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

Dried Blood Spot Analyses for the Diagnosis of Anti-cytokine Autoantibodies

Background: High-titer neutralizing anti-cytokine autoantibodies have been shown to be involved in several acquired diseases, including pulmonary alveolar proteinosis, cryptococcal meningitis, and disseminated/extrapulmonary Nocardia infections (anti-GM-CSF autoantibodies), disseminated mycobacterial disease (anti-IFN-gamma autoantibodies), and some cases of severe COVID-19 infection (anti-type 1 interferons). Currently, patient blood samples are shipped via courier and require temperaturecontrolled conditions for transfer. This method is expensive and requires patients to have access to medical personnel to draw the blood. However, the well-established technique of collecting blood on a paper card as a dried blood spot (DBS) for diagnosis offers a point of care alternative which can be performed with a simple finger prick. This method is less invasive, cheaper, and allows for easy transport of patient samples. Method(s): 30 uL of whole blood from patients was blotted on filter paper and stored at 4C until use. The filter paper was hole punched and each punched spot was eluted with 150 uL of a 0.05% Tween PBS solution at room temperature overnight. The eluate was screened for anti-cytokine autoantibodies using a particle-based approach. Patient plasma was also screened in conjunction for comparison. Result(s): We confirmed the presence of autoantibodies in the DBS eluate from 4 previously diagnosed patients with anti-GM-CSF autoantibodies and 2 patients with anti-IFN-gamma autoantibodies. Functional studies showed the DBS eluate from a patient with anti-GM-CSF autoantibodies was able to block GM-CSF-induced STAT-5 phosphorylation in normal PBMC. As a proof of concept and to increase the number of patients evaluated, we also confirmed the presence of anti-cytokine autoantibodies using dried plasma eluate from 9 patients with known anti-GM-CSF autoantibodies and 9 patients with anti-IFN-gamma autoantibodies. Levels detected in DBS analyses were comparable to the levels found in plasma from the same patients not subjected to blotting and elution. Temperature studies showed that the autoantibodies were detected at similar levels when stored at 4C, 25C, and 40C for a week. Conclusion(s): The diagnosis of pathogenic anti-cytokine autoantibodies should be considered in the context of unusual or adult-onset infections, and screening for this diagnosis can be performed with dried blood spot testing.Copyright © 2023 Elsevier Inc.

Pharmaceutical consultations associated with dematerialized drug dispensation in exceptional health context: Proof of concept and perspectives

During the exceptional health crisis caused by the COVID-19 pandemic, a program of telepharmacy consultations, associated with dematerialized dispensing of treatments with delivery to the home or drive, was set up by the pharmacy department of our institution. The system has concerned 25 % of the ambulatory dispensations of the PUI over the period of the first containment, and allowed 351 patients to avoid coming to the hospital pharmacy, while maintaining a quality pharmaceutical service. Although certain limitations were identified, such as access to technology or the increase in dedicated pharmaceutical time, this system, appreciated by patients and physicians, has enabled a privileged relationship to be maintained with many patients. Expert clinical pharmacists now also perform PT, and treatments are now sent to patient's pharmacies.Copyright © 2022 Elsevier Masson SAS

ID: 218414 Queen Mary University London Postgraduate Certification in Neuromodulation- Accreditation in Neuromodulation

