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Performance evaluation is essential for an industry's ability to operate successfully. Efficiency management is becoming crucial and important to enhancing the sustainability of the industry. The industry needs to measure its performance for the following reasons: (i) develop the economy and its operation efficiency in a sustainable way; (ii) supply data for decision-making units (DMUs); and (iii) optimize output using the fewest resources. Performance measurement indicators relate to the performance of the industry itself, such as: added value/cost of production factors, indirect taxes, number of workers, input costs, number of companies, added value/market prices, and production index. The purpose of this research is to measure the performance of large and medium-sized industries (LMIs) in Indonesia. LMIs have a strategic role as the main engine and driver of the economy. Measuring LMI performance is very necessary so that LMI can grow and develop sustainably. Data envelopment analysis (DEA) is a method for measuring performance. DEA is a non-parametric linear programming technique and used to determine comparisons between DMUs with different inputs and outputs. The research results indicate that there are three DMU classification categories, namely: Category 1 (ES = 1), Category 2 (ES = 0.9986-0.9998), and Category 3 (ES = 0.9971-0.9974). The percentages for each category are 50%, 37.5%, and 12.5%.

Summary: Background: Limited data exist from southeast Asia on the impact of SARS-CoV-2 variants and inactivated vaccines on disease severity and death among patients hospitalised with COVID-19. Methods: A multicentre hospital-based prospective cohort was enrolled from September 2020 through January 2023, spanning pre-delta, delta, and omicron periods. The participant hospitals were conveniently sampled based on existing collaborations, site willingness and available study resources, and included six urban and two rural general hospitals from East Nusa Tenggara, Jakarta, and North Sumatra provinces. Factors associated with severe disease and day-28 mortality were examined using logistic and Cox regression. Findings: Among 822 participants, the age-adjusted percentage of severe disease was 26.8% (95% CI 22.7–30.9) for pre-delta, 50.1% (44.0–56.2) for delta, and 15.2% (9.7–20.7) for omicron. The odds of severe disease were 64% (18–84%) lower for omicron than delta (p

Indramayu is one of the regencies in West Java Province that produces food crop production in the agricultural and plantation sectors. Many people work in the agricultural sector, one of which is by growing vegetables on their land. Planting vegetables on land in the Indramayu area often experiences problems, for example the land used is not in accordance with the type of vegetables grown. Some farmers have difficulty in evaluating land due to their lack of understanding of the land to be planted so that farmers rely on the system of planting habits that they usually do. The wrong land selection can result in energy and financial losses used for maintenance. Vegetables will develop imperfectly, even vegetables can die because of the inappropriateness of the land used. This study aims to assist farmers in determining what types of vegetable crops can be planted on their land using the k-means clustering method. There are 7 data criteria used for processing k-means so that later it can produce output a recommendation of vegetable types that can be planted by farmers according to the criteria they enter into the system. The results of this study produce an expert system that can provide information about vegetables selected according to the criteria selected by each user and with this system, ordinary people can find out how the selection of types of vegetables is practically on the land to be planted with vegetables.

In this research, researchers aspire to examine the theory of whether there is a cash flow effect on stock changes. Stock returns which are used as stock measurement tools are a reflection of market reactions to what happens within the company in terms of fundamentals. Therefore to measure the fundamental factors that exist within the company researchers utilise operating cash flow. Operating cash flow is seen as being able to represent because operating cash flow data exists in every company. Moreover, hence that the comparison is balanced the researchers choose to use the population of companies in the LQ 45 area. After being tested using simple linear regression, the results are as previously thought that there are influences on the company's Fundamental factors which in this study is the Operating Cash Flow with market factors which in this study represented by Stock Return. Keywords: financial statements, operating cash flow, stock return.

