Immune System Development Processes with Special Emphasis on Relationship to Potential Mechanisms of MIS-C

Development of the mammalian immune system requires the intersection of myriad internal and external signals, from the migration of pluripotent stem cells to interactions with the vaginal microbiome during partuition to environmental factors that shape immune processes throughout life. Because the sequence of immune developmental events is fairly transcripted across time, multiple windows of susceptibility exist that can lead to immune dysfunction when these developmental events are perturbed. Additionally, early-life immune dysfunction can persist, leading to increased disease risk across the lifespan. Immune dysfunction can present functionally as suppression, hyperresponsivity, or inappropriate inflammation and molecularly, may involve multiple cells and signaling pathways. Thus, scenarios that lead to multisystem inflammatory syndrome in children (MIS-C) can be complex and multifaceted. This presentation will consider windows of susceptibility as well as external factors that may increase the risk of MIS-C.

Lichen planus after COVID-19 infection and vaccination

Background: Lichen planus (LP) is an inflammatory disorder believed to result from CD8+ cytotoxic T-cell (CTL) mediated autoimmune reactions against basal keratinocytes. We present a review of LP following COVID-19 infection and vaccination. Method(s): Literature searches were conducted on PubMed and Google Scholar from 2019 to 7/2022. 35 articles were selected based on subject relevance, and references within articles were also screened. Result(s): 39 cases of post-vaccination LP and 6 cases of post-infection LP were found among case reports and case series. 150 cases of postvaccination LP and 12 cases of post-infection LP were found in retrospective and prospective studies. Conclusion(s): LP is a rare complication of COVID-19 infection and vaccination that may be mediated by overstimulation of T-cell responses and proinflammatory cytokine production. However, it does not represent a limitation against COVID-19 vaccination, and the benefits of vaccination considerably outweigh the risks.

Prescription Opioid Use Among Cancer Patients before and after the Onset of COVID-19: Evidence from Real-World Data

Objectives: Opioids play a significant role in the effective management of cancer-related pain. The COVID-19 lock down may have reduced access to opioids and caused a decline in the use of prescription of opioids among cancer survivors. This study compared opioid prescription rates among cancer survivors before and after the onset of COVID-19 pandemic using real-world electronic health records (EHR). Method(s): Cohort analyses of cancer patients using data from EHR database from the TriNetX, a global federated health research network across 76 healthcare organizations. We analyzed changes in prescription opioid use before (March 1, 2018, through March 1, 2019) and after onset of COVID-19 (April 01, 2020, through March 2021) among cancer survivors. The key outcome variable was any opioid prescription within 1 year of cancer diagnosis. One-to-one propensity score matching was used to balance the characteristics (age, sex, race, diagnoses including diabetes, hypertensive diseases, overweight, mood disorders, and visual disturbances) of the two cohorts. Data were analyzed using the TriNetX platform. Result(s): There were 1,502,143 cancer survivors before COVID-19 and 1,412,599 cancer survivors after the onset of COVID-19. The one-to-one propensity-score match yielded 1,382,561 cancer patients, mean age 64 at cancer diagnosis, and 73% were white. Percentage of opioid use among cancer patients declined from 35.6% before the COVID-19 to 35.1% after the onset of the pandemic (OR=0.976, 95% CI 0.971-0.981). Average number of opioid prescriptions within 1 year of cancer diagnosis declined from 5.7 before to 5.3 after the COVID-19 onset (p<0.001). Conclusion(s): Among cancer survivors, a small decline in prescription opioid use was observed after the onset of COVID-19 pandemic. Future studies are needed to distinguish the impact of revised guidelines, opioid prescription policy changes, and COVID-19 lock down on lower rates of prescription opioid use among cancer survivors.Copyright © 2023

Intermediate Results of the Research for Percutaneous and Surgical Treatment for Left Anterior Descending Artery Chronic Total Occlusion

