1 patient completed 2 years of study treatment. Conclusions: The primary endpoint of PFS rate at 4 months was not met but the preliminary measures of PFS1 and OS1 are much longer than expected, and hypothesis generating for rational combination of PARP inhibitor with maintenance immunotherapy in this rare cancer. Exploratory endpoint of association of genomic analysis with efficacy is ongoing and will be discussed. Clinical trial information: NCT03639935 .

Different diabetes

Different diabetes

Prevalence and risk factors of Q fever (Coxiella burnetii) in cattle on farms of Limpopo province, South Africa.

Q fever in animals and humans and its economic and public health significance has been widely reported worldwide but in South Africa. There are few studies on the prevalence of this zoonosis and its associated risk factors in South African livestock. Therefore, a cross-sectional study was conducted to determine the seroprevalence, molecular prevalence, and risk factors associated with C. burnetii in cattle on farms in South Africa's Limpopo province. Out of 383 cattle tested for antibodies, the overall seroprevalence was 24.28%. Herd size of >150 (OR: 9.88; 95%CI: 3.92-24.89; p < 0.01) remained associated with C. burnetii seropositivity in cattle. For PCR detection, targeting IS1111 fragment, cattle with no abortion history (OR: 0.37; 95%CI: 0.18-0.77; p < 0.01) and herd size of >150 (OR: 3.52; 95%CI: 1.34-9.24; p < 0.01) remained associated with C. burnetii positivity. The molecular prevalence in sheath scrapings and vaginal swabs by IS1111 PCR was 15.67%. Cohen's kappa agreement test revealed a fair agreement between the PCR and ELISA results (k = 0.40). Sequence analysis revealed that the amplicons had similarities to the C. burnetii transposase gene fragment, confirming the presence of the pathogen. The higher seroprevalence than molecular prevalence indicated a past C. burnetii infection, no bacterial shedding through vaginal mucus in cows, or preputial discharge in bulls. Similarly, the detection of C. burnetii by PCR in the absence of antibodies could be partly explained by recent infections in which antibodies have not yet been produced against the bacteria, or the level of these antibodies was below the detectability threshold. The presence of the pathogen in cattle and the evidence of exposure, as shown by both PCR and ELISA suggests an active circulation of the pathogen. This study demonstrated that C. burnetii is widespread in the study area and that a herd size of >150 is associated with C. burnetii seroprevalence and molecular prevalence.

Paraneoplastic Neurological Syndromes: A Single-Center Retrospective Study in Argentina (P9-13.005)

<h3>Objective:</h3> To describe the clinical features, diagnostic approach and treatments in patients diagnosed with paraneoplastic neurological syndromes (PNS). <h3>Background:</h3> PNS are due to an abnormal response of the immune system against the nervous system. In many cases, their identification allows early diagnosis of hidden tumors. Argentina ranks fifth in cancer frequency in Latin America, however data about PNS is lacking. <h3>Design/Methods:</h3> We performed a retrospective study including 42 adult patients with PNS treated between 2010 and 2021 in a referral center of Argentina. <h3>Results:</h3> Mean age at symptom onset was 59.6 years (range 20 to 82). The onset of symptoms was acute in 11 cases (26%), subacute in 25 (59.5%) and chronic in 6 (14.3%). The median time between the onset of symptoms and suspicion of PNS was 16.25 months (SD 16.7). The most frequent symptoms were paresthesias (23.8%) and limb weakness (19%). Classic PNS was found in 6 patients (14.3%) and non-classic PNS were identified in 26 cases (61.9%). An onconeural antibody was identified in 36 patients (85.7%). Primary tumors were found in 14 patients (33.3%). Lung cancer was the most frequent tumor (28.57%). The latency between suspected PNS and tumor diagnosis was 1.89 years (range 0.31 to 4.79). Twenty eight patients (66.7%) received immunological therapy. Nine patients received onco-specific treatment (chemotherapy or radiotherapy) and two patients were treated with tumor resections. Symptoms improved in 21.4% of patients, 57.1% remained stable and 21.4% worsened. Four patients died (9.5%). <h3>Conclusions:</h3> The clinical manifestations were under a non-classical syndrome, had a subacute course and were associated with lung cancer in the majority of cases. The latency between PNS onset and tumor identification was also variable despite the use of appropriate imaging techniques. The absence of antibodies does not rule out an occult tumor, which should not delay immunomodulatory treatment in the suspected cases. <b>Disclosure:</b> Mr. Caiza Zambrano has nothing to disclose. Fabio Gonzalez has nothing to disclose. Dr. Galarza Menoscal has nothing to disclose. Dr. Benetti has nothing to disclose. The institution of Marcela Uribe Roca has received research support from Roche. Dr. Bonardo has nothing to disclose. Manuel Fernandez Pardal has nothing to disclose. Dr. Leon Cejas has nothing to disclose. Dr. Reisin has nothing to disclose.

