Immunotherapy: RAPID ACCESS TO VIRUS-SPECIFIC T CELLS FOR ADOPTIVE IMMUNOTHERAPY FOR COMPASSIONATE USE IN AUSTRALIA

Background & Aim: Adoptive T cell immunotherapy holds great promise for the treatment of viral complications. Our group has been developing and trialling virus-specific T cell therapies for more than 20 years. Recently, we have generated a repository of multi-virus-specific T cells for our clinical trials. Unfortunately, for many patients with viral complications, there is no suitable trial through which to access these therapies. In Australia, the Therapeutic Goods Administration has a Special Access Scheme (SAS) to enable provision of unapproved therapies for compassionate use. Our research group is now a leading Australian provider of "off-the-shelf" and custom-grown allogeneic virus-specific T cells to hospitals for patients with no other treatment options. Methods, Results & Conclusion(s): We have generated a repository of multi-virus-specific T cells from 20 healthy donors, with up to 150 doses of T cells per donor generated from a single blood sample. Each product batch is thoroughly characterised in terms of viral antigen specificity, HLA restriction and alloreactivity. These T cells target a combination of Epstein-Barr virus, cytomegalovirus, BK polyomavirus, John Cunningham virus and adenovirus epitopes. We have also generated a repository of SARS-CoV-2-specific T cells and occasionally grow custom patient-specific batches of T cells from nominated donors, on request. Since 2008, we have provided virus-specific T cells to 15 hospitals across Australia, and the volume of supply requests has significantly increased in recent years, as clinicians have gained interest in adoptive immunotherapy. In 2022, we provided T cells for 26 patients via the SAS. The majority were experiencing post-transplant complications, including cytomegalovirus disease, BK virus-associated haemorrhagic cystitis and post-transplant lymphoproliferative disorder. Through our clinical trials, we have developed rigorous processes for T cell therapy manufacture and characterisation, in addition to a computer-based selection algorithm, which we apply to SAS cases. As these cases are not part of a clinical trial, concomitant therapy varies, and monitoring is not uniform. However, we have received reports of clinical benefit from adoptive T cell therapy. These include cases of reduction in viral load, improvement in symptoms, and complete resolution of infection. We believe that these promising T cell therapies should be available to hospitals through a nationally funded centre for cellular therapies for critically ill patients.Copyright © 2023 International Society for Cell & Gene Therapy

Immunotherapy: ADOPTIVE T CELL IMMUNOTHERAPY FOR SARS-COV-2

Background & Aim: Despite the successful implementation of vaccines worldwide, COVID-19 remains a risk in patients with a compromised immune system. Emerging viral variants have also reduced the effectiveness of monoclonal antibody therapies in these patients. New treatment options are therefore required to improve clinical outcomes. Methods, Results & Conclusion(s): T cell immunotherapy has proven effective for the treatment of a number of refractory viral diseases in patients with a compromised immune system. We have now completed the manufacture of a bank of SARS-CoV-2 specific T cells and commenced an open-label phase I clinical trial at the Royal Brisbane and Women's Hospital, Australia. Patients enrolled in the study receive two doses of partially HLA-matched allogeneic T cells at a fortnightly interval. We have thus far recruited and treated three immune compromised patients with SARS-CoV-2 T cells. In two of the three patients treated thus far, the administration of T cell therapy was coincident with the clearance of viral load after 28 days. Viral clearance in these patients was also associated with an increase in circulating SARS-CoV-2 specific T cells. Our preliminary observations suggest that SARS-CoV-2 specific T cell therapy is well tolerated and has the potential to impact viral control in immune compromised patients.Copyright © 2023 International Society for Cell & Gene Therapy

[Impact of the French 2020 COVID-19 lockdown on the treatment and follow-up of patients with exudative age-related macular degeneration]. / Impact du confinement français en 2020 sur la prise en charge des patients atteints de dégénérescence maculaire liée à l'âge exsudative.