Objective: Is to find out which revascularization methods have less of risk factors and complications after the surgery and long-term period. Method(s): From January 2018 to December 2019 were operated 134 patients with LAD CTO. 48 of them underwent MIDCAB: 36 (75%) males and 12 (25%) females;aged 58.7 +/-8.7;7 (14.6%) with previous diabetes;10 (20.8%) with previous PCI of LAD with drug-eluting stent. In the PCI group there were 86 patients: 52 (60.5%) males and 34 (39.5%) females;aged 64.8 +/-8.3;23 (26.7%) with previous diabetes. Result(s): Hospital mortality was 0 (0%) in MIDCAB unlike 1 (1.2%) in PCI. Myocardial infarction was 0 (0%) in both the groups. In MIDCAB the number of conversions to onpump and sternotomy was 0 (0%), there were 6 (12.5%) pleuritis with pleural puncture and 3 (6.2%) with long wound-aches. The hospitalization period was 10.7+/-2.9 days for MIDCAB and 9.9 +/-3.9 days for PCI. In the PCI group 2.0 +/-1.0 drug-eluting stents were used. In-hospital costs were higher for PCI 3809 unlike 3258 for MIDCAB. After one year in MIDCAB group died 2 (4.2%) patients, from noncardiac causes. In PCI group died 3 (3.5%) patients, all from cardiac causes. Because of pandemic COVID-19 were checked only 48 patients by angiography and general clinical examination: 25 after MIDCAB and 23 after PCI. 5 patients have a graft failure, caused by surgical mistakes. 4 patients have stents restenosis and 1 has LAD's reocclusion. Conclusion(s): Both methods of revascularization for LAD CTO are demonstrated similar results. EuroSCORE II (P = 0.008) and glomerular filtrating rate (P = 0.004) are significant potential risk factors for mortality in both groups, age is potential risk factor for graft failure (P = 0.05). Dyslipidemia is significant risk factor for LAD restenosis in PCI group (P = 0.02). MIDCAB is associated with lower incidence of revascularization repeat and in-hospital mortality in the literature data and it costs lower than PCI for LAD CTO as our study has shown.

Impact of ICER Assessments on Payer Decision Making in the United States

Objectives: To evaluate how payers utilize Institute for Clinical and Economic Review (ICER) assessments to inform coverage or formulary decisions. Method(s): Double-blinded, web-based survey was fielded through Xcenda's research panel, the Managed Care Network, from June to July 2022. Result(s): A total of 51 payers from health plans (n=27), integrated delivery networks (n=12), and pharmacy benefit managers (n=12) participated in the survey. When assessing the usefulness of ICER's value assessment framework (VAF) to inform formulary decisions within their organizations, 57% of payers indicated it was extremely/very useful, 33% indicated somewhat useful, and 10% indicated not at all/not very useful. Most respondents (73%) agreed that ICER assessments are aligned with their organization's internal assessment. Utilization of ICER's VAF was most prevalent in high-cost drug or disease states (78%), rare/orphan disease states (71%), and oncology/hematology disease states (67%). Payers reported less use in primary care disease states (29%), COVID-19 (8%), and digital therapeutics (4%). In the last 24 months, 20% of payers reported ICER's recommendations often influenced coverage decisions, 59% indicated occasional influence, and 22% indicated no influence. In the last 24 months, payers indicated the top 5 ICER assessments that influenced their coverage decisions included high cholesterol (38%), Alzheimer's disease (36%), atopic dermatitis (33%), multiple myeloma (31%), and chemotherapy-induced neutropenia (28%). ICER assessments that were less impactful included beta thalassemia (3%), digital health technologies (3%), and supervised injection facilities (3%). Payers reported using ICER assessments to inform both expanded and restricted coverage decisions. Conclusion(s): Payers find ICER's VAF useful to inform their organization's formulary decisions. ICER's assessments often align with payers' internal assessments and are most frequently utilized for high-cost drugs or disease states. Payers indicate ICER assessments have affected both expansion and restriction in their coverage policies.Copyright © 2023

Clinical analysis of liver dysfunction in pregnant patients with mild SARS CoV-2 infection