Introduction: There is a distinct unmet need in structured, curriculum based, unbiased education in neuromodulation. Current teaching is through sporadic industry workshops, cadaver courses and peer proctorship. The COVID pandemic has created a unique opportunity where online platforms have enabled education to be delivered remotely in both synchronous and asynchronously. The William Harvey Research Institute, Queen Mary University, London, UK have initiated University based accreditation- Post Graduate Certificate in neuromodulation (PGCert) that provides candidate a qualification in one academic year through part-time study. Method(s): The program underwent rigorous staged university approval process (figure 1). To ensure market feasibility, two short proof of concept CPD programs "Executive Education in Neuromodulation (EEPIN)" were delivered in 2021. These courses attracted 87 candidates across Australia, Singapore, India, Germany, Poland, Czech Republic, Ireland, and UK. The faculty includes key opinion leaders that will deliver the program ensuring the candidates gain academic background and specialist skills to understand safe practice of neuromodulation. The PGCert advisory board has been established to ensure strict governance in terms of content and unbiased delivery confirming ACCME guidance. In order to obtain PGCert, candidates are required to complete 4 x 15 credit modules (60 credits). The four modules include Anatomy & Neurophysiology;Patient care and Procedurals skills;Devices and available technology;Intrathecal drug delivery for cancer and non-cancer pain. The modular nature of the program is designed to provide cumulative knowledge, from basic science to clinical application in line with the best available evidence. The modules comprise nine lectures, spreading over three consecutive days, followed by a written assignment with 40 direct contact hours in each module. The webpage can be accessed at Results: The anonymous data from EEPIN reported on Likert scale 1-5: Objectives defined 30.6% - 4 and 69.4% -5;Relevance of topics 10.2%- 4 and 89.8% -5;Content of presentations 22.4%- 4 and 77.6% -5;Organization 24.5% -4 and 69.4% -5;Candidate faculty interaction 14.3% -4 and 81.6% -5. 97% of the EEPIN candidates recommended the program to others whilst 81.8% expressed their strong interest to enroll for university-based post graduate qualification if offered. Conclusion(s): This PGcert Neuromodulation is a unique, university accredited program that provides qualification in neuromodulation with access to a flexible online e-learning platform to discuss and exchange ideas, share knowledge in candidate's own time. This will support the ongoing need for formal curriculum-based education in neuromodulation. Disclosure: Kavita Poply, PHD: None, Phillippe Rigoard: None, Jan Kallewaard, MD/PhD: None, FRANK J.P.M. HUYGEN, MD PhD: ABBOTT: Speakers Bureau:, Saluda: Consulting Fee:, Boston Scientific: Consulting Fee:, Grunenthal: Speakers Bureau:, Pfizer: Speakers Bureau:, Ashish Gulve, FRCA, FFPMRCA, FFPMCAI, DPMed, FCARCSI, MD, MBBS: None, Ganesan Baranidharan, FRCA: None, Sam ELDABE, MD, FRCA, FFPMRCA: Medtronic: Consulting Fee:, Medtronic: Contracted Research:, Mainstay Medical: Consulting Fee:, Saluda Medical: Consulting Fee:, Boston Scientific: Contracted Research:, Saluda Medical: Contracted Research:, James Fitzgerald, MA,PhD: St Jude Medical: Consultant: Self, Medtronic: Consulting Fee:, UCB: Contracted Research:, Merck: Contracted Research:, Serge Nikolic, MD: None, Stana Bojanic, BSc MBBS FRCS (SN): Abbott: Contracted Research:, Habib Ellamushi: None, Paresh Doshi, MS MCh: None, Preeti Doshi, MBBS, MD, FRCA: None, Babita Ghai, MBBS, MD, DNB: None, Marc Russo, MD: Presidio Medical: Ownership Interest:, Saluda Medical: Ownership Interest:, Boston Scientific: Contracted Research: Self, Mainstay Medical: Contracted Research: Self, Medtronic: Contracted Research: Self, Nevro: Contracted Research: Self, Saluda Medical: Contracted Research: Self, Presidio Medical: Contracted Research: Self, Freedom Ne ro: Ownership Interest - Own Stocks: Self, Lungpacer: Ownership Interest - Own Stocks: Self, SPR Therapeutics: Ownership Interest - Own Stocks: Self, Lawrence Poree, MD,MPH,PHD: Medtronic: Consulting Fee: Self, Saluda Medical: Contracted Research: Family, Nalu Medical: Contracted Research: Family, Gimer Medical: Consulting Fee: Self, Nalu Medical: Consulting Fee: Self, Saluda Medical: Consulting Fee: Self, Nalu: Ownership Interest:, Saluda Inc: Ownership Interest:, Alia Ahmad: None, Alaa Abd Sayed, MD: Medtronic, Abbott, SPR and StimWave: Consulting Fee:, Salim Hayek, MD,PhD: None, CHRISTOPHER GILLIGAN, MD MBA: Persica: Consulting Fee: Self, Saluda: Consulting Fee: Self, Mainstay Medical: Contracted Research: Self, Sollis Therapeutics: Contracted Research: Self, Iliad Lifesciences, LLC: Owner: individuals with legal ownership in a company:, Vivek Mehta: NoneCopyright © 2023

Framing blockchain-integrated digital twins for emergent healthcare management at local and city levels: A proof of concept

It has been witnessed that digital technology has the potential to improve the efficiency of emergent healthcare management in COVID-19, which however has not been widely adopted due to unclear definition and configuration. This research aims to propose a proof of concept of digital twins for emergent healthcare management through configuring the cyber and functional interdependencies of healthcare systems at local and city levels. Critical interdependencies of healthcare systems have been firstly identified at both levels, then the information and associated cyber and functional interdependencies embedded in seven critical hospital information systems (HISs) have been identified and mapped. The proposed conceptual digital twin-based approach has been then developed for information coordination amongst these critical HISs at both local and city levels based on permissioned blockchain to (1) integrate and manage the information from seven critical HISs, and further (2) predict the demands of medical resources according to patient trajectory. A case study has been finally conducted at three hospitals in London during the COVID-19 period, and the results showed that the developed framework of blockchain-integrated digital twins is a promising way to provide more accurate and timely procurement information to decision-makers and can effectively support evidence-based decisions on medical resource allocation in the pandemic. © 2023 ICE Publishing: All rights reserved.

