BACKGROUND: COVID-19 convalescent plasma is one of the experimental therapies used widely in moderately sick COVID-19 patients. However, there are a few risks involved in plasma transfusion; notably, transfusion-related acute lung injury (TRALI) caused by antibodies against human leukocyte antigens (HLA). This study was designed to assess the prevalence of anti-HLA antibodies in convalescent plasma donors using the single antigen bead method.
METHODS: This was a hospital-based observational study of consecutive plasma donors. A total of 252 samples were screened for anti-HLA Class I and Class II antibodies using the microbead assay with the identification of anti-HLA Ab in positive samples being performed using a single antigen bead assay. Luminex-based normalized background cutoff ratios of 10.8 for Class I and 6.9 for Class II and mean fluorescence intensity cutoffs of 2500 for Class I and 1500 for Class II were used for screening and the single bead assay, respectively.
RESULTS: Of 252 screened samples, 28 (11.1 %) were positive for Class I, Class II or both Class I and Class II anti-HLA antibodies in donors with no history of a previous immunizing event. Moreover, 20/252 (7.9%) donors without any history of prior immunization had specific anti-HLA antibodies of Class I or Class II or both by the single bead assay.
CONCLUSIONS: The high prevalence of anti-HLA antibodies in our cohort of donors raises an urgent and immediate need for anti-HLA antibody screening in all convalescent plasma donors for safe therapy of COVID-19 patients.

OBJECTIVE: The molecular mechanism of the protective effect of Cordyceps cicadae polysaccharides (CCPs) on renal tubulointerstitial fibrosis in diabetic nephropathy (DN) is still unclear. This study aims to further understand the molecular mechanisms behind the therapeutic benefits of CCP on diabetic nephropathy.
METHODS: Mice were randomly assigned into six groups (n = 8). Cordyceps cicadae polysaccharide dissolved in 5% dimethyl sulfoxide was administered by gavage for 12 consecutive weeks. The CCP doses were divided into low, medium, and high, 75, 150, and 300 mg/kg/day, respectively. The efficacy of CCP was determined by assessing the renal function and histological alterations in diabetic db/db mice. The degree of glomerular mesangial dilatation and sclerosis was evaluated using semiquantitative markers. Cell viability, apoptosis, epithelial-mesenchymal transition (EMT), inflammation, oxidative stress, and mitochondrial reactive oxygen species (ROS) in high glucose (HG)-cultured MPC5 podocytes were determined. The interaction of miR-30a-3p and tripartite motif-containing protein 16 (TRIM16) was examined by luciferase reporter assay. Western blotting, reverse transcription-polymerase chain reaction, and immunofluorescence were used to analyze gene and protein expressions.
RESULTS: The in vivo findings illustrated that CCP may protect mice with type 2 diabetes from inflammation and oxidative damage (P < 0.05). Furthermore, CCP has a therapeutic value in protecting renal function and morphology in diabetic nephropathy by reversing podocyte EMT. The in vitro results indicated that CCP dose-dependently inhibited HG-induced apoptosis, EMT, inflammation, oxidative stress, and mitochondrial ROS levels in MPC5 podocytes (P < 0.05). Luciferase reporter assay confirmed the interaction between miR-30a-3p and TRIM16 in MPC5 podocytes cultured in high glucose (P < 0.05).
CONCLUSIONS: The protective effect of CCP on HG-induced MPC5 can be achieved by miR-30a-3p/TRIM16 axis.

Singleton distractors may inadvertently capture attention, interfering with the task at hand. The underlying neural mechanisms of how we prevent or handle distractor interference remain elusive. Here, we varied the type of salient distractor introduced in a visual search task: the distractor could be defined in the same (shape) dimension as the target, a different (color) dimension, or a different (tactile) modality (intra-dimensional, cross-dimensional, and, respectively, cross-modal distractor, all matched for physical salience); and besides behavioral interference, we measured lateralized electrophysiological indicators of attentional selectivity (the N2pc, Ppc, PD , CCN/CCP, CDA, and cCDA). The results revealed the intra-dimensional distractor to produce the strongest reaction-time interference, associated with the smallest target-elicited N2pc. In contrast, the cross-dimensional and cross-modal distractors did not engender any significant interference, and the target-elicited N2pc was comparable to the condition in which the search display contained only the target singleton, thus ruling out early attentional capture. Moreover, the cross-modal distractor elicited a significant early CCN/CCP, but did not influence the target-elicited N2pc, suggesting that the tactile distractor is registered by the somatosensory system (rather than being proactively suppressed), without, however, engaging attention. Together, our findings indicate that, in contrast to distractors defined in the same dimension as the target, distractors singled out in a different dimension or modality can be effectively prevented to engage attention, consistent with dimension- or modality-weighting accounts of attentional priority computation.