Objective: The current study aimed to describe the clinical characteristics of mild SARS-CoV-2 infected pregnant women with abnormal liver function (ALF), explore the association between ALF with maternal and fetal outcomes. Method(s): This retrospective analysis included 87 pregnant patients with mild SARS-CoV-2 infection admitted and treated from December 1, 2022, to 31, 2022 in the department of Obestircs at Beijing Obstetrics and Gynecology Hospital. We evaluated patients for demographic and clinical features, laboratory parameters and pregnancy complications. Result(s): 27 Patients in this cohort had clinical presentations of ALF. Compared with the control group, the peripheral blood platelet (PLT), D-dimer quantitative determination (D-Dimer), lactate dehydrogenase (LDH), total protein (TP), albumin (ALB), indirect bilirubin (DBIL), gamma- glutamyltranspeptidase (GGT) and total bile acid (TBA) showed significantly differences (p<0.05). 12 cases (44.44%) complicated with pregnancy induced hypertension (PIH), 14 cases (51.85%) complicated with intrahepatic cholestasis of pregnancy (ICP), 2 cases (7.4%) complicated with acute fatty liver during pregnancy (AFLP) and 5 cases (14.81%) complicated with postpartum hemorrhage in patients with abnormal LFT were significantly higher than those in the control group (p<0.05). Compared with the control group, the incidence of premature delivery (22.22%) and fetal distress (37.04%) in the experiment group were significantly higher (p<0.05), and the incidence of neonatal asphyxia was not significantly different (p>0.05). Conclusion(s): Pregnant women are generally susceptible to mild SARS-CoV-2 and may induce ALF. ALF is associated with increased risk of mother and infant. The maternal and infant outcomes of those who terminated pregnancy in time are acceptable. Therefore, pregnant women with COVID-19 who received antiviral treatment should be closely monitored for evaluating liver function and relevant indicators. The long-term outcomes in the future are worth to further study.Copyright © 2023

Malnutrition Prevalence and Economic Burden Among US Hospitalized Older Adult Patients with and without COVID-19

Objectives: Malnutrition is a prevalent condition affecting 30-50% of hospitalized patients. Malnutrition is linked to impairments in health outcomes and increased economic burden on healthcare systems. We assessed the prevalence and burden of malnutrition by examining demographic characteristics, Disease Related Group (DRG) payments and associated claims among Medicare inpatients (65+ years) with and without COVID-19. Method(s): Hospital inpatient COVID-19 claims from the Centers for Medicare & Medicaid Services (CMS) Inpatient Prospective Payment System (IPPS) between October 2020 - September 2021 were analyzed. The International Classification of Diseases, Tenth Revision, and Clinical Modification (ICD-10-CM) were used for malnutrition diagnoses. Demographic variables were compared based on the COVID-19 status;economic burden was analyzed by DRG payment of malnutrition cases with and without COVID-19. Result(s): Among 7,394,657 Medicare inpatient claims, only 12% had a documented malnutrition diagnosis. Of these patients, 1.2% had COVID-19. Regardless of COVID-19 status, malnourished patients averaged 75 years of age, and were predominantly female (54%) and White (78%) followed by Black (14%), and Hispanic (2%). Sepsis, kidney failure, and urinary tract infection (UTI) were the most common primary diagnoses in malnourished patients, regardless of COVID-19 status. Malnourished patients with COVID-19 had significantly higher DRG payments ($27,407 vs. $18,327) and increased cost of outlier payment ($3,208 vs. $2,049) compared to those without COVID-19, regardless of other diagnoses. Conclusion(s): Malnutrition diagnosis was confirmed in only 12% of the Medicare inpatients, thus suggesting that malnutrition continues to be underdiagnosed and undertreated - evidenced by high rates of hospitalizations/claims and payments in both COVID-19 and non-COVID-19 cases. It is imperative for hospitals to implement nutrition-focused protocols to identify, diagnose and address malnutrition among all Medicare inpatients regardless of COVID-19 status (and especially among patients with sepsis, kidney failure, and UTI). Nutrition-focused protocols can effectively improve patient health outcomes and reduce healthcare costs.Copyright © 2023

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

Using implementation science in youth mental health workforce development: Adapting to the COVID-19 pandemic in Australia

Aims: Globally, mental illness and substance use disorders are the leading cause of disability and disease burden for young people. Orygen is an Australian youth mental health organization with a mission to reduce the impact of mental ill-health on young people, families and society, and one of only a few known research and clinical centres with a dedicated Knowledge Translation division. This paper provides a case study of the workforce development team within Orygen Knowledge Translation, outlining how implementation science informs their work and how the division has adapted its model of service support in the face of COVID-19. Method(s): Process data on training and resources developed and delivered by the workforce development team at Orygen over the period 2017-2021 was collated and synthesized with team reflections about the adaptations made by team in response to the COVID-19 pandemic. Results and Conclusion(s): Since 2017, the team has delivered training to more than 4000 youth mental health workers across Australia, on the topics of trauma, psychosis, mood and anxiety disorders, brief interventions, cognition and other areas of youth mental health. The COVID-19 pandemic generated abrupt and dramatic changes to the delivery of workforce and service development initiatives in Australia due to significant restrictions to travel and in-person events. It also placed major delivery demands on youth mental health services. The COVID-19 pandemic facilitated profound and rapid changes to service delivery and development in Australian youth mental health. Implementation science offers flexible models to support a changing system.