PURPOSE: To assess the impact of the measures taken during the lockdown period from March 17 to May 11, 2020 on the management of patients with exudative age related macular degeneration treated by intravitreal anti-VEGF injections at the University Hospital of Tours. METHODS: In this retrospective study, patients were included after analysis of the computerized medical records of patients with age related macular degeneration. Those who were treated for exudative age related macular degeneration who received at least 1 intravitreal injection in the 12 months prior and at least one consultation in the 6 months prior to the lockdown period, were included. The initial and final mean visual acuity were compared with a 5 letter non-inferiority margin. A subgroup analysis was performed according to outcomes. The visual acuities immediately after this period were also recorded. RESULTS: In all, 595 eyes of 493 patients were included. The mean initial visual acuity was 59.6 letters, vs. 58.5 for the final visual acuity, i.e. a difference of -1.13 letters with a lower limit of the confidence interval of less than 5. The visual acuity on release from lockdown was comparable to the other 2 measurements. Initial visual acuity and the number of missed treatments were the main factors associated with functional loss. CONCLUSION: Patients' visual acuity during the lockdown period was able to be maintained despite the restrictive measures and limitation of care access in France. The most common cause of substantial visual decline was missed intravitreal injections.

Does Covid-19 Increase the Risk of Atrial Fibrillation? A Retrospective Analysis of a Large Administrative Claims Database of Commercially Insured Non-Elderly and Medicare Advantage Beneficiaries in the United States

Background: Studies have suggested that myocardial damage due to severe acute respiratory syndrome-2 (SARS-CoV-2), commonly referred to as COVID-19, may increase the risk of arrhythmias. Objective(s): To compare the one-year incidence of atrial fibrillation (AF) among patients with COVID-19 as compared to patients with non-COVID-19 acute upper respiratory infection (AURI). Method(s): The Optum Clinformatics database, an administrative claims databaseof commercially insured beneficiaries in the United States (US), was used for study purposes. Three cohorts of patients were identified: patients with COVID-19 diagnosis in any setting (April 2020-June 2021);patients with AURI in the pandemic period (April 2020-June 2021);and patients with AURI in the pre-pandemic period (January 2018-December 2018). Patients with prior AF diagnosis were excluded from each cohort. Three sets of analysis comparing AF incidence were performed: COVID-19 cohort vs AURI pandemic cohort;COVID-19 cohort vs AURI pre-pandemic cohort;and AURI pandemic cohort vs AURI pre-pandemic cohort. For each of the three comparisons, a matching weight method was used to help ensure balance among groups on baseline socio-demographic and clinical comorbidities. Logistic regression was used to assess the odds of 1-year incident AF among matched patients. Result(s): When comparing the matched COVID-19 (n=102,227) and AURI pandemic (n=102,101) cohorts, one-year incidence of AF was significantly higher in the COVID-19 cohort (2.2% vs 1.2%;p<0.001), who were 83% more likely to develop AF (odds ratio [OR] 1.83;95% confidence interval [CI] 1.72-1.95) as compared to the AURI group. COVID-19 patients were also observed to have significantly higher risk of incident AF as compared to AURI pre-pandemic cohort (2.7% vs 1.6%;p<0.001;OR 1.70, 95% CI 1.63-1.78). No significant difference was observed in AF incidence among the AURI pandemic versus AURI pre-pandemic cohort (1.1% vs 1.2%;p=0.133;OR 0.95, 95% CI 0.90-1.01). Figure 1 depicts differences in AF incidence across the comparator cohorts. Conclusion(s): Patients with COVID-19 were observed to have a higher incidence of AF as compared to those with upper respiratory infections. Awareness amongst clinicians of an increased AF incidence in COVID-19 affected patients appears warranted. [Formula presented] French language not detected for EMBFRA articles source xmlCopyright © 2023

PIVOTING IN A PANDEMIC: THE IMPACT OF COVID-19 ON THE PROVISION OF CARE FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE: A PRELIMINARY ANALYSIS