Forecasting Residential Energy Consumption: A Case Study for Greece

Residential energy consumption forecasting has immense value in energy efficiency and sustainability. In the current work we tried to forecast energy consumption on residences in Athens, Greece. As a proof of concept, smart sensors were installed into two residences that recorded energy consumption, as well as indoors environmental variables (humidity and temperature). It should be noted that the data set was collected during the COVID-19 pandemic. Moreover, we integrated weather data from a public weather site. A dashboard was designed to facilitate monitoring of the sensors' data. We addressed various issues related to data quality and then we tried different models to forecast daily energy consumption. In particular, LSTM neural networks, ARIMA, SARIMA, SARIMAX and Facebook (FB) Prophet were tested. Overall SARIMA and FB Prophet had the best performance. Copyright © 2023 by SCITEPRESS - Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

Smartwatch-based ecological momentary assessments for occupant wellness and privacy in buildings

This paper describes the adaptation of an open-source ecological momentary assessment smartwatch platform with three sets of micro-survey wellness-related questions focused on i) infectious disease (COVID-19) risk perception, ii) privacy and distraction in an office context, and iii) triggers of various movement-related behaviors in buildings. This platform was previously used to collect data for thermal comfort, and this work extends its use to other domains. Several research participants took part in a proof-of-concept experiment by wearing a smartwatch to collect their micro-survey question preferences and perception responses for two of the question sets. Participants were also asked to install an indoor localization app on their phone to detect where precisely in the building they completed the survey. The experiment identified occupant information such as the tendencies for the research participants to prefer privacy in certain spaces and the difference between infectious disease risk perception in naturally versus mechanically ventilated spaces. © 2022 17th International Conference on Indoor Air Quality and Climate, INDOOR AIR 2022. All rights reserved.

Targeting virus-induced vulnerabilities using synthetic lethality as a new class of host-based antivirals

RNA viruses are the major class of human pathogens responsible for many global health crises, including the COVID-19 pandemic. However, the current repertoire of U.S. Food and Drug Administration (FDA)-approved antivirals is limited to only nine out of the known 214 human-infecting RNAviruses, and almost all these antivirals target viral proteins. Traditional antiviral development generally proceeds in a virus-centric fashion, and successful therapies tend to be only marginally effective as monotherapies, due to dose-limiting toxicity and the rapid emergence of drug resistance. Host-based antivirals have potential to alleviate these shortcomings, but do not typically discriminate between infected and uninfected cells, thus eliciting unintended effects. In infected cells where host proteins are repurposed by a virus, normal host protein functions are compromised;a situation analogous to a loss-of-function mutation, and cells harboring the hypomorph have unique vulnerabilities. As well-established in model systems and in cancer therapeutics, these uniquely vulnerable cells can be selectively killed by a drug that inhibits a functionally redundant protein. This is the foundation of synthetic lethality (SL). To test if viral induced vulnerabilities can be exploited for viral therapeutics, we selectively targeted synthetic lethal partners of GBF1, a Golgi membrane protein and a critical host factor for many RNA viruses including poliovirus, Coxsackievirus, Dengue, Hepatitis C and E virus, and Ebola virus. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. A genome-wide chemogenomic CRISPR screen identified synthetic lethal partners of GBF1 and revealed ARF1 as the top hit. Disruption of ARF1, selectively killed cells that synthesize poliovirus 3A alone or in the context of a poliovirus replicon. Combining 3A expression with sub-lethal amounts of GCA - a specific inhibitor of GBF1 further exacerbated the GBF1-ARF1 SL effect. Together our data demonstrate proof of concept for host-based SL targeting of viral infection. We are currently testing all druggable synthetic lethal partners of GBF1 from our chemogenomic CRISPR-screen, in the context of dengue virus infection for their abilities to selectively kill infected cells and inhibit viral replication and infection. Importantly, these SL gene partners of viral-induced hypomorphs only become essential in infected cells and in principle, targeting them will have minimal effects on uninfected cells. Our strategy to target SL interactions of the viral-induced hypomorph has the potential to change the current paradigm for host-based therapeutics that can lead to broad-spectrum antivirals and can be applied to other intracellular pathogens. This work is supported by National Institutes of Health grants R01 GM112108 and P41 GM109824, R21 AI151344 and foundation grant FDN-167277 from the Canadian Institutes of Health Research.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Johan Sverdrup: the Final Lap of a True North Sea Giant