Intensive Care Consultant: Superhero or normal human being but more capable!

Submission content Introduction: Intensive care medicine has become an admired, loved, hated, and definitely more interesting Specialty due to a special situation (COVID-19) that exposed the training process to numerous criticisms, positives, and negatives, and this is how I believe we could improve our beloved world. Proposal: 1. Ideal training program from medical school to Certificate of Completion of Training (CCT): * Medical school: In their last year they should do more than 1 week in the Intensive Care Unit (ICU) * Stage 1: there should be a core surgical training of at least 6 months * Stage 2: there should be a rotation on Psychiatry of at least 4 weeks with on calls in ICU and 2 weeks in Palliative Care * Stage 3: acting as a consultant for the last six months on ST7 with backup from a formal consultant, and * Surgical training should be included in the possible dual or triple CCT 2. How would we be assessed? I agree with the Faculty of Intensive Care Medicine (FICM) staging program assessment, with some modifications: * As ST7 the trainee should act as a consultant with back support at least 50% of the stage and need to be evaluated by a Multi-Source Feedback (MSF). * Clinical Fellows should have a consultant as a Certificate of Eligibility for Specialist Registration (CESR) guide who establishes the equivalent stage of training supporting them and assessing them under the same model. * Changing the way, the General Medical Council (GMC) conducts the CESR application and making it really equivalent to the ICM training with the FFICM curriculum. 3. What do we need to be taught? * Hot topics for ICU (academic), * Overseas talks to share experiences, * Ultrasound (FUSIC), * Wellbeing strategies, * Leadership training * Psychiatric and physiological effects post ICU for patients and staff, * The administrative and political model of the National Health Service (NHS), and * Communication skills to establish excellent relationships with the other specialties. 4. What would our working life look like? * Normal day: 8 am to 3 pm * Midday shift: 1 pm to 8:30 pm * Night shift: 8 pm to 8:30 am * A rolling rota of 12 weeks with 2 weekends during this time 5. How would you produce Intensive Care Medicine (ICM) Consultants of the future who both love their job and their life: * Starting with less intense shifts, * More cordial relationships between the teams, * Supporting ICM trainees and Fellows going through their CESR pathway, * Making the training more attractive to either male-female doctors getting them involved in as many different specialties as ICM can cover, Conclusion(s): Having full-time ICM Consultants should be welcome in all ICUs in the country, which is not at the moment. This will definitely attract a lot of excellent doctors who are 100% focused on ICM.

Study of Pharmacists' Awareness Regarding Coronavirus Disease (COVID-19) in Ukraine

Objectives: Data showed that during the SOVID-19 pandemic the pharmacy is the first place for patient care. The purpose was to study the awareness of pharmacists about the COVID-19 for 2021-2022 in Ukraine to provide complete and quality care. Method(s): Survey was developed to determine the level of knowledge of pharmacists regarding the main symptoms, methods of diagnosis, treatment and prevention of uncomplicated forms of the COVID-19 by using Google form. The heads of pharmacies, pharmacists in eight regions of Ukraine were involved. The research period was December 2021 - December 2022. Result(s): We received, 725 completed questionnaires from 8 regions of Ukraine, of which 69.7% were pharmacy managers, 12.0% were pharmacists, and 18.3% were intern- pharmacists. Of the surveyed pharmacists, 95% called the method of airborne transmission, but 4.7% believe that the coronavirus is transmitted by the contact-household method, and 0.3% - transmissible. We found that 100% of respondents correctly named the main indicators of the condition of a patient with the COVID-19. However, only 95.4% of pharmacists correctly defined the concept of saturation, which requires improvement of information support. For the symptomatic treatment of uncomplicated forms, 91.7% of respondents correctly determined that Paracetamol, Ibuprofen are for the symptomatic treatment of uncomplicated forms, but 8.3% of pharmacists named other drugs. Assessing the need to take antibiotics, 88.5% of pharmacists gave the correct answer, but 5.5% believe that the reason for prescribing antibiotics is an increase in body temperature, and 5.4% named a decrease in saturation, 0.6% - dry a cough, that does not meet the requirements of thee national guideleines Covid-19. Conclusion(s): We found that pharmacists are 100% well-informed with the symptoms and causes of the Covid-19. However, it is necessary to improve the provision of information about the requirements for the treatment of uncomplicated forms of Covid-19 and the dispensing of antibiotics from pharmacies.Copyright © 2023