The absence of antibodies in longitudinally extensive transverse myelitis and the impact on prognosis (P9-5.029)

<h3>Objective:</h3> Evaluation of clinical outcomes in LETM. <h3>Background:</h3> Longitudinally extensive transverse myelitis (LETM) is typically defined as spinal cord inflammation that spans 3 or more vertebral segments on MRI. It is a prototypical manifestation of neuromyelitis optica spectrum disorder (NMOSD) but is also seen in myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and much less commonly multiple sclerosis. In some cases, despite extensive investigation, a definitive diagnosis cannot be reached, a condition referred to as double seronegative LETM (dsLETM). <h3>Design/Methods:</h3> Cohort study of LETM cases reviewed in NMO UK Highly Specialised Service at the Walton Centre NHS Foundation Trust between Jan 2008-March 2022. Clinical presentation, radiological characteristics, aquaporin-4 antibodies (AQP4-IgG) and MOG antibodies, relapses, treatment, and EDSS at follow-up were extracted from case records. <h3>Results:</h3> LETM=93 cases were identified; NMOSD=41 (AQP4-IgG positive; 88%), dsLETM=29, MOGAD=17, others=6. The median onset age was 46 (15–85) yrs with a median follow-up of 46 (1–144) months. EDSS at nadir was similar between subgroups (NMOSD; 7, MOGAD; 7.5, dsLETM; 6.7, p&gt;0.05) but patients with dsLETM were less likely to relapse (dsLETM; 21% vs. NMOSD; 56% vs. MOGAD; 29%, p=0.008). Long term immunosuppression was used in NMOSD (100%), MOGAD (76%) and dsLETM (34%) and was associated with a reduction in median annualised relapse rate (NMOSD; 1.65 to 0.09, MOGAD; 0.75 to 0.07, and dsLETM; 1 to 0.11). Although EDSS scores at last review were higher in NMOSD than MOGAD (6 vs. 4; p=0.018) and dsLETM (6 vs 4.5; p=0.04), dsLETM patients still reached a significant disability (EDSS&gt;6) in 35% of cases. <h3>Conclusions:</h3> Patients with dsLETM relapsed less as compared to NMOSD and MOGAD and immunosuppression reduced the risk further. Although last EDSS was lower in dsLETM as compared to NMOSD, a third of patients still suffered from significant disability. <b>Disclosure:</b> Dr. Rocchi has nothing to disclose. Dr. Forcadela has nothing to disclose. Dr. Jacob has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ALEXION. Dr. Hamid has nothing to disclose. Dr. Huda has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Guidepoint.

Semi-quantitative thigh magnetic resonance imaging scores in assessing disease activity and determining long-term clinical outcome in idiopathic inflammatory myopathies: a causal mediation analysis.

To evaluate the relationship of thigh MRI (t-MRI) with manual muscle testing-8 (MMT-8), muscle enzymes and autoantibodies. To determine the causal and mediating factors resulting in poor recovery of MMT-8 in inflammatory myositis (IIM). This was a single-centre retrospective study in IIM patients. t-MRI was semi-quantitatively scored for muscle oedema, fascial oedema, muscle atrophy and fatty infiltration. Spearman correlation of t-MRI scores was done with muscle enzymes at baseline, and MMT-8 at baseline and on follow-up. Causal mediation analysis was performed with age, sex, symptom duration, autoantibodies, diabetes and BMI as independent variables, follow-up MMT-8 as dependent and t-MRI scores as mediating variables. Baseline evaluation was done on 59 and follow-up on 38 patients. Median follow-up of the cohort was 31 (10-57) months. Baseline MMT-8 negatively correlated with muscle oedema (r = -0755), fascial oedema (r = -0.443) and muscle atrophy (r = -0.343). Creatinine kinase (r = 0.422) and aspartate transaminase (r = 0.480) positively correlated with muscle oedema. Follow-up MMT-8 correlated negatively with baseline atrophy (r = -0.497) and fatty infiltration (r = -0.531). On follow-up, MMT-8 males had positive total effect (estimate (95%CI)) via atrophy [2.93 (0.44, 4.89)] and fatty infiltration [2.08 (0.54, 3.71)]. Antisynthetase antibody had a positive total effect via fatty infiltration [4.50 (0.37, 7.59)]. Age had a negative total effect via atrophy [-0.09 (0.19, -0.01)] and fatty infiltration [-0.07 (-0.15, -0.01)]. Disease duration had a negative total effect via fatty infiltration [-0.18 (-0.27, -0.02)]. Baseline fatty infiltration and muscle atrophy resulting from older age, female sex, longer disease duration and absent anti-synthetase antibodies, partly mediate muscle recovery in IIM.

Основные принципы дифференциальной диагностики типов сахарного диабета у лиц молодого возраста

Aim: To study peculiarities of various types of diabetes mellitus (DM) in young patients. Key points. In patients with DM onset in young age, it is challenging to correctly identify the DM type, therefore, it is essential to know the peculiarities of the onset and progression of each type. DM1 patients present with severe pancreatic β-cell dysfunction. Slow immunemediated DM is diagnosed in the presence of glutamic acid decarboxylase antibodies, but without any need to use insulin for 1 year after the diagnosis. DM2 is characterised with normal or elevated C-peptide levels, absence of antibodies, and presence of some signs of metabolic syndrome. In young patients, DM with autosomal dominant inheritance can be verified, which is caused by pathogenic mutations in associated genes — MODY (Maturity Onset Diabetes of the Young). Conclusion. A review of literature demonstrates the need in thorough differential diagnosis of a DM type if young patients present with hyperglycaemia. Keywords: slow immune-mediated diabetes mellitus, MODY, diabetes mellitus, young patients.

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?