The second phase of Johan Sverdrup came on stream in December 2022. This paper focuses on the execution of Johan Sverdrup phase 2 and describes the assessments and investments for improved oil recovery (IOR) from one of the largest oil fields in Norway. The Johan Sverdrup field development has been called Equinor's ‘digital flagship', and this paper includes the proof of concept for the digital initiatives after more than three years of operation. Despite the Covid-19 pandemic Johan Sverdrup phase 2 has been able to deliver on schedule, under budget, and with an excellent safety record. The paper includes experiences from the concept development and engineering phase to the global contracting strategy, through the construction on multiple building sites in Norway and globally, and until the end of the completion phase offshore Norway. Johan Sverdrup is the third largest oil field on the Norwegian Continental Shelf (NCS), and with recoverable reserves estimated at 2.7 billion barrels of oil equivalents, has the resources to be a North Sea Giant. Start-up of the Johan Sverdrup phase 2 extends and accelerates oil and gas production from the NCS for another five decades. This paper aims to highlight what it took to make Johan Sverdrup a true North Sea Giant, fit for the 21st century: a safe and successful execution of a mega-project, with next-generation facilities adapted to a more digital way of working, with an ambition to profitably recover more than 70% of the resources, while limiting carbon emissions from production to a minimum. In many ways the Johan Sverdrup development has set a new standard for project execution in Equinor. The impact of different variables made during the execution of the project, such as the Covid-19 pandemic, market effects, procurement strategies, value improvement initiatives, execution performance and reservoir characteristics is addressed, as well as describing assessments and investments for improved oil recovery (IOR). Data acquisition, Permanent Reservoir Monitoring (PRM), fibre-optic monitoring of wells, innovative technologies, and digitalization, as well as new ways of working are included. Equinor ´s digital strategy was established in 2017, and Johan Sverdrup was highlighted as a digital flagship at that time and a frontrunner in applying digital solutions to improve safety and efficiency from the development to the operational phase. What has been implemented so far together with experiences will be shared. © 2023, Offshore Technology Conference.

Using Synthetic Biology methods to construct a functional estrogen biosensor based on split Nanoluciferase activity

The presence of estrogenic compounds (endocrine-disruptors, EDCs) in the water supply raises concerns about human and aquatic health. Current methods for detecting estrogen contamination require expensive, time-consuming techniques such as liquid chromatography-mass spectrometry and high-performance liquid chromatography. Previously reported estrogen biosensors required multiple cloning and transformation steps for successful detection in bacteria. Synthetic biology allows for the construction of genetic devises composed of DNA sequences modified to be interchangeable and provide novel functions. New tools and devices are constantly needed to enhance the already extensive list of novel genetic parts. Our approach to the design of an estrogen responsive element uses methodology developed in the Wells lab (Elledge et al, 2021) to detect SARS-CoV-2 antibodies. This methodology takes advantage of the split Nanoluciferase (spLUC) protein divided into two functional domains (designated SmBit and LgBit). Based on rational engineering design we express dimerization dependent LgBit and SmBit fused to the Estrogen Receptor alpha protein (ERalpha) in bacteria cells. These two monomeric proteins will dimerize in the presence of estrogen, reconstitute the split luciferase enzyme and reestablish enzyme activity. Cells can be lysed, and luminescence detected to quantify estrogen present in the sample. We present here the construction strategy and proof of concept data demonstrating the efficiency of this dual-functional biosensor and its effectiveness for detection of estrogenic compounds in contaminated water. NSF-REU-1852150, REU Site: A multisite REU in Synthetic Biology, 2019.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Extracellular vesicles as delivery vectors to enhance killing of bacteria and viruses by airway-recruited human neutrophils

Background: Polymorphonuclear neutrophils (PMNs) recruited to the airway lumen in cystic fibrosis (CF) undergo a rapid transcriptional program, resulting in exocytosis of granules and inhibition of bacterial killing. As a result, chronic infection, feed-forward inflammation, and structural tissue damage occur. Because CF airway PMNs are also highly pinocytic, we hypothesized that we could deliver protein- and ribonucleic acid (RNA)-based therapies to modulate their function to benefit patients. We elected to use extracellular vesicles (EVs) as a delivery vector because they are highly customizable, and airway PMNs have previously been shown by our group to process and use their cargo efficiently [1]. Furthermore, our prior work on CF airway PMNs [2] led to identification of the long noncoding RNA MALAT1, the transcription factor Ehf, and the histone deacetylase/long-chain fatty deacylase HDAC11 as potential targets to modulate CF airway PMN dysfunction. Method(s): H441 human club epithelial cells were chosen for EV production because they efficiently communicate with lung-recruited primary human PMNs [1]. Relevant constructs were cloned into an expression plasmid downstream of a constitutive cytomegalovirus or U6 promoter with an additional puromycin selection cassette. EVs were generated in serumdepleted media and purified by differential centrifugation. Quality and concentration of EVs was determined by electron microscopy and nanoparticle tracking analysis and cargo content by western blot (protein) or qualitative reverse transcription polymerase chain reaction (RNA). Enhanced green fluorescent protein and messenger ribonucleic acid (mRNA) were used as controls. To test delivery to primary human PMNs, generated EVs were applied in the apical fluid of an airway transmigration model [2]. PMN activation was assessed by flow cytometry, and bacterial (PA01 and Staphylococcus aureus 8325-4) killing and viral (influenza Avirus [IAV] H1N1/PR/8/34;SARS-CoV-2/Washington) clearance assays were conducted. Result(s): To package protein, we used EV-loading motifs such as the tetraspanin CD63, Basp1 amino acids 1-9, and the palmitoylation signal of Lyn kinase. To load mRNA, a C'D box motif recognized by the RNA-binding protein L7Ae was included in the 3' untranslated region of the expressed RNA, and CD63-L7Ae was co-expressed. Airway-recruited PMNs treated with EVs containing small interfering RNAs against MALAT1 or HDAC11 showed greater ability to clear bacteria. Conversely, PMNs treated with constructs encasing MALAT1 or HDAC11 efficiently cleared IAV and SARSCoV- 2. PMNs expressing Ehf showed greater clearance of bacteria and viruses. Conclusion(s): Our findings suggest mutually exclusive roles of MALAT-1 and HDAC11 in regulating bacterial and viral clearance by airway-recruited PMNs. Expression of Ehf in airway PMNs may be a pathogen-agnostic approach to enhancing clearance by airway-recruited PMNs. Overall, our study brings proof-of-concept data for therapeutic RNA/protein transfer to airway-recruited PMNs in CF and other lung diseases and for use of EVs as a promising method for cargo delivery to these cells. It is our expectation that, by treating the immune compartment of CF airway disease, pathogentherapies, such as antibiotics will be more effective, and epithelial-targeted therapies, such as CFTR modulators, will have greater penetrance into the cell types of interest.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Prognosis Score for Overall Survival with CAR-T Therapy in Aggressive Lymphoma