Abstract Objective:To determine the incidence of postpartum urinary retention (PUR) after vaginal delivery and to specify any obstetric risk factors that contributing PUR. Methods: Case control study. Six hours after vaginal delivery, urethral catheterization was implemented for estimation of post void residual bladder and diagnosis PUR. Patient data, including age, gestational age, body mass index, parity, mode of delivery, labor duration, perineal laceration or episiotomy, and fetal birth weight, were compared between women with and those without PUR to determine which obstetric factors that develops PUR. Results: Of the 365 participants recruited, 38 (10,67%) had PUR: 33 (9,27%) with covert PUR and 5 (1,4%) with overt PUR. Women with perineal laceration or episiotomy (p

Writing is one of the efforts made by the writer to express ideas and ideas to others. But sometimes when writing, there are many errors in typing spelling, especially English spelling, resulting in errors in capturing the meaning and meaning of the writing. To overcome this problem, we need a system that can detect word spelling errors. Damerau Levenshtein and Jaro Winkler Distance Algorithms are algorithms that can be used as a solution to detect English typing errors. From the test results, it can be concluded that the Damerau Levenshtein and Jaro-Winkler Distance are able to optimally detect word mismatches and look for similarities of words compared. The Damerau Levenshtein Distance works by finding the smallest distance value, while the Jaro-Winkler Distance works by finding the greatest proximity value of the string being compared. Using this algorithm, errors in writing the spelling of words can be minimized. Keywords— Algorithm; Damerau Levenshtein; Jaro Winkler; Spelling Cheker; String Matching.

Polymer is an insulating substance that has become increasingly popular in recent years due to its benefits. Light density, superior dielectric and thermal properties, and water-resistant or hydrophobic properties are only a few of the benefits. The presence of impurities or pollutants on the insulator’s surface lowers its dielectric capacity, which can lead to current leakage. The influence of seawater and fly ash pollutants on the distribution of the electric field and the current density of the insulator was simulated in this study. The finite element method was used to execute the simulation (FEM). Polymer insulators are subjected to testing in order to gather current leakage statistics. The tested insulator is exposed to seawater pollution, which varies depending on the equivalent salt density deposit value (ESDD). The pollutant insulator for fly ash varies depending on the value of non-soluble deposit density (NSDD). The existence of a layer of pollutants increased the value of the electric field and the value of the surface current density, according to the findings. Both in simulation and testing, the ESDD value of seawater pollutants and the NSDD value of fly ash contaminants influenced the value of the leakage current that flowed. The greater the ESDD and NSDD values are, the bigger the leakage current will be.

This study examines a new attachment concept called job embeddedness as antecedent of organizational citizenship behavior (OCB). Firstly, we tested hypothesis concerning positive relationship between job embeddedness and OCB as predicted by Mitchell et al. (2001). Secondly, we tested hypothesis concerning the mediation effect of sense of responsibility in the relationship between job embeddedness and OCB. Nurses (N = 170) and their immediate supervisors ( N = 41) from five privately owned hospital in Jogjakarta participated in this study. Of 340 questionnaires distributed to the respondents, 339 were returned yielding a response rate of 99 percent. Of those returned, 300 questionnaires were available for further analyses. Nurses were asked to respond to a questionnaire of 40 items concerning perception of embeddedness and 4 item concerning sense of responsibility to their employing organization. Nurses’ citizenship behavior were measured using 12 items as rated by their immediate supervisors. The results support the hypothesis that job embeddedness correlates positively with OCB. However, our result failed to support the prediction of the mediating effect of employees’ sense of responsibility in causal relationship between job embeddedness and OCB. The implications of the findings for further research on relationship between job embeddedness and OCB research are discussed.