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, also known as COVID-19, was declared a worldwide pandemic in March of 2020. Since the onset of the pandemic, the focus of many healthcare systems has shifted toward limiting non-essential visits to hospitals in order to prioritize and allocate resources toward treating those affected by COVID-19, and preventing further exposures. While the effect of COVID-19 has been felt amongst many patient populations, those with inflammatory bowel disease (IBD) have been particularly impacted through delayed appointments and endoscopy, which is critical in disease monitoring. Aims: We aimed to determine how changes to the provision of IBD care due to the COVID-19 pandemic have affected IBD patients. Methods: A retrospective cohort study was conducted using administrative data comparing IBD patients admitted to the gastroenterology ward from March 17 to August 31 2019, with IBD patients admitted from March 17 to August 31 2020 at a tertiary care centre in London, Ontario. Patients were reviewed to assess differences in care utilization and IBD-related outcomes such as hospitalization, surgery and length of stay and in-patient drug therapy. Results: A total of 538 patients (259 in 2019 cohort and 279 in 2020 cohort) were reviewed with 48 and 60 IBD patients meeting the inclusion criteria for 2019 and 2020 respectively. Patient demographics were similar between 2019 and 2020 cohort for age, sex, rurality, disease type, and biologic exposure. A greater proportion of patients were admitted with IBD flares in 2020 (86.7% vs 75%, p=0.03). Furthermore, the 2020 cohort also had a 45% increase in in-patient surgical consultations (p=0.07), a 50% increase in in-patient IBD-related surgeries (p=0.39), a 69% increase in inpatient Remicade prescription (p=0.13) and a 70% increase in infectious complications at presentation to hospital (p=0.21). A shorter median length of stay was reported for patients in the 2020 cohort (4 days IQR 3.95 vs 5.85 IQR 4.65, p=0.09). Conclusions: Preliminary data suggest that during the COVID-19 pandemic, we have seen more deleterious outcomes in our IBD patients such as increased flares necessitating hospital admission. There was also a non-significant trend toward increased infectious complications as well as in-patient surgeries and need for inpatient Remicade. Though these results cannot be fully interpreted due to the need for further sampling, they suggest that IBD patients may be at-risk for poor outcomes in the current climate of medical care. Completion of this study will help define the full impact of care shifts related to reducing the spread of the novel coronavirus on IBD patients and highlight areas of care that need careful assessment and consideration to protect IBD patient health.

DEFINING IMMUNOGENIC PEPTIDES TARGETING SARS-CoV-2 VARIANTS of CONCERN

Background: Identifying Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) specific T-cell epitope-derived peptides that are also found within variants of concern (VOC) is critical for measuring the duration of cellular immunity induced by the virus and COVID-19 vaccines. Therefore, we assessed whether the peptides selected from topologically important regions of SARS-CoV-2 proteins avoid major mutations of VOC and induce T-cell immune response. Methods: We selected 32 peptides within topologically important regions of SARS-CoV-2 Spike (S) and Nucleocapsid (NC) proteins by applying an insilico pipeline to 607 viral sequences in 2019. To determine if these peptides avoid VOC mutations, we analyzed S and NC protein regions derived from 1.7 x 106 viral genomic sequences compiled from Mar 2020-Aug 2021. We identified α-, β-and δ-VOC mutations found within >1% of the S and NC protein sequences. These mutations were compared to the peptides. To determine T-cell immune response to these selected peptides as a pool, we assessed interferon-γ (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and CD107a/b (degranulation marker) production within peripheral blood mononuclear cell (PBMC) samples derived from COVID-19 post-recovery donors (n=23) by employing dual color FluoroSpot and intracellular cytokine staining (ICS). Results: We found 88% of S protein-derived peptides did not contain mutations of α-, β-and δ-VOC. All peptides from S protein (n=25) avoided known T-cell escape mutations. Of the 7 NC-derived peptides, three contained the L139F mutation found within α-and δ-VOC, however, this mutation was observed within <2% NC protein sequences. A peptide pool containing our 32 selected peptides elicited an immune response within PBMCs from 17/23 COVID-19 post-recovery donors. FluoroSpot analysis revealed IFN-γ and IL-2 production to our peptide pool was similar/higher compared to the commercial S and NC peptide pools. The response of CD4 and CD8 T-cells to our peptide pool was polyfunctional expressing ≥2 markers within most of the donors when ICS was performed, with IFN-γ and TNF-α being the main cytokines produced. Conclusion: Applying an immunoinformatics pipeline allowed us to select peptides from the S and NC proteins which avoid the majority of mutations found within the α-, β-and δ-VOC. Our peptide pool elicited a polyfunctional T-cell response making it an ideal candidate for assessing the duration of cellular immunity induced by SARS-CoV-2 variants and vaccines.

Impact of the first lockdown related to the COVID-19 pandemic on ophthalmic emergencies in a French University Hospital.

