Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

The evolution of consumers' demand for hotels under the public health crisis: opinion mining from online reviews

This research aims to grasp the evolution of consumer demand and improve the resilience of the hotel industry under the public health crisis (COVID-19). Online reviews of 7,679 hotels in 10 cities were collected from Ctrip, China's major online hotel platform. Then, we applied opinion mining and time evolution to mine the change in consumer demand before, during, and after the COVID-19 pandemic. Findings show that some consumer demands (e.g. epidemic safety) will change during the outbreak period. However, during the nonoutbreak period, users were more concerned about their own check-in experience (e.g. hotel facilities, front desk services). This article provides new ideas for identifying the dynamic value of online reviews. We suggest that businesses focus on ensuring hotel safety during the crisis period. The results contribute essential theoretical and practical significance to the hotel industry's crisis management during public health crises.

Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

Salt steps and sugar checks - Making arterial line use safer in our trust

Introduction: Arterial lines are used within our intensive care unit to allow invasive blood pressure monitoring and regular blood gas analysis. Inadvertent use of dextrose containing fluids in the flush have been associated with falsely high glucose readings. When these are acted on with insulin, it can cause devastating hypoglycaemic brain injury. There have been a number of deaths and other incidents relating to the wrong fluid being used in arterial line set up reported within the UK in recent years. In 2014 the AAGBI released a safety guideline on the use of arterial lines specifically to reduce to the risk of hypoglycaemic brain injury. Objective(s): Our objective was to ensure that 100% of arterial lines in use within Royal Victoria Hospital's intensive care unit were compliant with our trust policy on the management of arterial lines. Method(s): We audited our intensive care unit's compliance with our trust policy and found that we were 80% compliant. We formed a multi-disciplinary arterial line working group in order to tackle the problem. Our quality improvement project consisted of two main approaches: 1. To educate staff on how to manage arterial lines correctly. We divided the management of arterial lines into S.A.L.T steps (a 7 step bundle on "Setting up an Arterial Line Transducer") and SUGAR checks ( a series of red flag moments to prompt staff to review the patient prior to starting or increasing insulin administration).We developed educational posters for key areas in ICU and presented our findings at departmental meetings. 2. To change the system, in order to make it easier to do the right thing. We developed a Universal Adult Arterial Pack (UAAP) containing key components in the setup of an arterial line. This also included aide memoires for the S.A.L.T steps and SUGAR checks. In order to measure the effect of these changes, we: 1. Audited compliance on a regular basis. 2. Monitored serious bundle breaches ( for example no label, wrong fluid used) 3. Assessed usage of the UAAP. Result(s): 1. Bundle compliance improved during the first half of 2021, however then reduced in the second half with the number of serious bundle breaches increasing. This coincided with COVID surge 4 - associated with reduced nursing ratios and staff redeployment. 2. UAAP usage increased throughout the project, from an average of 6 to 9 per day. 86% of staff found the packs useful and 85% thought that they reduced the potential for error. Conclusion(s): The presence of a policy does not ensure that staff will know about it or adhere to it. Although we have not yet achieved our target of 100% compliance, we have seen evidence of how our project has the potential to do so in the near future. We aim to roll out our new e-learning module for staff education, manufacture our UAAP on a bigger scale, and disseminate the project to other departments within the trust.

Multi2Claim: Generating Scientific Claims from Multi-Choice Questions for Scientific Fact-Checking

In automated scientific fact-checking, machine learning models are trained to verify scientific claims given evidence. A major bottleneck of this task is the availability of large-scale training datasets on different domains, due to the required domain expertise for data annotation. However, multiple-choice question-answering datasets are readily available across many different domains, thanks to the modern online education and assessment systems. As one of the first steps towards addressing the fact-checking dataset scarcity problem in scientific domains, we propose a pipeline for automatically converting multiple-choice questions into fact-checking data, which we call Multi2Claim. By applying the proposed pipeline, we generated two large-scale datasets for scientific-fact-checking: Med-Fact and Gsci-Fact for the medical and general science domains, respectively. These two datasets are among the first examples of large-scale scientific-fact-checking datasets. We developed baseline models for the verdict prediction task using each dataset. Additionally, we demonstrated that the datasets could be used to improve performance measured by weighted F1 on existing fact-checking datasets such as SciFact, HEALTHVER, COVID-Fact, and CLIMATE-FEVER. In some cases, the improvement in performance was up to a 26% increase. The generated datasets are publicly available. © 2023 Association for Computational Linguistics.