Opportunistic viral infections in individuals with severe immunodeficiency can lead to fatal conditions such as progressive multifocal leukoencephalopathy (PML), for which treatment options are limited. These infections pose significant risks, especially when co-infections with other viruses occur. We describe a combined therapy approach using directly isolated allogeneic Human Polyomavirus 1 (also known as BKV) and Epstein–Barr virus (EBV) specific cytotoxic T-cells for the treatment of PML in conjunction with identified EBV in the cerebrospinal fluid (CSF) of a male patient infected with human immunodeficiency virus (HIV). A 53-year-old HIV-positive male, recently diagnosed with PML, presented with rapidly worsening symptoms, including ataxia, tetraparesis, dysarthria, and dysphagia, leading to respiratory failure. The patient developed PML even after commencing highly active antiretroviral therapy (HAART) 3 months prior. Brain magnetic resonance imaging (MRI) revealed multifocal demyelination lesions involving the posterior fossa and right thalamus suggestive of PML. In addition to the detection of human polyomavirus 2 (also known as JCV), analysis of CSF showed positive results for EBV deoxyribonucleic acid (DNA). His neurological condition markedly deteriorated over the following 2 months. Based on MRI, there was no evidence of Immune Reconstitution Inflammatory Syndrome contributing to this decline. The patient did not have endogenous virus-specific T-cells. We initiated an allogeneic, partially human leukocyte antigen-matched transfer of EBV and utilizing the cross-reactivity between BKV and JCV–BKV specific T-cells. This intervention led to notable neurological improvement and partial resolution of the MRI lesions within 6 weeks. Our case of a patient with acquired immune deficiency syndrome demonstrates that PML and concurrent EBV co-infection can still occur despite undergoing HAART treatment. This innovative experimental therapy, involving a combination of virus-specific T-cells, was demonstrated to be an effective treatment option in this patient.

Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.

IntroductionChimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since “on-target/off-tumor” cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no “on-target/off-tumor” cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts.MethodsUsing the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity.ResultsSpecific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific.DiscussionGenetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding “on-target/off-tumor” cytotoxicity.

BACKGROUND Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODS We provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis.RESULTS Forty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1–14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients’ blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response.CONCLUSION Personalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction.TRIAL REGISTRATION Not applicable.FUNDING This study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).

Groundwater nowadays has become one of the public necessities. Tambakboyo Artificial Lake in Sleman Regency, Special Region of Yogyakarta Province mainly functions as a recharge lake for the local groundwater. The location of this lake at the economic and educational center leads to an increase in groundwater use, affecting the quality and quantity of groundwater. The groundwater flows through hydrogeological conditions around Tambakboyo Artificial Lake, part of the Sleman-Yogyakarta Groundwater Basin. This study aims to know how groundwater system works by developing the hydrogeology conceptual model of the Tambakboyo Artificial Lake. Hydrogeological direct observation in the field consists of measuring groundwater level, geoelectrical survey, slug test, and secondary data of bore log and climate data. All those data were analyzed and interpreted to develop a 2- dimensional conceptual model of the hydrogeological condition. The analysis shows that the study area is urban with a recharge of approximately 331.80 mm/year. The hydrostratigraphy around Tambakboyo Artificial Lake is commonly formed by the gravelly sand, silty sand, and breccia layers, with sand and silty sand acting as one aquifer system. The clay layer was found as an aquifer base at a depth ranging between 68 and 120 meters. The thickness of the aquifer decreases from north to south with the permeability value (K) around 4•10-5 – 2•10-4 m•s−1. Based on the relationship between surface water and groundwater, Tambakboyo Artificial Lake can act as a recharge lake for its main purpose.