Background: Despite the transformative potential of chimeric antigen receptor T (CAR-T) therapy, more tools to assist with identifying patients with increased likelihood of benefitting from this therapy will be helpful, particularly given the logistical complexity and socio-economic demands for CAR-T relative to other therapies. Health care resource restriction during the COVID-19 pandemic highlights the need for these tools. We present a simple survival score that uses 3 readily available clinical labs: platelet (plt), absolute lymphocyte count (ALC), and Lactate dehydrogenase (LDH), to predict the risk of dying within 6 months of CAR-T therapy in patients with aggressive lymphoma. Method(s): We conducted a retrospective chart review of patients with aggressive non-Hodgkin lymphoma (NHL) who received FDA-approved CAR-T between Jan 2018 to Jan 2022 at Mayo Clinic Rochester.(Table Presented)Results: Among a total of 110 pts who received CAR-T, 27 (25%) pts died within the first 6 months post CAR-T infusion (OS <= 6 months). Disease progression was the main cause of death (18/25, 72%), followed by infection (4/25, 16%), CAR-T related (HLH/MAS, 2/25, 8%), second primary malignancy (1/25, 4%) and unknown (2/25, 8%).Baseline demographics were comparable between the OS>6months and <=6months groups (Table 1). Patients' ECOG, Karnofsky performance status and 11 labs at the time of evaluation for CAR-T therapy (initial eligibility assessment, prior to leukapheresis) were compared between those who died from any cause within 6 months of CAR-T infusion and those who did not. Hemoglobin, plt, ALC, absolute monocyte count, CRP, ferritin, and LDH were selected as clinically and/or statistically significant variables for multivariate testing. Multivariate regression with boot-strap testing identified plt, ALC, and LDH as the most predictive variables with 80.9+/-11.7% accuracy for predicting death within 6 months of CAR-T infusion. Patients were scored 0-3 using these 3 labs, with 1 point assigned for plt <= 100 X109/L, ALC <= 0.4 X109/L, or LDH > 222 U/L (upper limit of normal). OS by this survival score is shown in Figure 1.(Figure Presented)Discussion: Due to the curative potential of CAR-T, patients with broader characteristics than those treated on registration studies have been treated in standard of care practice. While an estimated 5%-10% risk of CAR-T associated deaths in the first 3 months is seen across all patients in clinical trials, predictors for early death after CAR-T in real-world patient populations can provide additional context for pts and providers when selecting treatment. This survival score is important proof of concept that a simple model using readily accessible clinical labs at the time of CAR-T evaluation could provide additional context to help with additional clinical decision-making. Multicenter prospective studies will help define and validate the definitive survival scoring system.Copyright © 2023 American Society for Transplantation and Cellular Therapy

Using ex vivo bioengineered lungs to model pathologies and screening therapeutics