New Paradigm: HR Professional Transformation in Manufacturing Company: Acces la Success

This study aimed to optimize the line managers performances in the human resources (HR) division in answering the role of the HR management function problem in Medan City Manufacturing Company. The novelty proposed is a concept of HR management called "Human Resources Professional Transformation". Specifically, this concept discussed the ability of HR division line managers to make adaptive changes to the company's business-oriented functional divisions with managerial competence, commitment, innovation capability, and readiness for changes towards work performance. The population of this research was the line manager of the HR division, totaling 185 respondents. The sampling technique used a probability sampling approach with simple random sampling through the slovin formula, totaling 126 respondents. The analytical tool used is structural equation software through the SmartPLS application program. The results showed that managerial competence, commitment, innovation capability had a positive and significant effect through the HR professional transformation on the performance of line managers in the HR division. Meanwhile, readiness for change has a positive and insignificant effect on the HR Professional Transformation. Readiness for change also has a positive and insignificant effect on the Line Managers Performances in the Human Resources Division through HR Professional Transformation. Based on the suitability test of the research model, it proved that the HR Professional Transformation can answer the problem of the role of the management function to improve the line managers performances in the HR division with managerial competence, commitment, innovation capability, and readiness for change of 0.907.

Perception of teachers towards on-line education with specific context to hospitality education in India

Background: On-line education in a way was a forced introduction in our education system in wake of COVID-19 pandemic. Teachers as well as students became a part of this shift in education delivery mostly by force and rather by choice. However, in the short run itself it was realised that while shifting to this new-medium has its own challenges it also comes with its own set of advantages. Background: This research paper attempts to study and analyse the perception of teachers in hospitality education towards on-line education. Objective of study is to identify the major challenges and benefits of hospitality education as perceived by faculty members. Methodology: Descriptive research design was employed. The study was conducted by administering a structured questionnaire among faculty members of various IHMs and analysis of data was done. Locale is pan-India reached through google questionnaire method with a sample size of 50 faculty members from different IHMs in the country. Data was analysed with the help of excel tools, bar diagrams and graph. Results: Research revealed that in spite of the sudden paradigm shift in the macro environment faculty members responded well to the challenge of optimising learning for students in an on-line mode. Initially 80% faculty members found this shift challenging but now 80 percent believe that blended learning is future. Assessments and sustaining interest of students however are major challenges with 82 and 84 percent of faculty members respectively agreeing to this being a major issue. Conclusion: Teachers perceive blended learning to be a norm in future. It is perceived that while it's very difficult to impart skill training in an on-line mode, for theoretical classes this could be a preferred mode.

Heterologous prime-boost viral vector vaccines for the treatment of a P1A-expressing BGL-1 glioblastoma model

Glioblastoma is an extremely aggressive and difficult cancer to treat, which may partly be due to its limited ability to induce T-cell responses. However, combining viral vector vaccines with other therapies to generate tumor-specific T cells may provide a meaningful benefit to patients. Here, we investigated whether heterologous prime-boost vaccination with chimpanzee-derived adenoviral vector ChAdOx1 and modified vaccinia Ankara (MVA) vaccines could generate therapeutically effective CD8+ T-cell responses against a model antigen P1A, a mouse homolog of human tumorassociated Melanoma Antigen GenE (MAGE)-type antigens, expressed by a BGL-1 mouse glioblastoma cell line. We demonstrated that heterologous prime-boost vaccination with ChAdOx1/MVA vaccines targeting P1A generated a high magnitude of CD8+ T cells specific for the P1A35-43 epitope presented by the MHC class I molecule H-2Ld . Prophylactic vaccination with ChAdOx1/MVA-P1A significantly prolonged the survival of syngeneic mice subcutaneously challenged with P1A-expressing BGL-1 tumors. Furthermore, different vaccination schedules significantly impact the magnitude of antigen-specific CD8+ T-cell responses and may impact protective efficacy. However, the substantial induction of myeloid-derived suppressor cells (MDSCs) by this tumor model presents a significant challenge in the therapeutic setting. Future work will investigate the efficacy of this vaccination strategy on intracranial P1A-expressing BGL-1 models.

SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse model

Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARSCoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1- induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer.

Teclistamab in combination with daratumumab and lenalidomide in multiple myeloma (MajesTEC-2 study)

Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.

The impact of the COVID-19 pandemic on medical education: adaptability and remote learning experience of the Peruvian American Medical Society

The COVID-19 pandemic had a significant impact on medical care and medical education in Peru. In response, the Peruvian American Medical Society (PAMS), a charitable medical organization based in the USA, pursued its medical and educational missions in Peru by adopting virtual learning technology. We developed closer collaborative relationships with several medical schools and the Peruvian Association of Medical Schools (ASPEFAM) while offering a faculty panel of twenty-four members to provide lectures and multidisciplinary webinars in Spanish. We conducted 19 webinars including COVID -19 and non-COVID-19 related topics that over the last two years attracted 14,489 participants from 23 countries. They were the foundation for twenty publications in Peruvian medical journals. Our clinical investigations competition was positively received as was our pilot project on research mentorship. The COVID -19 pandemic had a positive effect on the educational mission of PAMS in Peru.

Function and interaction of coronavirus ion channel proteins

Objective: COVID-19 has emerged as a significant global health crisis causing devastating effects on world population accounting for over 6 million deaths worldwide. Although acute RTI is the prevalent cause of morbidity, kidney outcomes centered on a spectrum of AKI have evolved over the course of the pandemic. Especially the emerging variants have posed a daunting challenge to the scientific communities, prompting an urging requirement for global contributions in understanding the viral dynamics. In addition to canonical genes, several subgroup- specific accessory genes are located between the S and E genes of coronaviruses regarding which little is known. Previous studies have shown that accessory proteins (aps) in viruses function as viroporins that regulate viral infection, propagation and egress [1]. In this study we attempted to characterize the function of aps of coronavirus variants as ion channels. Furthermore, we also probed the interaction of ap4 with the host system. Method(s): Serial passaging (selection pressure), growth kinetics, confocal imaging, genome sequence analysis and proteomics were performed in Huh-7, MRC5 cells and/or human monocyte derived macrophages. Potassium uptake assay was performed in a Saccharo myces cerevisiae strain, which lacks the potassium transporters trk1 and trk2. Ion conductivity experiments were performed in Xenopus laevis oocytes using Two Electrode Voltage Clamp (TEVC) method. Result(s): Serial passaging demonstrated the acquisition of several frameshift mutations in ORF4 resulting in C-terminally truncated protein versions (ap4 and ap4a) and indicate a strong selection pressure against retaining a complete ORF4 in vitro. Growth kinetics in primary cells illustrated a reduction of viral titers when the full-length ap4 was expressed compared to the C-terminally truncated protein ap4a. Confocal imaging showed that ap4 and ap4a are not exclusively located in a single cellular compartment. Potassium uptake assay in yeast and TEVC analyses in Xenopus oocytes showed that ap4 and ap4a act as a weak K+ selective ion channel. In addition, accessory proteins of other virus variants also elicited microampere range of currents. Conclusion(s): Our study provides the first evidence that ap4 and other accessory proteins of coronavirus variants act as viroporins. Future studies are aimed at demonstrating the role of ap4 during the viral life cycle by modulating ion homeostasis of host cell in vivo (interacting proteins obtained from proteomic studies) and thereby serve as a tool for potential drug target.

A Review on the analysis of Behavioral pattern of Students during pandemic COVID-19

The widespread of (covid-19) has become the major reason for many physical illnesses in addition to psychological encounters to the whole world. The psychological challenges brought in due to the Covid-19 pandemic have resulted in decrease in the learning curve of students to a very large extent risking the academic ability of students due to psychological/mental health. Hence it is a challenge to identify valid cues for disorientation in the learning ability of the student at the right time and to suggest necessary support and guidance. This paper aims to describe about the work done so far and analyzes the future challenges to be addressed based on the learning curve of a student and gives an insight of how a student can be identified to be psychologically disturbed. © 2023 IEEE.