IntroductionIn immunocompromised patients, Epstein-Barr virus (EBV) infection or reactivation is associated with increased morbidity and mortality, including the development of B-cell lymphomas. The first-line treatment consists of reduction of immunosuppression and administration of rituximab (anti-CD20 antibody). Furthermore, the presence of EBV-specific T cells against latent EBV proteins is crucial for the control of EBV-associated diseases. Therefore, in addition to effective treatment strategies, appropriate monitoring of T cells of high-risk patients is of great importance for improving clinical outcome. In this study, we hypothesized that rituximab-mediated lysis of malignant EBV-infected B cells leads to the release and presentation of EBV-associated antigens and results in an augmentation of EBV-specific effector memory T-cell responses.MethodsEBV-infected B lymphoblastoid cell lines (B-LCLs) were used as a model for EBV-associated lymphomas, which are capable of expressing latency stage II and III EBV proteins present in all known EBV-positive malignant cells. Rituximab was administered to obtain cell lysates containing EBV antigens (ACEBV). Efficiency of cross-presentation of EBV-antigen by B-LCLs compared to cross-presentation by professional antigen presenting cells (APCs) such as dendritic cells (DCs) and B cells was investigated by in vitro T-cell immunoassays. Deep T-cell profiling of the tumor-reactive EBV-specific T cells in terms of activation, exhaustion, target cell killing, and cytokine profile was performed, assessing the expression of T-cell differentiation and activation markers as well as regulatory and cytotoxic molecules by interferon-γ (IFN-γ) EliSpot assay, multicolor flow cytometry, and multiplex analyses.ResultsBy inhibiting parts of the cross-presentation pathway, B-LCLs were shown to cross-present obtained exogenous ACEBV-derived antigens mainly through major histocompatibility complex (MHC) class I molecules. This mechanism is comparable to that for DCs and B cells and resulted in a strong EBV-specific CD8+ cytotoxic T-cell response. Stimulation with ACEBV-loaded APCs also led to the activation of CD4+ T helper cells, suggesting that longer peptide fragments are processed via the classical MHC class II pathway. In addition, B-LCLs were also found to be able to take up exogenous antigens from surrounding cells by endocytosis leading to induction of EBV-specific T-cell responses although to a much lesser extent than cross-presentation of ACEBV-derived antigens. Increased expression of activation markers CD25, CD71 and CD137 were detected on EBV-specific T cells stimulated with ACEBV-loaded APCs, which showed high proliferative and cytotoxic capacity as indicated by enhanced EBV-specific frequencies and increased secretion levels of cytotoxic effector molecules (e.g. IFN-γ, granzyme B, perforin, and granulysin). Expression of the regulatory proteins PD-1 and Tim-3 was induced but had no negative impact on effector T-cell functions.ConclusionIn this study, we showed for the first time that rituximab-mediated lysis of EBV-infected tumor cells can efficiently boost EBV-specific endogenous effector memory T-cell responses through cross-presentation of EBV-derived antigens. This promotes the restoration of antiviral cellular immunity and presents an efficient mechanism to improve the treatment of CD20+ EBV-associated malignancies. This effect is also conceivable for other therapeutic antibodies or even for therapeutically applied unmodified or genetically modified T cells, which lead to the release of tumor antigens after specific cell lysis.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the highly infectious Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). There is an urgent need for biomarkers that will help in better stratification of patients and contribute to personalized treatments. We performed targeted proteomics using the Olink platform and systematically investigated protein concentrations in 350 hospitalized COVID-19 patients, 186 post-COVID-19 individuals, and 61 healthy individuals from 3 independent cohorts. Results revealed a signature of acute SARS-CoV-2 infection, which is represented by inflammatory biomarkers, chemokines and complement-related factors. Furthermore, the circulating proteome is still significantly affected in post-COVID-19 samples several weeks after infection. Post-COVID-19 individuals are characterized by upregulation of mediators of the tumor necrosis (TNF)-α signaling pathways and proteins related to transforming growth factor (TGF)-ß. In addition, the circulating proteome is able to differentiate between patients with different COVID-19 disease severities, and is associated with the time after infection. These results provide important insights into changes induced by SARS-CoV-2 infection at the proteomic level by integrating several cohorts to obtain a large disease spectrum, including variation in disease severity and time after infection. These findings could guide the development of host-directed therapy in COVID-19.

