Complete substitution with modified nucleotides suppresses the early interferon response and increases the potency of self-amplifying RNA (preprint)

Self-amplifying RNA (saRNA) will revolutionize vaccines and in situ therapeutics by enabling protein expression for longer duration at lower doses. However, a major barrier to saRNA efficacy is the potent early interferon response triggered upon cellular entry, resulting in saRNA degradation and translational inhibition. Substitution of mRNA with modified nucleotides (modNTPs), such as N1-methylpseudouridine (N1m{Psi}), reduce the interferon response and enhance expression levels. Multiple attempts to use modNTPs in saRNA have been unsuccessful, leading to the conclusion that modNTPs are incompatible with saRNA, thus hindering further development. Here, contrary to the common dogma in the field, we identify multiple modNTPs that when incorporated into saRNA at 100% substitution confer immune evasion and enhance expression potency. Transfection efficiency enhances by roughly an order of magnitude in difficult to transfect cell types compared to unmodified saRNA, and interferon production reduces by >8 fold compared to unmodified saRNA in human peripheral blood mononuclear cells (PBMCs). Furthermore, we demonstrate expression of viral antigens in vitro and observe significant protection against lethal challenge with a mouse-adapted SARS-CoV-2 strain in vivo. A modified saRNA vaccine, at 100-fold lower dose than a modified mRNA vaccine, results in a statistically improved performance to unmodified saRNA and statistically equivalent performance to modified mRNA. This discovery considerably broadens the potential scope of self-amplifying RNA, enabling entry into previously impossible cell types, as well as the potential to apply saRNA technology to non-vaccine modalities such as cell therapy and protein replacement.

IMPACT OF VIRTUAL INTERPROFESSIONAL COVID-19 DISASTER SIMULATION TABLETOP EXERCISE (VICTER) WORKSHOP ON DISASTER PREPAREDNESS AMONG INTERPROFESSIONAL TRAINEES IN A TERTIARY CARE TEACHING HOSPITAL IN INDIA

INTRODUCTION: Disaster planning is of significant importance for the healthcare professional and the healthcare setting. Hospital-based disaster protocols form the cornerstone of disaster response. There is a paucity of data on disaster preparedness training using the virtual tabletop exercise (VTTX) module for interprofessional education from in-hospital and prehospital settings. With the coronavirus disease 2019 (COVID-19) pandemic, we have seen a paradigm shift of education strategies to the virtual realm. Here we attempt to study the impact of an online tabletop exercise workshop on the knowledge and confidence of disaster preparedness among Interprofessional trainees. MATERIAL AND METHODS: Interprofessional trainees from medical, dental, nursing, respiratory therapy, and paramedic domains who consented were included in this study. Institutional ethics committee approval was received and the study was registered with the clinical trials registry India (CTRI), before initiation. The VTTX module has been adapted from the World Health Organization (WHO) COVID-19 training resources. Three international experts from the disaster medicine domain validated the module, questionnaire, and feedback. Wilcoxon signed-rank test was used to compare the parameters (Knowledge and confidence level) pre and post-workshop. RESULTS: A total of 76 candidates with a mean age was 21.67 ± 2.5 (range:19-36) were part of the workshop. Comparison of the median scores and interquartile range of confidence level and knowledge respectively before [38 (29.25-45.75), 9 (7-11)] and after [51.50 (45-60), 11 (10-12)] the workshop showed vital significance (p-value < 0.001). All participants gave positive feedback on the workshop meeting the objectives. The majority agreed that the workshop improved their self-preparedness (90%) and felt that the online platform was appropriate (97.5%) CONCLUSIONS: This study sheds light on the positive impact of the online VTTX based workshop on disaster preparedness training among interprofessional trainees. Disaster preparedness training using available online platforms may be effectively executed with the VICTEr workshop even during the COVID-19 pandemic. The VICTEr workshop serves as a primer for developing online modules for effective pandemic preparedness training in interprofessional education. Copyright © 2023 Via Medica.

Characteristics of nursing home residents and healthcare personnel with repeated severe acute respiratory coronavirus virus 2 (SARS-CoV-2) tests positive ≥90 days after initial infection: Four US jurisdictions, July 2020-March 2021.