Worldwide pandemic with coronavirus disease-2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As November 2, 2022, World Health Organization (WHO) received 628,035,553 reported incidents on COVID-19, with 6,572,800 mortalities and, with a total 12,850,970,971 vaccine doses have been delivered as of October 31, 2022. The infection can cause mild or self-limiting symptoms of pulmonary and severe infections or death may be caused by SARS-CoV-2 infection. Simultaneously, antivirals, corticosteroids, immunological treatments, antibiotics, and anticoagulants have been proposed as potential medicines to cure COVID-19 affected patients. Among these initial treatments, COVID-19 convalescent plasma (CCP), which was retrieved from COVID-19 recovered patients to be used as passive immune therapy, in which antibodies from cured patients were given to infected patients to prevent illness. Such treatment has yielded the best results in earlier with preventative or early stages of illness. Convalescent plasma (CP) is the first treatment available when infectious disease initially appears, although few randomized controlled trials (RCTs) were conducted to evaluate its effectiveness. The historical record suggests with potential benefit for other respiratory infections, as coronaviruses like Severe Acute Respiratory Syndrome-CoV-I (SARS-CoV-I) and Middle Eastern Respiratory Syndrome (MERS), though the analysis of such research is constrained by some non-randomized experiments (NREs). Rigorous studies on CP are made more demanding by the following with the immediacy of the epidemics, CP use may restrict the ability to utilize it for clinical testing, non-homogenous nature of product, highly decentralized manufacturing process; constraints with capacity to measure biologic function, ultimate availability of substitute therapies, as antivirals, purified immune globulins, or monoclonal antibodies. Though, it is still not clear how effectively CCP works among hospitalized COVID-19 patients. The current review tries to focus on its efficiency and usage in clinical scenarios and identifying existing benefits of implementation during pandemic or how it may assist with future pandemic preventions.

In August 2020, the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for COVID-19 convalescent plasma (CCP) specified 12 authorized serologic assays and associated assay-specific cutoff values for the selection of high-titer CCP for use in hospitalized patients. The criteria used for establishing these cutoff values remains unclear. Here, we compare the overall agreement and concordance of five serologic assays included in the August 2020 FDA EUA at both the manufacturer-recommended qualitative cutoff thresholds and at the FDA-indicated thresholds for high-titer CCP, using serum samples collected as part of the CCP Expanded Access Program (EAP). The qualitative positive percent agreement (PPA) across assays ranged from 92.3% to 98.8%. However, the high-titer categorization across assays varied significantly, with the PPA ranging from 26.5% to 82.7%. The Roche anti-NC ECLIA provided the lowest agreement compared to all other assays. Efforts to optimize high-titer cutoffs could reduce, although not eliminate, the discordance across assays. The consequences of using nonstandardized assays are apparent in our study, and the high-titer cutoffs chosen for each assay are not directly comparable to each other. The generalized findings in our study will be relevant to any future use of convalescent plasma for either COVID-19 or future pandemics of newly emerged pathogens. IMPORTANCE COVID-19 convalescent plasma (CCP) was one of the first therapeutic options available for the treatment of SARS-CoV-2 infections and continues to be used selectively for immunosuppressed patients. Given the emergence of novel SARS-CoV-2 variants which are resistant to treatment with available monoclonal antibody (MAb) therapy, CCP remains an important therapeutic consideration. The FDA has released several emergency use authorizations (EUA) that have specified which serological assays can be used for qualification of CCP, as well as assay-specific cutoffs that must be used to identify high-titer CCP. In this study, a cohort of donor CCP was assessed across multiple serological assays which received FDA EUA for qualification of CCP. This study indicates a high degree of discordance across the assays used to qualify CCP for clinical use, which may have precluded the optimal use of CCP, including during clinical trials. This study highlights the need for assay standardization early in the development of serological assays for emerging pathogens.

OBJECTIVE: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood.
OBJECTIVE: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood. Our study aims to determine the safety and efficacy of treating hospitalized COVID-19 patients with 2 units of COVID-19 convalescent plasma (CCP).
METHODS: This was a retrospective study of Arkansas patients treated with CCP using the (US) Food and Drug Administration (FDA) emergency Investigational New Drug (eIND) mechanism from April 9, 2020, through August 9, 2020. It was a multicenter, statewide study in a low-resource setting, which are areas that lack funding for health care cost coverage on various levels including individual, family, or social. Adult patients (n = 165, volunteer sample) in Arkansas who were hospitalized with severe or life-threatening acute COVID-19 disease as defined by the FDA criteria were transfused with 2 units of CCP (250 mL/unit) using the FDA eIND mechanism. The primary outcome was 7- and 30-day mortality after the second unit of CCP.
RESULTS: Unadjusted mortality was 12.1% at 7 days and 23.0% at 30 days. The unadjusted mortality was reduced to 7.7% if the first CCP unit was transfused on the date of diagnosis, 8.7% if transfused within 3 days of diagnosis, and 32.0% if transfused at or after 4 or more days of diagnosis. The risk of death was higher in patients that received low, negative, or missing titer CCP units in comparison to those that received higher titer units.
CONCLUSIONS: The provision of 2 units of CCP was associated with a reduction in mortality in patients treated with high titer units within 3 days of COVID-19 diagnosis. Given the results, CCP is a viable, low-cost therapy in resource-constrained states and countries.