Acute myeloid leukemia (AML) patients with minimal residual disease and receiving allogeneic hematopoietic stem cell transplantation (HCT) have poor survival. Adoptive administration of dendritic cells (DCs) presenting the Wilms tumor protein 1 (WT1) leukemia-associated antigen can potentially stimulate de novo T and B cell development to harness the graft-versus-leukemia (GvL) effect after HCT. We established a simple and fast genetic modification of monocytes for simultaneous lentiviral expression of a truncated WT1 antigen (tWT1), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-α, promoting their self-differentiation into potent “induced DCs” (iDCtWT1). A tricistronic integrase-defective lentiviral vector produced under good manufacturing practice (GMP)-like conditions was validated. Transduction of CD14+ monocytes isolated from peripheral blood, cord blood, and leukapheresis material effectively induced their self-differentiation. CD34+ cell-transplanted Nod.Rag.Gamma (NRG)- and Nod.Scid.Gamma (NSG) mice expressing human leukocyte antigen (HLA)-A∗0201 (NSG-A2)-immunodeficient mice were immunized with autologous iDCtWT1. Both humanized mouse models showed improved development and maturation of human T and B cells in the absence of adverse effects. Toward clinical use, manufacturing of iDCtWT1 was up scaled and streamlined using the automated CliniMACS Prodigy system. Proof-of-concept clinical-scale runs were feasible, and the 38-h process enabled standardized production and high recovery of a cryopreserved cell product with the expected identity characteristics. These results advocate for clinical trials testing iDCtWT1 to boost GvL and eradicate leukemia.

Theological discussions related to the post-pandemic condition of the church have attracted significant attention. Generally speaking, those discussions focus on the mode of worship in the future: whether to remain online, back offline or adopt the hybrid mode of worship. In this article, the authors argue that the mode of worship in the post-pandemic condition should not be seen as operative per se, but it should be based on a deep reflection of the church on what is the essence of worship and how could the church reflect it to the congregations in the church and the world outside the church. To reflect the Gospel appropriately, the church should seek to revitalize worship in the post-pandemic condition. This article suggests that such a revitalization could be achieved through constructing a thanksgiving liturgy. The post-pandemic condition could be seen as a suitable opportunity for the church to reflect its joy and gratitude for the grace of God that renews and heals the creation.

Objectives: Evaluation of the feasibility of SARS-CoV-2-specific T cell manufacturing for adoptive T cell transfer in COVID-19 patients at risk to develop severe disease.Methods: Antiviral SARS-CoV-2-specific T cells were detected in blood of convalescent COVID-19 patients following stimulation with PepTivator SARS-CoV-2 Select using Interferon-gamma Enzyme-Linked Immunospot (IFN-γ ELISpot), SARS-CoV-2 T Cell Analysis Kit (Whole Blood) and Cytokine Secretion Assay (CSA) and were characterized with respect to memory phenotype, activation state and cytotoxic potential by multicolor flow cytometry, quantitative real-time PCR and multiplex analyses. Clinical-grade SARS-CoV-2-specific T cell products were generated by stimulation with MACS GMP PepTivator SARS-CoV-2 Select using CliniMACS Prodigy and CliniMACS Cytokine Capture System (IFN-gamma) (CCS). Functionality of enriched T cells was investigated in cytotoxicity assays and by multiplex analysis of secreted cytotoxic molecules upon target recognition.Results: Donor screening via IFN-γ ELISpot allows for pre-selection of potential donors for generation of SARS-CoV-2-specific T cells. Antiviral T cells reactive against PepTivator SARS-CoV-2 Select could be magnetically enriched from peripheral blood of convalescent COVID-19 patients by small-scale CSA resembling the clinical-grade CCS manufacturing process and showed an activated and cytotoxic T cell phenotype. Four clinical-grade SARS-CoV-2-specific T cell products were successfully generated with sufficient cell numbers and purities comparable to those observed in donor pretesting via CSA. The T cells in the generated products were shown to be capable to replicate, specifically recognize and kill target cells in vitro and secrete cytotoxic molecules upon target recognition. Cell viability, total CD3+ cell number, proliferative capacity and cytotoxic potential remained stable throughout storage of up to 72 h after end of leukapheresis.Conclusion: Clinical-grade SARS-CoV-2-specific T cells are functional, have proliferative capacity and target-specific cytotoxic potential. Their function and phenotype remain stable for several days after enrichment. The adoptive transfer of partially matched, viable human SARS-CoV-2-specific T lymphocytes collected from convalescent individuals may provide the opportunity to support the immune system of COVID-19 patients at risk for severe disease.