One in six nursing home residents and staff with positive SARS-CoV-2 tests ≥90 days after initial infection had specimen cycle thresholds (Ct) <30. Individuals with specimen Ct<30 were more likely to report symptoms but were not different from individuals with high Ct value specimens by other clinical and testing data.

Quantifying impacts of competition and demand on the risk for fertilizer plant locations

Fertilizer is an essential commodity traded in international and domestic markets and spatial competition is important feature impacting interfirm rivalry. In the case of North American fertilizer, numerous plants have been announced to either expand or open new plants (nitrogen-based fertilizer plants), exerting competitive pressures on an industry with surplus capacity but highly competitive in terms of production costs and technology. Proposed new plants and expansions are being induced by changes in the composition of crops, changes in the price of natural gas which affects the cost of producing domestic anhydrous ammonia. Developments in the fertilizer industry have become more volatile in the post-COVID period, and concurrent with the escalation in fuel prices, the Ukraine invasion, related embargoes on Russian trade, the world's largest exporter, and operations of the Grain Corridor. The purpose of this study is to quantify risks for plant expansion (brownfield and greenfield) of nitrogen fertilizer plants in North America, given the spatial competition and the corresponding dynamic market boundaries. Specifically, we quantify risks associated with fertilizer plant expansions, identify the optimal locations of new plants, and characterize spatial competition as a result of new entrants. A model is specified that integrates Geographical Information Systems (GIS) data into a stochastic mixed-integer network spatial optimization model using Monte Carlo simulations to account for risk in the random variables. The results are reprocessed into GIS for interpretation. The impact of risk in these variables results in market boundaries that are random. Specifically, competition for these new plants has embedded risks for new entrants on the probability of production and market penetration. © 2023 The Author(s)

Outbreaks of SARS-CoV-2 Infections in Nursing Homes during Periods of Delta and Omicron Predominance, United States, July 2021-March 2022.

SARS-CoV-2 infections among vaccinated nursing home residents increased after the Omicron variant emerged. Data on booster dose effectiveness in this population are limited. During July 2021-March 2022, nursing home outbreaks in 11 US jurisdictions involving >3 infections within 14 days among residents who had received at least the primary COVID-19 vaccine(s) were monitored. Among 2,188 nursing homes, 1,247 outbreaks were reported in the periods of Delta (n = 356, 29%), mixed Delta/Omicron (n = 354, 28%), and Omicron (n = 536, 43%) predominance. During the Omicron-predominant period, the risk for infection within 14 days of an outbreak start was lower among boosted residents than among residents who had received the primary vaccine series alone (risk ratio [RR] 0.25, 95% CI 0.19-0.33). Once infected, boosted residents were at lower risk for all-cause hospitalization (RR 0.48, 95% CI 0.40-0.49) and death (RR 0.45, 95% CI 0.34-0.59) than primary vaccine-only residents.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) outbreaks in nursing homes involving residents who had completed a primary coronavirus disease 2019 (COVID-19) vaccine series-13 US jurisdictions, July-November 2021.

Among nursing home outbreaks of coronavirus disease 2019 (COVID-19) with ≥3 breakthrough infections when the predominant severe acute respiratory coronavirus virus 2 (SARS-CoV-2) variant circulating was the SARS-CoV-2 δ (delta) variant, fully vaccinated residents were 28% less likely to be infected than were unvaccinated residents. Once infected, they had approximately half the risk for all-cause hospitalization and all-cause death compared with unvaccinated infected residents.

SAFETY AND EFFICACY FINDINGS OF AUTO1, A FAST-OFF RATE CD19 CAR, IN RELAPSED/REFRACTORY B-CELL NON-HODGKIN'S LYMPHOMA (B-NHL), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) / SMALL LYMPHOCYTIC LYMPHOMA (SLL)

