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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
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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.
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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
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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
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Burnout encompassed a host of medical, psychological, emotional and performance-related issues that can always be affected by individual and coach factors in elite athletes;therefore, the aim of this study was to investigate the relationship between perfectionism and burnout, mediated by perceived coaching style in the context of the Covid-19 epidemic. In this cross-sectional study, 258 elite athletes (M = 22.05 years, SD = 3.08;148 male) participated and completed scales of multidimensional perfectionism, athlete burnout and coaching style. Data were analyzed using descriptive statistics by structural equation modeling .The results indicate that direct paths perfectionism to burnout, perfectionism to coaching style, coaching style to burnout, and indirect pathways to perfectionism to burnout were mediating by coaching style, significant. The results indicate that during the COVID 19 , athletes who are less able to organize performance standards and expectations of themselves and others, and who are more committed to meeting external demands, are at higher risk of burnout. One could develop coach-education programmes that challenge beliefs regarding the effectiveness of controlling coaching behaviors to reduce perfectionist tendencies and expectations in athletes. In doing so, one might curtail the risk of burnout in athlete during the COVID 19. (PsycInfo Database Record (c) 2023 APA, all rights reserved)
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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.
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Objectives: The aim of this study was to assess Jordanian physicians' awareness about venous thromboembolism (VTE) risk among COVID-19 patients and its treatment protocol. Method(s): This was a cross-sectional-based survey that was conducted in Jordan in 2020. During the study period, a convenience sample of physicians working in various Jordanian hospitals were invited to participate in this study. Physicians' knowledge was evaluated and physicians gained one point for each correct answer. Then, a knowledge score out of 23 was calculated for each. Key Findings: In this study, 102 physicians were recruited. Results from this study showed that most of the physicians realize that all COVID-19 patients need VTE risk assessment (n = 69, 67.6%). Regarding VTE prophylaxis, the majority of physicians (n = 91, 89.2%) agreed that low molecular weight heparin (LMWH) is the best prophylactic option for mild-moderate COVID-19 patients with high VTE risk. Regarding severe/critically ill COVID-19 patients, 75.5% of physicians (n = 77) recognized that LMWH is the correct prophylactic option in this case, while 80.4% of them (n = 82) knew that mechanical prevention is the preferred prophylactic option for severe/critically ill COVID-19 patients with high bleeding risk. Moreover, 77.5% of physicians (n = 79) knew that LMWH is the treatment of choice for COVID-19 patients diagnosed with VTE. Finally, linear regression analysis showed that consultants had an overall higher knowledge score about VTE prevention and treatment in COVID-19 patients compared with residents (P = 0.009). Conclusion(s): All physicians knew about VTE risk factors for COVID-19 patients. However, consultants showed better awareness of VTE prophylaxis and treatment compared with residents. We recommend educational workshops be conducted to enhance physicians' knowledge and awareness about VTE thromboprophylaxis and management in COVID-19 patients.Copyright © 2022 The Author(s). Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved.
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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are increasingly initiated as treatment for type 2 diabetes due to favourable cardiorenal characteristics. However, studies have identified an increased risk of diabetic ketoacidosis (DKA). We carried out a retrospective, case-based study at East and North Herts NHS Trust between February 2018 and December 2020. Fifteen cases of SGLT2i associated DKA were identified in people with presumed type 2 diabetes;33.3% were classed as euglycaemic DKA with a blood glucose of <11mmol/L. All cases were associated with a significant precipitating factor including diarrhoea, vomiting, reduced oral intake and sepsis. One case was related to COVID-19. Two people were subsequently found to have raised islet autoantibodies suggesting type 1 diabetes or latent autoimmune diabetes in adults. It is important that awareness of SGLT2i associated DKA is raised among users and health care practitioners, including the recognition of euglycaemic DKA. Sick day rules should be emphasised and reiterated at clinical encounters. Non-specialists in primary care, oncology and in perioperative settings should be empowered to advocate for temporary withdrawal and there should be readier access to blood ketone monitoring when required. When SGLT2i associated DKA occurs, due consideration should be given to evaluate the diabetes classification and investigate the circumstances of the event. Copyright © 2023 John Wiley & Sons.Copyright © 2023 John Wiley & Sons, Ltd.
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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.