A Case of X-Linked Moesin-Associated Immune Deficiency in a Pediatric Patient

Background: X-Linked Moesin-Associated Immune Deficiency (X-MAID) is a rare severe combined immunodeficiency (SCID) subtype that can present at any age due to its variability. Depending on severity, patients demonstrate failure to thrive, recurrent bacterial and viral infections, and increased susceptibility to varicella zoster. It has been characterized by marked lymphopenia with hypogammaglobulinemia and impaired T-cell migration and proliferation. Case Presentation: This is a report of a Cuban 7-year-old male with poor weight gain and facial dysmorphia. He had a history of recurrent bacterial gastrointestinal infections and pneumonia beginning at 4 months of age. He additionally had 4-6 upper respiratory tract and ear infections annually. While still living in Cuba, he was admitted for a profound EBV infection in the setting of significant leukopenia. A bone marrow biopsy confirmed no malignancy. After he moved to the United States, his laboratory work-up revealed marked leukopenia with low absolute neutrophil and lymphocyte count with low T and B cells, very low immunoglobulin levels IgG, IgA, and IgM, and poor vaccination responses to streptococcus pneumonia, varicella zoster, and SARS-CoV-2. Genetic testing revealed a missense pathogenic variant c.511C>T (p.Arg171Trp) in the moesin (MSN) gene associated with X-MAID. He was managed with Bactrim and acyclovir prophylaxis, and immunoglobulin replacement therapy, and considered for hematopoietic stem cell transplantation. Discussion(s): Diagnosis of X-MAID should be considered in patients with recurrent infections and profound lymphopenia. As with SCID, early diagnosis and intervention is of utmost importance to prevent morbidity and mortality. This case demonstrates the importance of genetic testing in identifying this disease as it may prompt an immunologist to consider HSCT if conservative management is suboptimal. In the current literature, HSCT appears promising, but the long-term outcomes have yet to be described.Copyright © 2023 Elsevier Inc.

Depression Severity Among Patients with Psychiatric Disorders during the COVID-19 Pandemic

Objectives: The impact of the COVID-19 pandemic on mental health is not yet well-studied. This study's objective is to describe demographic characteristics of the population diagnosed with depression or anxiety, and to compare PHQ9 scores before and after the pandemic. Method(s): A retrospective cohort study was performed using Komodo Health's healthcare claims and EMR data, which included Patient Health Questionnaire-9 (PHQ9) survey responses. The study's baseline and follow-up periods were set as one year before and after 03/01/2020. Patients selected were >=18 years of age, had a MDD, GAD, or other psychiatric diagnosis in both periods, and had taken at least one PHQ9 survey in both periods, resulting in 10,433 patients. Demographic characteristics were described across age, gender, and race/ethnicity, and a subgroup analysis was performed on PHQ9 scores and depression categories using averages (mean, SD) and odds ratios. Result(s): Demographic analysis showed depression severity correlated with patients who were younger, female, and Black or Hispanic. Younger patients (<30) were more likely than older (>=30) to be in the moderately severe category or worse (PHQ9 score >=15) in both time periods (ORs 1.72 and 1.62, p<0.001). This was also true for female as compared to male (ORs 1.45 and 1.49, p<0.001), and Black or Hispanic as compared to White (ORs 1.87 and 1.47, p<0.001). However, mean PHQ9 scores tended to decrease in the follow-up period. The overall mean decreased slightly from 6.28 (SD 6.05) to 5.68 (SD 5.82), which was consistent in nearly all age, gender, and race/ethnicity subcategories. Conclusion(s): While the improvements in average PHQ9 scores were counterintuitive, given the harmful impacts of the pandemic, existing correlations between demographics and depression severity remained. One possible explanation is that this cohort definition selected for patients who received more consistent mental healthcare. Further study will investigate this and other possible factors.Copyright © 2023