The appearance of synapses was a crucial step in the creation of the variety of nervous systems that are found in the animal kingdom. With increased complexity of the organisms came a greater number of synaptic proteins. In this review we describe synaptic proteins that contain the structural domains CUB, CCP, or TSP-1. These domains are found in invertebrates and vertebrates, and CUB and CCP domains were initially described in proteins belonging to the complement system of innate immunity. Interestingly, they are found in synapses of the nematode C. elegans, which does not have a complement system, suggesting an ancient function. Comparison of the roles of CUB-, CCP-, and TSP-1 containing synaptic proteins in various species shows that in more complex nervous systems, these structural domains are combined with other domains and that there is partial conservation of their function. These three domains are thus basic building blocks of the synaptic architecture. Further studies of structural domains characteristic of synaptic proteins in invertebrates such as C. elegans and comparison of their role in mammals will help identify other conserved synaptic molecular building blocks. Furthermore, this type of functional comparison across species will also identify structural domains added during evolution in correlation with increased complexity, shedding light on mechanisms underlying cognition and brain diseases.

Many studies already reported on the association between patient characteristics on the severity of COVID-19 disease outcome, but the relation with SARS-CoV-2 antibody levels is less clear. To investigate this in more detail, we performed a retrospective observational study in which we used the IgG antibody response from 11,118 longitudinal antibody measurements of 2,082 unique COVID convalescent plasma donors. COVID-19 symptoms and donor characteristics were obtained by a questionnaire. Antibody responses were modelled using a linear mixed-effects model. Our study confirms that the SARS-CoV-2 antibody response is associated with patient characteristics like body mass index and age. Antibody decay was faster in male than in female donors (average half-life of 62 versus 72 days). Most interestingly, we also found that three symptoms (headache, anosmia, nasal cold) were associated with lower peak IgG, while six other symptoms (dry cough, fatigue, diarrhoea, fever, dyspnoea, muscle weakness) were associated with higher IgG concentrations.

The COVID-19 pandemics has caused the death of almost six million people worldwide. In order to establish collective immunity, the first vaccines that were approved in Germany were the vector virus-based vaccine Vaxzevria and the mRNA vaccines Comirnaty and Spikevax, respectively. As it was reported that SARS-CoV-2 can trigger autoimmunity, it is of significant interest to investigate whether COVID-19 vaccines evoke the formation of autoantibodies and subsequent autoimmunity. Here, we analyzed immune responses after different vaccination regimens (mRNA/mRNA, Vector/Vector or Vector/mRNA) with respect to anti-SARS-CoV-2-specific immunity and the development of autoantibodies well known for their appearance in distinct autoimmune diseases. We found that anti-SARS-CoV-2 antibody levels were 90% lower after Vector/Vector vaccination compared to the other vaccinations and that Vector/mRNA vaccination was more effective than mRNA/mRNA vaccination in terms of IgM and IgA responses. However, until 4 months after booster vaccination we only detected increases in autoantibodies in participants with already pre-existing autoantibodies whereas vaccinees showing no autoantibody formation before vaccination did not respond with sustained autoantibody production. Taken together, our study suggests that all used COVID-19 vaccines do not significantly foster the appearance of autoantibodies commonly associated with lupus erythematodes, rheumatoid arthritis, Celiac disease and antiphospholipid-syndrome but provide immunity to SARS-CoV-2.

COVID-19 convalescent plasma (CCP) ideally contains high titers of (neutralizing) anti-SARS-CoV-2 antibodies. Several scalable immunoassays for CCP selection have been developed. We designed an enzyme-linked immunosorbent assay (ELISA) that measures neutralizing antibodies (of all isotypes) in plasma by determining the level of competition between CCP and a mouse neutralizing antibody for binding to the receptor binding domain (RBD) of SARS-CoV-2.
Plasma was collected from 72 convalescent individuals and inhibition of viral infection was determined by plaque reduction neutralization (PRNT50). The level of neutralizing antibodies was measured in the novel competition ELISA and in a commercially available ELISA that measures inhibition of recombinant ACE2 binding to immobilized RBD. These results were compared with a high throughput chemiluminescent microparticle immunoassay (CMIA).
The results from both ELISAs were correlating, in particular for high titer CCP (PRNT50 ≥ 1:160) (Spearman r = .73, p < .001). Moderate correlation was found between the competition ELISA and CMIA (r = .57 for high titer and r = .62 for low titer CCP, p < .001). Receiver operator characteristic analysis showed that the competition ELISA selected CCP with a sensitivity and specificity of 61% and 100%, respectively. However, discrimination between low and high titer CCP had a lower resolution (sensitivity: 34% and specificity: 89%).
The competition ELISA screens for neutralizing antibodies in CCP by competition for just a single epitope. It exerts a sensitivity of 61% with no false identifications. These ELISA designs can be used for epitope mapping or for selection of CCP.