Preliminary results from phase 2 of CC-92480- MM- 001: Mezigdomide plus dexamethasone in relapsed/refractory multiple myeloma (RRMM)

In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.

Newborn-onset chronic urticaria as the first manifestation of NLRP3 mosaicism

Objectives: A 7-month-old boy presented with generalized urticaria since the first week of life, without any other clinical manifestation. Cow's milk allergy was ruled out. His development was normal for his age. Maternal history was significant for COVID-19 infection in the third trimester of pregnancy with mild symptoms. Family history was significant for dermatographism in a maternal uncle. Hives were migratory with no single lesion persisting more than 24 h. There were no recognizable triggers and only relieved for 1-2 days after each vaccination. Patient was treated with optimal doses of antihistamines without improvement. Method(s): Laboratory tests and further studies were performed Results: Laboratory tests were normal including complete blood testing, circulating autoantibodies and infectious studies. C-reactive protein level and erythrocyte sedimentation rate were elevated. Due to chronic urticaria of newborn onset unresponsive to antihistamines a monogenic autoinflammatory disease was suspected. A targeted gene panel covering causative genes revealed the unreported p.Gly307Ala variant in the NLRP3 gene with a variant allele frequency (VAF) of 3% compatible with gene mosaicism. NLRP3 variant was classified as "likely pathogenic" based on its location, where a different variant has been reported as causing a severe form of cryopyrin-associated periodic syndromes (CAPS), and bioinformatic analyses. As expected, the variant was absent in patient's parents supporting for its de novo nature. Vision and hearing exams were normal. Treatment with canakinumab will start soon. Discussion(s): CAPS are dominantly-inherited autoinflammatory diseases caused by gain-of-function NLRP3 variants. These variants are often germline, but in some reported cases the variants are postzygotic causing gene mosaicism as in the patient here described. We believe that the mild presentation in our patient, despite having a likely pathogenic variant, may be explained by the low VAF. The genetic diagnosis in our patient allowed early initiation of anti-IL-1 treatment, which probably will prevent the development of other CAPS manifestations.

A retrospective observational study of CAR T-cell therapy outcomes-Experience from MSE Foundation Trust

The most common non-Hodgkin's lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma that can be cured with standard frontline chemo-immunotherapy in 60%-70% of patients but with historically poor outcomes for relapsed/refractory disease. Patients with relapsed DLBCL after autologous stem cell transplant (ASCT) or with chemotherapy-refractory disease have a particularly dismal prognosis, with a median overall survival (OS) of only 6 months. Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma, with multiple FDA approved CAR T products now commercially available in many developed world including European countries. Ongoing studies seek to move CAR T cells to earlier lines of therapy and to characterise the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukaemias. Other areas of active research address CAR T in combination with other lymphoma-directed therapies, and mechanisms of CAR T resistance. We conducted a retrospective observational study assessing the outcomes of patients referred to our tertiary centre, University College London hospital NHS foundation Trust (UCLH) from January 2018 to December 2022, over a 48-month period. We collected data including patients' demographics, types of lymphomas, prior lines of therapies including stem cell transplantation, bridging therapies as appropriate, complications and overall response rate. We also analysed the communication between teams during the challenging period of the COVID-19 pandemic.

Gene Editing/Gene Therapies: CHALLENGE TO DEVELOP GMP COMPLIANT MANUFACTURING PROCESS FOR COXSACKIE VIRUS TYPE B3

Background & Aim: Gene therapies has become recognized for its remarkable clinical benefits in a variety of medical applications, in particular recent approval of an Ad vector-based COVID-19 vaccines have attracted recent global attention. Here, we present key considerations for GMP compliant process development for Coxsackie virus type B3 (CVB3), an oncolytic virus designed for clinical trial in triple-negative breast cancer. Methods, Results & Conclusion(s): CVB3 is a non-enveloped, linear single-strand RNA virus with a size of approximately 27-33 um in diameter. From the initial type using the zonal rotor centrifuge to the advanced type using the tangential flow filtration system and ion chromatograph, we considered the points of the design concept in constructing the manufacturing process. The final design system is constructed as a closed and single-use manufacturing system in which all processes from upstream large-scale cell culture to downstream target purification and concentration steps. In brief, HEK293 cell suspension extended in 3L serum-free medium infected with CVB3, up to 3.6 times 10 to 7 of TCID50 /mL before going to downstream steps, made total 150 mL of final products as 8.43 times 10 to 7 of TCID50/mL concentration. Although further quality control challenges remain that is removal of product-related impurities such as human cellular proteins and residual DNA/RNA to increase virus purity, this concept is effectively applicable even for other types of viruses as GMP manufacturing processes, and would be also important for technology transfer to future commercial production.Copyright © 2023 International Society for Cell & Gene Therapy