Introduction: More than 8 million lives are claimed annually by various respiratory diseases including lung cancer. While therapeutics is the first line of defence, treatment failure always remains challenging and research studies face a lag of transition from preclinical to clinical phase. This is partly due to the inadequate representation of the preclinical models in clinical trials. In this proof-of-concept study, we sought to use an ex-vivo model to identify lung pathologies and therapeutically screen them in a rodent model. Method(s): Briefly, the heart-lung tissues were extracted and decellularized using a detergent-based decellularization technique. Subsequently, lungs were seeded and cultured (6-10 days) with human cell lines: BEAS-2B, A549, and Calu3, demonstrating healthy lung, cancerous state, and congenital pathologies (cystic fibrosis), respectively. By altering the cultural conditions and exploiting the unique characteristics of these cell lines, we were able to model a variety of novel pathological models in ex vivo, such as advanced-stage solid tumours and the primary phase of infection via SARS-COV2. We also validated the above-mentioned observations by histology and immunofluorescence staining. Another novel part of our study includes a qualitative screening of efficacy and impact of important Therapeutics (anti-neoplastic)- Cisplatin and Wogonin, in our cancer models. Result(s): Using A549 and BEAS-2B cells, we were able to model different stages of Non-small cell lung cancer, qualitatively validated the resemblance to clinical samples and monitor the impact of different therapeutics on these models. The qualitative assessment also demonstrated different levels of cell death depending on the efficacy of the drugs. Contribution to research : Collectively this study demonstrates the remarkable versatility and strength of the ex vivo model in representing important lung pathologies and screening therapeutics in the preclinical phase.

Development of Elbow-Wrist Telerehabilitation System - An Affordable, Available, Accessible, and Acceptable (4As) System

The application of telerehabilitation system has gained popularity and acceptance recently due to the restrictions in controlling the COVID-19 pandemic. This paper described the development of an elbow-wrist telerehabilitation system that complement the disrupted routine rehabilitation session. The developed system consists of a wearable exoskeleton system that assist in rehabilitation of the elbow and wrist joints for individuals with neurological conditions such as Parkinson's and Spinal Cord Injuries that affects movements of the upper extremities. The two modes of operation available enables the adoption of the 5G technology in the near future. This system also potentially fulfills the requirement of Accessibility, Availability, Affordability, and Acceptability (4As) of Telerehabilitation System in Malaysia. Overall development cost of the system is approximately MYR 500. The system enable rehabilitation to be performed at home-setting with a cloud-based monitoring system that will provide long-term monitoring for clinician's assessment. The project provides a proof-of-concept of such system in the Malaysian context.Clinical Relevance - This work demonstrated the proof-of concept of a 4A system is applicable in the Malaysian context. © 2022 IEEE.

Is Treating Post-Menopausal Women With Symptomatic Hand Osteoarthritis With Hormone Replacement Therapy Feasible?: Results From The Hope-E Randomised, Placebo-Controlled Feasibility Study

Purpose: Hand osteoarthritis (OA) is more common in women. Hand OA incidence increases further in females around the age of 50, the typical age of menopause. Estrogen-deficient states are associated with increased musculoskeletal pain and inflammation and with increased rates of symptomatic OA. Estrogen replacement and selective estrogen receptor modulators (SERMs) can improve pain and structure in some pre-clinical models of OA associated with estrogen loss, and in exploratory analysis from hormone replacement therapy (HRT) trials. However, no randomised clinical trials (RCTs) of HRT had been performed in symptomatic OA populations, specifically hand OA. By carrying out a RCT feasibility study of a form of HRT (conjugated estrogens (CE)-bazedoxifene) in post-menopausal women with painful hand OA, we set out to determine the feasibility and acceptability of this. We also aimed to generate proof-of concept data on likely outcomes, calculate a sample size and refine methods for a full trial. Method(s): We recruited females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and >=2 painful hand joints across three primary/secondary care sites and from the community. Medical exclusions included those typical for clinical HRT use. Design was parallel group, double-blind 1:1 randomisation of CE-bazedoxifene or placebo, taken orally once daily for 24 weeks, then tapering for 4 weeks before study end at Week 28. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Adverse events (AEs) were collected. Secondary clinical outcomes included the anticipated primary outcome in a full trial of mean hand pain over 14 days prior to each visit, scored on a 0-10 numerical rating scale (NRS) where 10 is worst pain possible, as well as hand function, appearance and menopause symptoms. Progression criteria to a full RCT were: (i) recruitment >=30 participants across all sites in 18 months (or proportionate to time open);(ii) a drop-out rate of <=30% of randomised individuals;and (iii) acceptability to the majority of participants, including acceptable AE rates. All clinical outcomes were analysed on an intention-to-treat basis. Though not powered to detect a treatment difference, change and treatment effects (the difference in the outcome between the two groups) were indicated with 95% CIs, with all models adjusted for clinical subtype of painful hand joint, study site, and baseline values. The sample size for a full trial was estimated using the standard deviation (SD) of week 24 mean hand pain. Result(s): Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. From May 2019 to December 2020, 434 enquiries/referrals were received. Of 96 telephone pre-screens, 35 individuals were potentially eligible and of these, 33 gave consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed, with the most common reason being not wanting to take HRT. 28/35 (80% (95%CI 63%,92%)) eligible participants were randomised to study medication. All 28 participants completed all follow-ups with high compliance (100% active, 13/14[93%] placebo) and outcome measure completeness (100%, mean hand pain). All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs occurred. Participants/investigators were well blinded (participant blinding index 0.50[95%CI 0.25 to 0.75]). All three prespecified progression criteria were therefore met for a full trial. The treatment effect difference over 24 weeks in mean hand pain between active and placebo was -0.71 (95% CI -2.20 to 0.78) (Fig 1A). During tapering/stopping medication, mean hand pain increased by 1.31 points in the active arm compared with 0.17 in the placebo arm, indicating a possible effect of cessation of medication (Fig 1A). Furthermore, 6/13 (46%) participants in the active group reported worsening pain at week 28 compared with week 24, but only 2/12 (17%) were worse on withdrawing placebo (Fig 1B). The sample size for a full trial was estimated as 296 (based on MCID 0.8 on NRS, SD 2.0, 90% power, 10% drop-out, alpha 5%). Conclusion(s): This first study of a RCT of HRT for painful hand OA met its progression criteria, indicating that a full trial of an HRT in this population is feasible and acceptable. Although not powered to detect an effect, there was a trend towards improvement in hand pain on treatment and worsening of hand pain on tapering in the active arm only. This adds to proof-of-concept data in this area, justifying more work.ISRCTN12196200. Funded by Research for Patient Benefit programme, National Institute for Health Research (UK) PB-PG-0416-20023 [Formula presented]Copyright © 2023