INTRODUCTION: At the beginning of the COVID-19 pandemic, the French government implemented its first national lockdown between March and May 2020 in order to limit the dissemination of the virus. This historic measure affected patients' daily lives and transportation, resulting in changes in the delivery of medical care, particularly emergency care. This study aimed to assess the impact of this restriction policy on the number and severity of ophthalmic emergencies seen in an ophthalmology emergency department. METHODS: This retrospective study conducted at the regional university Hospital of Tours included all patients presenting to the ophthalmology emergency department over four periods: lockdown (03/16/2020 to 05/10/2020), post-lockdown (05/11/2020 to 06/12/2020) and the two corresponding periods in 2019. The following data were recorded: sex, age, time of visit, reason for visit, diagnosis, severity of emergency graded on the BaSe SCOrE, time from first symptoms until visit, existence of a work-related injury, and referral source (ophthalmologist or other). RESULTS: A total of 1186 and 1905 patients were respectively included during the 2020 lockdown period and the corresponding period in 2019. The study populations for the 2019 and 2020 post-lockdown periods consisted of 1242 and 1086 patients respectively. During the lockdown, the number of consultations decreased significantly (-37.7%), affecting mild and severe emergencies similarly. During the post-lockdown period, the number of emergencies gradually increased but did not reach the level of the corresponding period in 2019 (-12.6%). CONCLUSION: The first French lockdown resulted in a significant decrease in ophthalmic emergency visits, similar for all levels of severity. All age groups were impacted similarly, without the expected exaggerated decrease for patients over 50 years of age, who are considered to be at greater risk for developing a severe form of COVID-19. The post-lockdown period showed a gradual increase in ophthalmic emergency visits, although these remained fewer than the previous year.

Dengue fever-a worldwide study

Nowadays, after coronavirus COVID 19, dengue fever is a problem of human beings that is spread by the Aedes aegypti mosquitoes. If proper protection arrangements from the particular mosquitoes are not done, this problem may lead to a pandemic. The main problem of this fever is that the starting symptoms are the same as viral fever as high fever, myalgia, muscular and joint pain, hemorrhagic episodes, and cutaneous rash. The purpose of this manuscript is to aware people of this health problem. Near the rain season, the problems of mosquitoes are increased. The awareness of the people could prevent this disease. In this manuscript, an analytic study on the worldwide dengue fever has been made. It is observed that after 2010, the cases of dengue fever are increased continuously. People should keep neat and clean their surroundings and cover maximum part of the body. © 2021 The authors.

Assessing asymmetric determinants of commodity-level exports: the role of policy responses to the COVID-19 pandemic

This paper explores the economic consequences of non-pharmaceutical government intervention to curb disease spread on Indian commodity-level exports. This is the first study to assess the export implications of the pandemic using a panel linear as well as a novel non-linear ARDL framework. Our results show that pandemic-related stringencies have a positive effect on Indian exports in the long-run. This result holds valid for domestic as well export destination countriesModified Letter Turned Comma stringencies. However, our evidence suggests that reducing stringencies has a more dominating effect on Indian exports than tightening of stringencies. Also, stringencies and uncertainty impact exports adversely in the short-run. Furthermore, pandemic-related financial uncertainty is found to have a dampening effect on exporting. Our results also show a significant asymmetric impact of policy responses on exports, especially for agriculture and manufacturing commodities, while mineral products are relatively less impacted.

Dexmedetomidine infusion for conscious sedation in fess for mucormycosis

Aim of study: To study the efficacy and safety of dexmedetomidine infusion for conscious sedation in post-covid patients for FESS. Method: we conducted a prospective study of 96 post-covid patients with mucormycosis posted for bilateral FESS after standard approval from the ethical committee in our institute. The patients included were ASA Grade I-3 presenting 4 to 6 weeks after covid infection. 78 out of 96 patients were severely diabetic with mean HbA1c between 8 to 9. 48 patients had severe lung infection with a CT severity scoring > 15/25. Surgery was performed under local anaesthesia with 2% lignocaine and adrenaline infiltration. Patient was premedicated with injection glycopyrrolate 0.2 mg, intravenous midazolam 0.03- 0.05 mg/ kg and intravenous fentanyl 1-2 μg/kg. Intravenous dexmedetomidine infusion was started preoperatively. initial loading dose was a bolus of 1 μg/kg over 20 minutes followed by a continuous infusion of 0.5 μg/kg intraoperatively. The entire surgery was conducted under local anaesthesia with sedation in 90 patients. General anaesthesia was given in 6 patients because of patient non- cooperation and increased bleeding. Observation: Dexmedetomidine is a potent selective alpha 2 adrenergic agonist. It caused dosedependent sedation and anxiolysis, potentiation of opioid analgesia, minimal respiratory depression and had additional antisialagogue, antitussive and sympatholytic properties. Its use improved the surgical field significantly without compromising patient safety. 10 patients developed bradycardia/ hypotension intraoperatively, so the infusion was discontinued. Conclusion: Easy administration of dexmedetomidine and lack of toxic side effects while maintaining adequate perfusion of vital organs makes it a near-ideal hypotensive agent. Its additional antiinflammatory property is particularly beneficial in post-covid patients. It is an invaluable adjunct In cases where general anaesthesia is avoided. We conclude that dexmedetomidine plays a pivotal role in conscious sedation for FESS.