Mortality due to COVID-19 is not increased in immunosuppressed individuals after liver transplantation (OLT) compared to individuals without immunosuppression. Data on long-term protective immunity against SARS-CoV-2 in immunosuppressed convalescents, is limited. We prospectively measured immune responses against SARS-CoV-2 by quantifying antibodies against 4 different antigens (spike protein 1 and 2, receptor binding domain, nucleocapsid) and T cell responses by IFN-γ ELISPOT against 4 antigens (membrane, nucleocapsid, spike protein 1 and 2) in 24 OLT convalescents with immunosuppressive therapy longitudinally in the first year after COVID-19 including a booster vaccination in comparison to a matched cohort of non-immunosuppressed convalescents (non-IS-Con). Pre-pandemic OLT samples were retrieved from our prospective OLT biorepository (n = 16). No relevant T cell reactivity or immunoglobulin G (IgG) against SARS-CoV-2 were detectable in pre-pandemic samples of OLT recipients despite reactivity against endemic corona-viruses. OLT convalescents had a lower prevalence of IgG against nucleocapsid (54% vs. 90%) but not against spike protein domains (98-100% vs. 100%) after vaccination in the second half-year after COVID-19 compared to non-IS-Con. Also, concentrations of anti-nucleocapsid IgG were lower in OLT convalescents than in non-IS-Con. Concentration of IgG against spike protein domains was significantly increased by a booster vaccination in OLT convalescents. But concentration of IgG against two of three spike protein domains remains slightly lower compared to non-IS-Con finally. However, none of these differences was mirrored by the cellular immunity against SARS-CoV-2 that remained stable during the first year after COVID-19 and was not further stimulated by a corona vaccination in OLT convalescents. In conclusion, despite lower concentrations of anti-SARS-CoV-2 IgG in OLT convalescents anti-SARS-CoV-2 cellular immunity was as robust as in non-IS-Con.

Since its declaration as a pandemic in March 2020, SARS-CoV-2 has infected more than 217 million people worldwide and despite mild disease in the majority of the cases, more than 4.5 million cases of COVID-19-associated death have been reported as of September 2021. The question whether recovery from COVID-19 results in prevention of reinfection can be answered with a “no” since cases of reinfections have been reported. The more important question is whether during SARS-CoV-2 infection, a protective immunity is built and maintained afterwards in a way which protects from possibly severe courses of disease in case of a reinfection. A similar question arises with respect to vaccination: as of September 2021, globally, more than 5.2 billion doses of vaccines have been administered. Therefore, it is of utmost importance to study the cellular and humoral immunity toward SARS-CoV-2 in a longitudinal manner. In this study, reconvalescent COVID-19 patients have been followed up for more than 1 year after SARS-CoV-2 infection to characterize in detail the long-term humoral as well as cellular immunity. Both SARS-CoV-2-specific T cells and antibodies could be detected for a period of more than 1 year after infection, indicating that the immune protection established during initial infection is maintained and might possibly protect from severe disease in case of reinfection or infection with novel emerging variants. Moreover, these data demonstrate the opportunity for immunotherapy of hospitalized COVID-19 patients via adoptive transfer of functional antiviral T cells isolated from reconvalescent individuals.

[This corrects the article DOI: 10.1371/journal.ppat.1008560.].