Literature Review of Statistical Methods Comparisons through Simulations When Using External Control Arm for Regulatory or HTA Submissions

Objectives: Using a historical control or external control arm (ECA) to augment or replace a concurrent control arm in a randomized trial is a hot topic given the challenge of patient recruitment in rare diseases or during COVID-19 pandemic. The FDA released draft guidance in 2021 on effectiveness and safety submissions using real-world evidence. While the guidance focuses mainly on elements of study design and data source selection, there is a lack of consensus in the selection of appropriate statistical methods when constructing an ECA. This study discusses rigorous statistical methodology for ECA-supported trials in regulatory or HTA submissions. Method(s): Targeted literature reviews of statistical simulations comparing methods for ECA in statistical journals were performed. The articles compared commonly used ECA-construction and analysis methods were selected and summarized, including but not limited to propensity score (PS)-based matching, weighting, and stratification, and PS plus Bayesian integrated approaches. Result(s): Type I error, power, bias, and coverage probability are common criteria used to compare different methods. When imbalances only exist in known baseline covariates and the outcome distributions are the same between the trial concurrent control and ECA, the PS method alone or paired with commensurate prior yield almost unbiased estimates, good Type I errors, and coverage probability. PS plus Bayesian approaches have wider interval width and lower power compared with PS-only methods. When there is a change in the outcome distribution over time, the PS (matching or IPTW) and commensurate prior integrated methods yield the smallest biases among all methods. Conclusion(s): PS and Bayesian integrated methods outperformed the PS-only methods in terms of bias and Type I error when outcome distribution changed with current trial control. A "sweet spot" that balances all criteria through trial-specific simulations could provide the ideal setting of trial analyses plan based on specific trial design and scenarios.Copyright © 2023

Current Healthcare Policy and Environmental Status of Digital Health Medical Devices in South Korea

Objectives: COVID 19 and increasing unmet needs of health technology had accelerated an adoption of digital health globally and the major categories are mobile-health, health information technology, telemedicine. Digital health interventions have various benefit on clinical efficacy, quality of care and reducing healthcare costs. The objective of the study is to identify new reimbursement policy trend of digital health medical devices in South Korea. Method(s): Official announcements published in national bodies and supplementary secondary research were used to capture policies, frameworks and currently approved products since 2019. Result(s): With policy development, several digital health devices and AI software have been introduced as non-reimbursement by utilizing new Health Technology Assessment (nHTA) pathway including grace period of nHTA and innovative medical devices integrated assessment pathway. AI based cardiac arrest risk management software (DeepCARS) and electroceutical device for major depressive disorders (MINDD STIM) have been approved as non-reimbursement use for about 3 years. Two digital therapeutics for insomnia and AI software for diagnosis of cerebral infarction were approved as the first innovative medical devices under new integrated assessment system, and they could be treated in the market. In addition, there is remote patient monitoring (RPM) reimbursement service fee. Continuous glucose monitoring devices have been reimbursed for type 1 diabetes patients by the National Health Insurance Service (NHIS) since January 2019. Homecare RPM service for peritoneal dialysis patients with cloud platform (Sharesource) has been reimbursed since December 2019, and long-term continuous ECG monitoring service fee for wearable ECG monitoring devices (ATpatch, MEMO) became reimbursement since January 2022. Conclusion(s): Although Korean government has been developed guidelines for digital health actively, only few products had been reimbursed. To introduce new technologies for improved patient centric treatment, novel value-based assessment and new pricing guideline of digital health medical devices are quite required.Copyright © 2023

Repurposing of poly-gamma-glutamic acid, immunotherapeutic drug for cervical intraepithelial neoplasia 1, as covid-19 treatment