COVID-19 pandemic: lessons learned and future directions

Emerging pandemics show that humans are not infallible and communities need to be prepared. Coronavirus outbreak was first reported towards the end of 2019 and has now been declared a pandemic by the World Health Organization. Worldwide countries are responding differently to the virus outbreak. A delay in detection and response has been recorded in China, as well as in other major countries, which led to an overburdening of the local health systems. On the other hand, some other nations have put in place effective strategies to contain the infection and have recorded a very low number of cases since the beginning of the pandemics. Restrictive measures like social distancing, lockdown, case detection, isolation, contact tracing, and quarantine of exposed had revealed the most efficient actions to control the disease spreading. This review will help the readers to understand the difference in response by different countries and their outcomes. Based on the experience of these countries, India responded to the pandemic accordingly. Only time will tell how well India has faced the outbreak. We also suggest the future directions that the global community should take to manage and mitigate the emergency.

Doing Remote Controlled Studies with Humans: Tales from the COVID Trenches

How should empirical researchers conduct controlled, remote 'lab' studies in the uncontrolled, noisy conditions of each participant's own home? Volatility in participant home environments, hardware, internet connection, and surrounding distractions takes the 'controlled' out of controlled studies. This paper recounts our in-The-Trenches mitigations for designing and conducting two complex controlled studies under COVID, in which participants, from home, interactively localized faults in an AI system. The studies with our COVID-era mitigations in 5 categories-Privacy/Security, Data Collection, Control, Technology Issues, Payment-ultimately produced crisp results beyond what we thought possible under such uncontrolled circumstances. © 2021 IEEE.

Impact of the COVID-19 pandemic on the volumes and outcomes of acute ischemic stroke and myocardial infarction

Introduction: The COVID-19 pandemic has wreaked havoc on the presentation, care and outcomes of patients with acute cerebrovascular and cardiovascular conditions. We sought to measure the national impact of COVID-19 on the care for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). Methods: In this retrospective, observational study, we used the Premier Healthcare Database to evaluate the changes in the volume of care and hospital outcomes for AIS and AMI in relation to the pandemic. The pandemic months were defined from March 1, 2020- April 30, 2020 and compared to the same period in the year prior. Outcome measures were volumes of hospitalization and reperfusion treatment for AIS and AMI (including intravenous thrombolysis [IVT] and/or mechanical thrombectomy [MT] for AIS and percutaneous coronary interventions [PCI] for AMI) as well as inhospital mortality, hospital length of stay (LOS) and hospitalization costs were compared across a 2- month period at the height of the pandemic versus the corresponding period in the prior year. Results: There were 95,453 AIS patients across 145 hospitals and 19,744 AMI patients across 126 hospitals. There was a significant nation-wide decline in the absolute number of hospitalizations for AIS (-38.94%;95%CI,-34.75% to -40.71%) and AMI (-38.90%;95%CI,-37.03% to -40.81%) as well as IVT (-30.32%;95%CI,-27.02% to -33.83%), MT (-23.54%;95%CI,-19.84% to -27.70%), and PCI (-35.05%;95%CI,-33.04% to -37.12%) during the first two months of the pandemic. This occurred across low-, mid-, and high-volume centers and in all geographic regions. Higher in-hospital mortality was observed in AIS patients (5.7% vs.4.2%, p=0.0037;OR 1.41,95%CI 1.1-1.8) but not AMI patients. A shift towards an increase in the proportion of admitted AIS and AMI patients receiving reperfusion therapies suggests a greater clinical severity among patients that were hospitalized for these conditions during the pandemic. A shorter length of stay (AIS: -17%, AMI: -20%), and decreased hospitalization costs (AIS: -12%, AMI: -19%) were observed. Conclusions: Our findings shed light on the combined health outcomes and economic impact the COVID-19 pandemic has had on acute stroke and cardiac emergency care.