Allogeneic and autologous transplantation of hematopoietic stem cells (HSCT) are being routinely used to treat patients with leukemia and lymphoma. Due to the required immunosuppression after stem cell transplantation, infection and reactivation by viruses are life-threatening complications. In recent years, adoptive transfer using virus-specific T cells (VSTs) has emerged as alternative to conventional therapies. Since vitamins are described to influence the immune system and its cellular components, the aim of this study was to examine whether vitamins modulate VST function and thereby enable an improvement of therapy. For that, we investigated the impact of vitamin C and D on the functionality of cytomegalovirus (CMV)-specific T cells isolated from CMV-seropositive healthy donors. We were able to show that vitamin C increases the expansion and activation state of CMV-specific T cells, and an increased influence of vitamin C was observed on cells isolated from male donors and donors above 40 years of age. A higher frequency of the terminally differentiated effector memory CD8+ T-cell population in these donors indicates a connection between these cells and the enhanced response to vitamin C. Thus, here we provide insights into the impact of vitamin C on cytotoxic T cells as well as possible additional selection criteria and strategies to improve VST functionality.

Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.

Background Immunosuppressive therapy or T-cell depletion in transplant patients can cause uncontrolled growth of Epstein-Barr virus (EBV)-infected B cells resulting in post-transplant lymphoproliferative disease (PTLD). Current treatment options do not distinguish between healthy and malignant B cells and are thereby often limited by severe side effects in the already immunocompromised patients. To specifically target EBV-infected B cells, we developed a novel peptide-selective chimeric antigen receptor (CAR) based on the monoclonal antibody TÜ165 which recognizes an Epstein-Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context in a T-cell receptor (TCR)-like manner. In order to attract additional immune cells to proximity of PTLD cells, based on the TÜ165 CAR, we moreover generated T cells redirected for universal cytokine-mediated killing (TRUCKs), which induce interleukin (IL)-12 release on target contact.Methods TÜ165-based CAR-T cells (CAR-Ts) and TRUCKs with inducible IL-12 expression in an all-in-one construct were generated. Functionality of the engineered cells was assessed in co-cultures with EBNA-3C-peptide-loaded, HLA-B*35-expressing K562 cells and EBV-infected B cells as PTLD model. IL-12, secreted by TRUCKs on target contact, was further tested for its chemoattractive and activating potential towards monocytes and natural killer (NK) cells.Results After co-cultivation with EBV target cells, TÜ165 CAR-Ts and TRUCKs showed an increased activation marker expression (CD137, CD25) and release of proinflammatory cytokines (interferon-γ and tumor necrosis factor-α). Moreover, TÜ165 CAR-Ts and TRUCKs released apoptosis-inducing mediators (granzyme B and perforin) and were capable to specifically lyse EBV-positive target cells. Live cell imaging revealed a specific attraction of TÜ165 CAR-Ts around EBNA-3C-peptide-loaded target cells. Of note, TÜ165 TRUCKs with inducible IL-12 showed highly improved effector functions and additionally led to recruitment of monocyte and NK cell lines.Conclusions Our results demonstrate that TÜ165 CAR-Ts recognize EBV peptide/HLA complexes in a TCR-like manner and thereby allow for recognizing an intracellular EBV target. TÜ165 TRUCKs equipped with inducible IL-12 expression responded even more effectively and released IL-12 recruited additional immune cells which are generally missing in proximity of lymphoproliferation in immunocompromised PTLD patients. This suggests a new and promising strategy to specifically target EBV-infected cells while sparing and mobilizing healthy immune cells and thereby enable control of EBV-associated lymphoproliferation.

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.

Background: The use of fiber post has become commonplace among dental practitioners due to its several advantages. In accordance with the intended use of post which provides retention for coronal restoration, a cement is used that can provide high quality adhesion. Conventional resin cement has long been adopted as a cementation material for consumer fiber post. However, allowing attachment fiber post failure due to errors in the cementing procedure leads to complications. Purpose: This study aimed to compare the adhesion strength of zinc phosphate cement and self-adhesive resin cement as fiber post cementation material. Both consumer cements were easy to use and cheap. Methods: The samples used numbered up to 20 and were divided into two groups. group 1 used zinc phosphate cement, while group 2 used self-adhesive resin cement. Results: The value of the average adhesion strength of group 1 (zinc phosphate) was 82.65 N, whereas that of group 2 (self-adhesive resin) was 402.81 N. Conclusion: This study concluded that the adhesive strength of self-adhesive resin cement as fiber post cementation material was higher than that of zinc phosphate cement.