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Aim: Although most patients with COVID-19 experience respiratory tract infections, severe reactions to the virus may cause coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation and thrombotic microangiopathy. Fluctuations in platelet markers, which are an indicator of the acute phase response for COVID-19, are of clinical importance. The aim of this study is to evaluate the relationship between disease severity and Platelet Mass Index (MPI) parameters in COVID-19 patients. Material(s) and Method(s): This retrospective observational study was conducted with patients who were diagnosed with COVID-19 in a tertiary hospital. The study was continued with the remaining 280 patients. All laboratory data were scanned retrospectively from patient files and hospital information system. Result(s): A very high positive correlation was found between PMI and PLT. The PMI value in women was significantly higher than in men. It was observed that PMI did not differ significantly in terms of mortality, intubation, CPAP and comorbidity. PMI vs. Pneumonia Ct Severity Score, biochemistry parameters (AST, CRP), hemogram parameters (WBC, HGB, HCT, MCV, LYM, MPV EO) and coagulation factors (aPTT and FIB) at various levels of positive/negative, weak and strong, and significant relationship was found. There was no significant relationship between hormone and D-dimer when compared with PMI. Discussion(s): Although platelet count alone does not provide information about the prognosis of the disease, PMI may guide the clinician as an indicator of lung damage in seriously ill patients.Copyright © 2022, Derman Medical Publishing. All rights reserved.
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Background: The 2019 novel coronavirus disease (COVID-19) has been reported as pandemy and the number of patients continues to rise. Based on recent data, cardiac injury is a prominent feature of the disease, leading to increased morbidity and mortality. In the present study we aimed to evaluate myocardial dysfunction using transthoracic echocardiography (TTE) and tissue Doppler imaging (TDI) in hospitalized COVID-19 patients. Methods and Results: We recruited 30 patients (56.7% male, 55.80 +/- 14.949 years) who were hospitalized with the diagnosis COVID-19 infection. We analyzed left ventricular (LV) and right ventricular (RV) conventional and TDI parameters at the time of hospitalization and during the course of the disease. Patients without any cardiac disease and with preserved LV ejection fraction (EF) were included. TTE examination was performed and all the variables were recorded and analyzed retrospectively. We observed that both LV and RV conventional echocardiographic parameters were similar when the day of admission to the hospital was compared to the 5th day of the disease. Regarding TDI analysis, we demonstrated significant impairment in LV septal and lateral deformation (P < 0.001). In the correlation analysis no marked correlation was observed between impairment in LV deformation and inflammation biomarkers. Conclusion(s): Cardiac involvement is an important feature of the COVID-19 infection but the exact mechanism is still undefined. Echocardiography is an essential technique to describe myocardial injury and provide new concepts for the possible definitions of cardiac dysfunction.Copyright © 2023 The Author(s).
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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
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COVID-19 has a dramatic impact on human health, besides respiratory system, reproduction system would be impaired by SARS-CoV-2. For male, the virus has various negative impacts on testes, including overheating and hormone level fluctuation, which have impacts on the spermatogenesis or spermatogonia development. For female, COVID-19 may increase the risk of endocrine and metabolic dysfunction. However, the impact of SARS-CoV-2 on the ovaries is not clear, and further researches are needed to clarify it. Nearly 60% of the pregnant women develop symptoms of infection and more attention should be paid to the increased risk of adverse pregnancy outcomes including preeclampsia, eclampsia, and severe infection. For the newborns of infected pregnant women, vertical transmission of SARS-CoV-2 is still unclear, and further evaluation are required. Meantime, the pregnant women's fear of the potential infection may reduce their access to the prenatal genetic test. In this chapter, we summarize the latest basic and clinical researches on COVID-19 impacts on male, female reproduction, and prenatal genetic test, hoping to provide guidance and advice for people of reproductive age and reproductive healthcare practitioners. © 2023 Elsevier Inc. All rights reserved.
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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.
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Purpose: First, the key vulnerability factors from the literature are identified. Second, using the vulnerability factors as indicators, a composite index is developed. Last, from the index values, a set of vulnerability knowledge maps, showing the vulnerability hotspots, are prepared. Design/methodology/approach: This study aims to develop a pandemic vulnerability knowledge visualisation index to support the strategic decision-making efforts of authorities. Findings: Ten indicators are identified as vulnerability factors that could significantly impact the virus spread risks. Verifying the identified hotspots against the recorded infected cases and deaths has evidenced the usefulness of the index. Determining and visualising the high-vulnerability locations and communities could help in informed strategic decision-making and responses of the authorities to the pandemic. Originality/value: The study demonstrates that the developed pandemic vulnerability knowledge visualisation index is particularly appropriate in the context of Australia. Nonetheless, by replicating the methodologic steps of the study, customised versions can be developed for other country contexts. (PsycInfo Database Record (c) 2023 APA, all rights reserved)
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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.