Covid-19 virus variants identified so far are due to viral genetic diversity, genetic evolution, and variable infectivity, suggesting that high infection rates and high mortality rates may be contributed by these mutations. And it has been reported that the targeting strategies for innate immunity should be less vulnerable to viral evolution, variant emergence and resistance. Therefore, the most effective solution to Covid-19 infection has been proposed to prevent and treat severe exacerbation of patients with moderate disease by enhancing human immune responses such as NK cell and T cell. In previous studies, we demonstrated for the first time that gamma-PGA induced significant antitumor activity and antiviral activity by modulating NK cell-mediated cytotoxicity. Especially intranasal administration of gamma-PGA was found to effectively induce protective innate and CTL immune responses against viruses and we found out that gamma-PGA can be an effective treatment for cervical intraepithelial neoplasia 1 through phase 2b clinical trial. In this study, the possibility of gamma-PGA as a Covid-19 immune modulating agent was confirmed by animal experiments infected with Covid-19 viruses. After oral administration of gamma-PGA 300mug/mouse once a day for 5 days in a K18-hACE2 TG mouse model infected with SARS-CoV-2 (NCCP 43326;original strain) and SARS-CoV-2 (NCCP 43390;Delta variant), virus titer and clinical symptom improvement were confirmed. In the RjHan:AURA Syrian hamster model infected with SARS-CoV-2 (NCCP 49930;Delta variant), 350 or 550 mug/head of gamma-PGA was administered orally for 10 days once a day. The virus for infection was administered at 5 x 104 TCID50, and the titer of virus and the improvement of pneumonia lesions were measured to confirm the effectiveness in terms of prevention or treatment. In the mouse model infected with original Covid-19 virus stain, the weight loss was significantly reduced and the survival rate was also improved by the administration of gamma-PGA. And gamma-PGA alleviated the pneumonic lesions and reduced the virus titer of lung tissue in mice infected with delta variant. In the deltavariant virus infected hamster model, gamma-PGA showed statistically significant improvement of weight loss and lung inflammation during administration after infection. This is a promising result for possibility of Covid-19 therapeutics along with the efficacy results of mouse model, suggesting gammaPGA can be therapeutic candidate to modulate an innate immune response for Covid-19.

Enabling mRNA medicine for brain tumors

mRNA is a new class of drugs that has the potential to revolutionize the treatment of brain tumors. Thanks to the COVID-19 mRNA vaccines and numerous therapy-based clinical trials, it is now clear that lipid nanoparticles (LNPs) are a clinically viable means to deliver RNA therapeutics. However, LNP-mediated mRNA delivery to brain tumors remains elusive. Over the past decade, numerous studies have shown that tumor cells communicate with each other via small extracellular vesicles, which are around 100 nm in diameter and consist of lipid bilayer membrane similar to synthetic lipidbased nanocarriers. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain tumors without undue toxicity. We synthesized LNPs using four components similar to the formulation used in the mRNA COVID19 vaccines (Moderna and Pfizer): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. For the in vitro screen, we tested ten classes of helper lipids based on their abundance in extracellular vesicle membranes, commercial availability, and large-scale production feasibility while keeping rest of the LNP components unchanged. The transfection kinetics of GFP mRNA encapsulated in LNPs and doped with 16 mol% of helper lipids was tested using GL261, U87 and SIM-A9 cell lines. Several LNP formations resulted in stable transfection (upto 5 days) of GFP mRNA in all the cell lines tested in vitro. The successful LNP candidates (enabling >80% transfection efficacy) were then tested in vivo to deliver luciferase mRNA to brain tumors via intrathecal administration in a syngeneic glioblastoma (GBM) mouse model, which confirmed luciferase expression in brain tumors in the cortex. LNPs were then tested to deliver Cre recombinase mRNA in syngeneic GBM mouse model genetically modified to express tdTomato under LoxP marker cassette that enabled identification of LNP targeted cells. mRNA was successfully delivered to tumor cells (70-80% transfected) and a range of different cells in the tumor microenvironment, including tumor-associated macrophages (80-90% transfected), neurons (31- 40% transfected), neural stem cells (39-62% transfected), oligodendrocytes (70-80% transfected) and astrocytes (44-76% transfected). Then, LNP formulations were assessed for delivering Cas9 mRNA and CD81 sgRNA (model protein) in murine syngeneic GBM model to enable gene editing in brain tumor cells. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~94% of brain tumor cells in vivo. In conclusion, we have developed a library of safe LNPs that can transfect GBM cells in vivo with high efficacy. This technology can potentially be used to develop novel mRNA therapies for GBM by delivering single or multiple mRNAs and holds great potential as a tool to study brain tumor biology.