Blockchain-based vaccination certificates management

With the explosion of COVID-19 cases and the government's needs to control virus spreading, the development of effective and robust systems for managing vaccination certificates to restrict citizens' activities has been in the centre of many governments. This paper proposes a system that allows for the update of the status of certificates and bases its function on a specific form of logs stored on Blockchains and a set of rules for the interpretation of these logs. Also an outline of a proof of concept implementation of the system in Ethereum together with a cost and security analysis are provided in the paper. The proposed architecture provides several benefits with the most prominent one being the suspension of certificates in case an already vaccinated individual is found positive. In existing certificate management systems a vaccinated individual that is tested positive still holds a valid vaccination certificate during the self-isolation period. This vulnerability allows infected individuals to commute freely and thus facilitates the spread of the pandemic. The proposed solution is not limited to COVID-19 related certificates, but rather it could be deployed in any kind of digital certificate. © 2022 ACM.

Health Care Monitoring Application using IoT Devices

Nowadays, health monitoring is crucial, especially monitoring the temperature and heartbeat of the patient in Covid / non-Covid situations. Continued monitoring of the patient is not a possible and tedious job. IoT plays a critical role in Hospitals where patients are in Intensive Care Units (ICU), and patients are treated at home (isolation points). The devices receive data continuously and monitor by the doctors remotely. This paper presents temperature and heartbeat monitoring using Internet Of Things (IoT) devices with an algorithm to capture data from devices and sends it to computer devices at a reasonable cost. Proof Of Concept has been created with the help of an Arduino board, Pulse Sensor, Temperature Sensor, Breadboard, ESP8266 Wi-Fi module, and Liquid Crystal Display (LCD). The IoT devices capture data from different devices (patient health data) in real time. The Health Care Monitoring (HCM) Application builds using microservices architecture, runs on top of the Thingspeak data, and sends notifications to the doctors if there is an emergency. The doctors can act according to rather than monitor continuously. This model eliminates manual intervention for taking the reading from time to time. © 2022 IEEE.

Constructing custom-made radiotranscriptomic signatures from CT angiograms: An application in COVID-19 vascular inflammation

Background: Advances in computational methodologies have enabled processing of large datasets originating from imaging studies. However, most imaging biomarkers suffer from a lack of direct links with underlying biology, as they are only observationally correlated with pathophysiology. Purpose(s): To develop and validate a novel AI-assisted image analysis platform, by applying quantitative radiotranscriptomics that quantifies cytokinedriven vascular inflammation from routine CT angiograms (CTA) performed as part of clinical care in COVID-19. Method(s): We used this platform to train the radiotranscriptomic signature C19-RS, derived from the perivascular space around the aorta and the internal mammary artery in routine chest CTAs, to best describe cytokinedriven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies (A). This signature was validated externally in 358 clinically indicated CT pulmonary angiograms from patients with or without COVID-19 from 3 different geographical regions. Result(s): First, 22 patients who had a CTA before the pandemic underwent repeat CTA <6 months post COVID-19 infection (B). Compared with 22 controls (matched for age, gender, and BMI) C19-RS was increased only in the COVID-19 group (C). Next, C19-RS was calculated in a cohort of 331 patients hospitalised during the pandemic, and was higher in COVID-19 positives (adjusted OR=2.97 [95% CI: 1.43-6.27], p=0.004, D). C19-RS had prognostic value for in-hospital mortality in COVID-19, with HR=3.31 ([95% CI: 1.49-7.33], p=0.003) and 2.58 ([95% CI: 1.10-6.05], p=0.028) in two testing cohorts respectively (E, F), adjusted for clinical factors and biochemical biomarkers of inflammation and myocardial injury. The corrected HR for in-hospital mortality was 8.24 [95% CI: 2.16-31.36], p=0.002 for those who received no treatment with dexamethasone, but only 2.27 [95% CI: 0.69-7.55], p=0.18 in those who received dexamethasone subsequently to the C19-RS based image analysis, suggesting that vascular inflammation may have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0.61, p=0.0003) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. Conclusion(s): We present the first proof of concept study that combines transcriptomics with radiomics to provide a platform for the development of machine learning derived radiotranscriptomics analysis of routine clinical CT scans for the development of non-invasive imaging biomarkers. Application in COVID-19 produced C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation, that predicts inhospital mortality and identifies people who will have better response to anti-inflammatory treatments, allowing targeted therapy. This AI-assisted image analysis platform may have applications across a wide range of vascular diseases, from infections to autoimmune diseases.