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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.
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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
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Objectives: The COVID pandemic has imposed significant direct medical cost and resource use burden on healthcare systems. This study described the patient demographic and clinical characteristics, healthcare resource utilization and costs associated with acute COVID in adults in England. Method(s): This population-based retrospective study used linked primary care (Clinical Practice Research Datalink, CPRD, Aurum) and secondary care (Hospital Episode Statistics) data to identify: 1) hospitalized (admitted within 12 weeks of a positive COVID-19 PCR test between August 2020 and March 2021) and 2) non-hospitalized patients (positive test between August 2020 and January 2022 and managed in the community). Hospitalization and primary care costs, 12 weeks after COVID diagnosis, were calculated using 2021 UK healthcare reference costs. Result(s): We identified 1,706,368 adult COVID cases. For hospitalized (n=13,105) and non-hospitalized (n=1,693,263) cohorts, 84% and 41% considered high risk for severe COVID using PANORAMIC criteria and 41% and 13% using the UKHSA's Green Book for prioritized immunization groups, respectively. Among hospitalized cases, median (IQR) length of stay was 5 (2-7), 6 (4-10), 8 (5-14) days for 18-49 years, 50-64 years and >= 65 years, respectively;6% required mechanical ventilation support, and median (IQR) healthcare costs (critical care cost excluded) per-finished consultant episode due to COVID increased with age (18-49 years: 4364 (1362-4471), 50-64 years: 4379 (4364-5800), 65-74 years: 4395 (4364-5800), 75-84 years: 4473 (4364-5800) and 85+ years: 5800 (4370-5807). Among non-hospitalized cases, older adults were more likely to seek GP consultations (13% of persons age 85+, 9% age 75-84, 7% age 65-74, 5% age 50-64, 3% age 18-49). Of those with at least 1 GP visit, the median primary care consultation total cost in the non-hospitalized cohort was 16 (IQR 16-31). Conclusion(s): Our results quantify the substantial economic burden required to manage adult patients in the acute phase of COVID in England.Copyright © 2023
ABSTRACT
Objectives: To evaluate COVID-19 vaccines in primary prevention against infections and lessening the severity of illness following the most recent outbreak of the SARS-CoV-2 Omicron variant in Shanghai. Method(s): To investigate whether inactivated vaccines were effective in protecting against COVID-19 infections, we estimated the odds ratio (OR) of the vaccination in COVID-19 cases vs. matched community-based healthy controls. To evaluate the potential benefits of vaccination in lowering the risk of symptomatic infection (vs. asymptomatic), we estimated the relative risk (RR) of symptomatic infections among diagnosed patients. We also applied the multivariate stepwise Logistic regression analyses to measure the risk of disease severity (symptomatic vs. asymptomatic and moderate/severe vs. mild) in COVID-19 patient cohort with vaccination status as an independent variable while controlling for potential confounding factors. Result(s): Out of the 153,544 COVID-19 patients included in the analysis, 118,124 (76.9%) patients had been vaccinated and 143,225(93.3%) were asymptomatic patients. Of the 10,319 symptomatic patients, 10,031(97.2%), 281(2.7%) and 7(0.1%) experienced mild, moderate, and severe infections, respectively. There is no evidence that the vaccination helped protect from infections (OR=0.82, p=0.613). The vaccination, however, offered a small but significant protection against symptomatic infections (RR=0.92, p < 0.001) and halved the risk of moderate/severe infections (OR=0.48, 95% CI: 0.37 - 0.61). Older age (> 60 years) and malignant tumors were significantly associated with moderate/severe infections. Gender also appeared to be a risk factor for symptomatic infections, with females being associated with a lower risk for moderate/severe illness. Conclusion(s): Inactivated COVID-19 vaccines helped provide a small but significant protection against symptomatic infections and halved risk of moderate/severe illness among symptomatic patients. The vaccination was not effective in blocking COVID-19 Omicron variant community spread.Copyright © 2023