Mid-density Gene Expression profiling of SARSCOV-2 infected samples using Applied BiosystemsTM TaqManTM Flexible Array Panels

Background/Objectives: The broad spectrum of clinical manifestations from SARS-COV-2 infection and observed risk factors for severe disease highlight the importance of understanding molecular mechanisms underlying SARS-CoV-2 associated disease pathogenesis. Research studies have identified a large number of host proteins that play roles in viral entry, innate immune response, or immune signalling during infection. The ability to interrogate subsets of these genes simultaneously within SARSCOV-2 infected samples is critical to understanding how their expression contribute to phenotypic variability of the disease caused by the pathogen. Method(s): 30 Nasopharyngeal swab were obtained and included SARS-CoV-2 infected and control samples. RNA was extracted, reverse transcribed and loaded onto flexible TaqMan array panels designed specifically for targeting the most cited genes related to SARS-COV-2 entry and restriction factors as well as cytokines, chemokines, and growth factors involved in the pathogenesis. Result(s): Our data indicated that not only were the levels of several of these host factors differentially modulated between the two study groups, but also that SARS-CoV-2 infected subjects presented with greater frequency of several important inflammatory cytokines and chemokines such as CCL2, CCL3, IFNG, entry receptors such as ACE2, TMRPS11A, and host restriction factors including LY6E and ZBP1. Conclusion(s): TaqMan array plates provide a fast, midthroughput solution to determine the levels of several virus and host-associated factors in various cell types and add to our understanding of how the pathogenesis may vary depending on gender, age, infection site etc.

Optimizing mRNA vaccines and virusmediated CAR T-cell therapy for immuno-oncology: Synthetic tools for gene modification

With the success of mRNA vaccines during the COVID-19 pandemic and CAR T-cell therapies in clinical trials, there is growing opportunity for immunotherapies in the treatment of many types of cancers. Lentiviral vectors have proven effective at delivery of genetic material or gene editing technology for ex vivo processing, but the benefits and promise of Adeno-associated virus (AAV) and mRNA tools for in vivo immunotherapy have garnered recent interest. Here we describe complete synthetic solutions for immuno-oncology research programs using either mRNA-vaccines or virus-mediated cell and gene engineering. These solutions optimize workflows to minimize screening time while maximizing successful research results through: (1) Efficiency in lentiviral packaging with versatility in titer options for high-quality particles. (2) A highthroughput viral packaging process to enable rapid downstream screening. (3) Proprietary plasmid synthesis and preparation techniques to maintain ITR integrity through AAV packaging and improve gene delivery. (4) Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tail. The reported research demonstrates a streamlined approach that improves data quality through innovative synthesis and sequencing methodologies as compared to current standard practices.

Patients Characteristics, Vaccine Uptake, Healthcare Resource Utilization and Costs Associated with Acute COVID-19 during the Omicron Predominant Period in Brazil: A Nationwide Database Study

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has imposed significant burden on Brazil's health system. The present study aims to describe patients' demographic and clinical characteristics, vaccine uptake and assess healthcare resource utilization (HCRU) and costs associated with acute COVID-19 in Brazil during the Omicron predominant period. Method(s): A population-based retrospective study was conducted using the National Health Data Network (RNDS), National Vaccination Campaign against COVID-19 data and surveillance data in public setting. Individuals with positive COVID-19 test results between January-April 2022 were identified. Patients' demographics, comorbidities, vaccination status, HCRU for those who were admitted to hospitals and their associated costs were described by age groups. Result(s): A total of 8,160,715 COVID-19 cases were identified and 2.7% were aged <5 years, 11.6% were 5-19 years, 76.9% were 20-64 years and 8.7% were >= 65 years. The presence of comorbidity was 23.1% with a higher prevalence of comorbidities in the elderly (61.8% for 65-74 years and 71.2% for >=75 years). Regarding COVID -19 vaccination uptake, among those aged <=19 years, 20-64 years and >=65 years, 40.6%, 86.5% and 92.2% had primary series, respectively. Among adults, the booster uptake was 47.3% and 75.8% for those aged 20-64 years and >= 65 years, respectively. Among those with confirmed COVID-19, regardless of vaccination status, 87% were being symptomatic and 1.7% were hospitalized (3.8% in aged <5 years, 4.2% in 5-19 years, 34.3% in 20-64 years and 57.6% in >= 65 years). Among hospitalized patients, 32,6% were admitted to ICU and 80% required mechanical ventilation support. The average cost per day in normal wards and ICU without ventilation was R$291,89 and R$923,90, respectively. Conclusion(s): Our results quantify the public health and economic burden of COVID-19 in Brazil, suggesting substantial healthcare resources required to manage the COVID-19 pandemic.Copyright © 2023