The evaluation of practical learning instruction management and student satisfaction with the "photocolorimetric methodology platform for measuring egg yolk color" during the COVID-19 pandemic situation

Online teaching management has been widely used during the COVID-19 pandemic situation and it has a direct impact on practical teaching management because students do not have access to equipment, chemicals, and tools. This study's purpose is to evaluate practical learning instruction management and student satisfaction with "photocolorimetric methodology platform for measuring egg yolk color" during the COVID-19 pandemic. This study compared the student satisfaction and effectiveness of a learning instruction platform for measuring egg yolk color using a laboratory machine and an online teaching management platform using photocolorimetric methodology. The results of this experiment revealed that the two platforms evaluated yolk colors L*, a*, and b* similarly (P > 0.05). Furthermore, the students were satisfied with the learning instruction with the photocolorimetric methodology platform for measuring egg yolk color at 4.76 points or the most level.

Graph Neural Network Models for Chemical Compound Activeness Prediction For COVID-19 Drugs Discovery using Lipinski's Descriptors

In this study, we implemented graph neural network (GNN) methods to forecast in vitro inhibitory bioactivity or pharmacological concentration of chemical compounds against severe acute respiratory syndrome (SARS) coronaviruses from the graph representation amongst the compounds (i.e., nodes) and their respective features(i.e., node features) obtained by RDKit tool from their respectively SMILES (Simplified MolecularInput Line-Entry System), and we compared GNN models by experiments with our graph data of 375 nodes with 44,475 edges or links. This was done in response to the severe and significant consequences of the ongoing Coronavirus disease 2019 (COVID-19) disease. As a result, we discovered that implemented models, simple graph convolution (SGC), and graph convolution network (GCN) performed significantly well with comparable performance. © 2022 IEEE.

A survival genome-wide association study to identify variants associated with COVID-19 risk of death

Background/Objectives: SARS-CoV-2 infection clinical manifestations hugely vary among patients, ranging from no symptoms, to life-threatening conditions. This variability is also due to host genetics: COVID-19 Host Genetics Initiative identified six loci associated with COVID-19 severity in a previous case-control genome-wide association study. A different approach to investigate the genetics of COVID-19 severity is looking for variants associated with mortality, e.g. by analyzing the association between genotypes and time-to-event data. Method(s): Here we perform a case-only genome-wide survival analysis, of 1,777 COVID-19 patients from the GEN-COVID cohort, 60 days after infection/hospitalization. Case-only studies has the advantage of eliminating selection biases and confounding related to control subjects. Patients were genotyped using Illumina Infinium Global Screening Arrays. PLINK software was used for data quality check and principal component analysis. GeneAbel R package was used for survival analysis and age, sex and the first four principal components were used as covariates in the Cox proportional hazard model. Result(s): We found four variants associated with COVID-19 patient survival at a nominal P < 1.0 x 10-6. Their minor alleles were associated with a higher mortality risk (i.e. hazard ratios (HR)>1). In detail, we observed: HR=1.03 for rs28416079 on chromosome 19 (P=1.34 x 10-7), HR=1.15 for rs72815354 on chromosome 10 (P=1.66 x 10-7), HR=2.12 for rs2785631 on chromosome 1 (P=5.14 x 10-7), and HR=2.27 for rs2785631 on chromosome 5 (P=6.65 x 10-7). Conclusion(s): The present results suggest that germline variants are COVID-19 prognostic factors. Replication in the remaining HGI COVID-19 patient cohort (EGAS00001005304) is ongoing at the time of submission.