Pendahuluan: Pasien tidak bergigi lengkap yang sudah terlalu lama, umumnya mengalami perubahan anatomi dalam rongga mulut seiring bertambahnya usia, termasuk perubahan pada relasi maksilomandibula, sehingga keadaan ini akan menambah tingkat kesulitan dalam perawatan. American College of Prosthodontic telah mengembangkan suatu sistem klasifikasi untuk membantu dalam menyusun rencana perawatan gigi tiruan lengkap yang terdiri dari beberapa kriteria diagnostik utama salah satunya adalah relasi maksilomandibula. Tujuan penelitian adalah untuk mengidentifikasi klasifikasi relasi maksilomandibula pada rahang tidak bergigi lengkap pada pasien di Klinik Prostodonsia RSGM FKG Universitas Padjadjaran (Unpad). Metode: Jenis penelitian ini merupakan penelitian deskriptif dengan teknik survei. Pengambilan sampel menggunakan teknik purposive sampling. Sampel penelitian didapat dari 20 artikulator yang sudah dipasang model kerja rahang tidak bergigi lengkap atas dan bawah. Relasi maksilomandibula didapat dari pemeriksaan artikulator gigi tiruan lengkap secara langsung yang sedang dikerjakan oleh ko-ass atau residen. Hasil: Klasifikasi relasi maksilomandibula kelas I ditemukan sebanyak 12 responden (60%), kelas II sebanyak 2 responden (10%), dan kelas III sebanyak 6 responden (30%). Simpulan: Klasifikasi relasi maksilomandibula kelas I sebanyak 12 responden (60%) merupakan relasi yang paling banyak ditemukan pada pasien rahang tidak bergigi lengkap di RSGM FKG Unpad. Kata kunci: Rahang tidak bergigi lengkap, klasifikasi relasi maksilomandibula ABSTRACT Introduction: Patients with long period edentulous jaw, generally experience anatomic changes in the oral cavity as we get older, including changes in the maxillomandibular relation, so this condition will increase the level of difficulty in treatment. The American College of Prosthodontic has developed a classification system to assist in developing a complete denture treatment plan consisting of several main diagnostic criteria, one of which is maxillomandibular relations. The aim of the study was to identify the classification of maxillomandibular relations in edentulous patients at the RSGM FKG Prosthodontics Clinic, Padjadjaran University (Unpad). Methods: This type of research is a descriptive study with survey techniques. Sampling using purposive sampling technique. The research sample was obtained from 20 articulators that had been installed with a complete upper and lower toothless jaw working model. Maxillomandibular relation was obtained from direct complete denture articulator examination that was being done by co-ass or resident. Result: Classification of class I maxillomandibular relations was found as many as 12 respondents (60%), class II as many as 2 respondents (10%), and class III as many as 6 respondents (30%). Conclusion: Classification of class I maxillomandibular relationships as many as 12 respondents (60%) is the most common relation in incomplete toothless jaw patients at FKG Unpad RSGM. Keywords: Edentulous jaw, maxillomandibular relation classification

Construction of the 276 and 312 ha reclamation on the Holocene marine clay deposit in Jakarta Bay is on-going. Settlement has been measured during the construction in order to satisfy the requirement of residual settlement. This paper briefly discusses limitation of accuracy of settlement prediction based on purely parameters derived from laboratory and in situ testing, in particular the Holocene marine clay. A reliable ‘observational’ method which makes full use of the monitoring data is described and estimates reliable residual settlement. More accurate settlement method is then also briefly described taken into account complex loading history. Finally, the factors, which are source of inaccurate settlement predictions and its implications, are included in the discussion.