Slack as a virtual undergraduate dermatology community: a pilot

Dermatology has long been recognized as under-represented in UK's undergraduate curricula. With a diagnostic and educational toolkit that is heavily centred around face-to-face clinical examination, dermatology education has been disproportionately affected by the COVID-19 pandemic. Innovative approaches to distance teaching and learning within dermatology are essential, but historically have been unidirectional with a lack of community and patient-centred resources readily available. Online channel-based messaging apps such as Slack offer an opportunity to engage students in remote, multimodal collaborative learning by reproducing a classroom environment in the virtual space, while simultaneously maintaining a strong focus on patient care. The aim of this study was to determine the feasibility, acceptability and proof of concept for an online Slack community as an undergraduate dermatology learning platform. Undergraduate medical students participated in an online classroom for 6 weeks with a structured teaching programme encompassing online casebased discussions, seminars and journal clubs. The platform was facilitated by junior doctors (n = 10) and featured patient educators (n = 6). Students, faculty and patient educators completed a postcourse evaluation. In addition, students completed a pre-and postintervention dermatology quiz to determine knowledge acquisition. Mixed-methods analyses were applied including quantitative analyses to explore data trends and qualitative phenomenographic analyses to assimilate key underlying themes. Students (n = 65) were enrolled to join the platform for a 6-week period. The evaluation was completed by students (n = 52) from UK universities (n = 27). The majority of students (n = 27) interacted with the platform as passive observers (<= 5 active interactions). A small group of 'super users' (n = 4) actively engaged with the platform over 100 times during the study period. Ninety-six per cent of participants and 100% of faculty agreed that the overall quality of the course was excellent. No statistically significant difference in the pre-and postcourse dermatology quiz scores was noted, possibly owing to suboptimal levels of active engagement with the platform from many users. Barriers to engagement cited by the students included high university workload and the lack of a timetable for live sessions. A community-based online classroom can act as an enjoyable, acceptable and collaborative means of supplementing traditional educational methodologies for teaching dermatology to undergraduate medical students. Its ease of use and supportive nature can facilitate patient involvement, as well as other innovative approaches to teaching and learning dermatology, such as interuniversity collaboration and gamification of learning. Such advances may provide vital safeguards against the reduction in face-to-face learning that has accompanied the pandemic.

Saliva as an alternative to nasopharyngeal swabs for detection of respiratory syncytial virus (RSV)in children

Introduction: Nasopharyngeal swabs (NPS) are considered the gold standard for diagnosis of respiratory syncytial virus (RSV). Although highly sensitive, NPS come with sampling burden, a time interval between sampling and PCR test results, and high personnel and resource costs. Moreover, collection can cause discomfort in the patient. A saliva-based method for RSV detection would make large-scale and frequent clinical and community sampling more feasible. In this study, we evaluated detection of RSV in paired NPS and saliva samples. Method(s): Matched NPS and saliva samples were obtained by trained study personnel from hospitalised infants with viral respiratory infection. NPS and saliva samples were tested with SalivaDirect+, a saliva-based PCR test authorized by the US FDA for detection of SARS-CoV-2, expanded to also target RSV. Result(s): To date, 29 paired samples have been collected from infants with medically-attended respiratory infections. As a proof of concept, we analysed the first 10 samples including 5 samples from RSV positive infants and 5 from infants with other respiratory viruses. RSV, rhinovirus, and enterovirus could be detected in all 10 samples in both NPS and saliva. Sampling discomfort was considered to be significantly higher for NPS compared to saliva. More data will be available at the time of the conference. Conclusion(s): We detected RSV in all saliva samples. Our preliminary findings indicate that saliva is a viable and preferable alternative to NPS for RSV detection. Saliva could allow for frequent repeated testing. With further validation, widespread implementation of saliva sampling could transform RSV diagnosis and surveillance in children.