Background: We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR T-cell immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL (Ghorashian S et al., Nat Med 2019;Roddie C et al., JCO 2021). This data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Aims: We have initiated testing of AUTO1 in the setting of B-NHL and CLL/SLL (NCT02935257). Methods: Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised patient leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x106 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x106 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. Results: As of 8th February 2022, we enrolled 23 patients: 11 low grade NHL (LG-NHL:7 with FL and 3 with MCL), 7 DLBCL and 5 CLL. Apheresis was successful in all 23 patients and product manufacture was successful in 22 (pending in the last). 19 patients were infused: 10 with LG-NHL, 6 with DLBCL and 3 with CLL. 1 CLL patient was pending infusion at time of data cut-off and 2 patients died pre-infusion: 1 MCL patient, from COVID-19 and 1 CLL patient, from intracerebral haemorrhage. Patients treated with AUTO1 had a median age of 60 years (range 39-79), had received a median of 3 prior lines of treatment (range 2-8). Grade 1 CRS was reported in 6/19 and Grade 2 CRS in 3/19. No ICANS was observed in the B-NHL and CLL cohorts. CAR engraftment was observed in 13/13 patients evaluated by qPCR with ongoing persistence in 12/13 patients at last follow-up. In the LG-NHL and DLBCL cohorts 10/10 and 4/5 evaluable patients respectively were in CMR by 18FDG PET-CT post-treatment. Responses were ongoing in 9/10 LG-NHL at 12 months and in 4/4 DLBCL at months 1, 3, 3 and 6. In the CLL cohort, 2/3 evaluable patients achieved MRD negative remission in the bone marrow with residual small volume lymph nodes by CT at 6 and 3 months of follow-up respectively. 1 CLL patient did not engraft and had SD at month 1. Summary/Conclusion: AUTO1 has a tolerable safety profile in patients with r/r B-NHL and CLL despite high disease burden. Early data shows excellent complete remission rates and excellent CAR engraftment/expansion. Additional patients, updated data and longer follow up will be presented.

Multisystem Inflammatory Syndrome in Adults After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Coronavirus Disease 2019 (COVID-19) Vaccination.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the coronavirus disease 2019 (COVID-19) pandemic. MIS-A was included in the list of adverse events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines. METHODS: Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A. RESULTS: From 14 December 2020 to 30 April 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21-66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11-78 days) before MIS-A onset. All 20 patients had laboratory evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6-45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock. CONCLUSIONS: Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring.

Telemedicine to Timor-Leste: Implementing an International Cardiac Telehealth Service During Population Dislocation, Floods and COVID-19

Background: The East Timor Hearts Fund (ETHF) has provided cardiac services in Timor-Leste since 2010, conducting three clinics yearly. With international border closures due to the COVID-19 pandemic, development of collaborative telehealth services was required. Methods: Scoping discussions identified major challenges (structural, patient-related and medical system-related). At two pilot clinics, patient history, investigation and management were collated. Clinic metrics were compared to an index face-to-face clinic in February 2019. Post-clinic discussions identified areas of success and shortfall in the conduct of the telehealth clinics. Results: 23 patients were reviewed at the online telehealth clinics held onsite at Timorese medical facilities. Compared to an index 2019 clinic, there were markedly lower numbers of new referrals (2 vs 190 patients, 8.7% vs 59.4%). Patients seen at the online clinic were predominantly female (17/23, 73.9%) and Dili-based (18/23, 78.3%) with a mean age of 25.9 ± 7.2 years old. The majority (12/23, 52.2%) had isolated rheumatic mitral valve disease. Investigations including electrocardiography, pathology, echocardiography and 6-minute walk tests were conducted in select patients. Medication advice was provided for 10 (43.5%) patients. 11 patients (47.8%) were deemed to require urgent intervention. Post-clinic discussions indicated general satisfaction with telehealth clinics, although frustration at current inability to provide interventional services was highlighted. Conclusion: Our pilot telehealth clinics indicate that capacity-building telemedicine can be rapidly implemented in an emergency setting internationally. Clinic design benefits from careful identification and resolution of challenges to optimise flow. Cardiac patients in Timor-Leste have a significant burden of disease amenable to intervention.

Doctors With Borders: The Impact Of International Travel Bans on Timorese Citizens Awaiting Cardiac Intervention

Background: In Timor-Leste, cardiac interventions and surgical procedures are largely provided by the East Timor Hearts Fund. Since March 2020, no Timorese patients have been able to travel to Australia for humanitarian cardiac procedures. Methods: We describe patients awaiting cardiac intervention as of March 2020, documenting their outcomes eighteen months later in August 2021. Contact with healthcare facilities (the national hospital, local clinics or online telehealth) was identified. Major adverse cardiac events (MACE;death, heart failure admission or stroke) were documented and demographic characteristics compared between patients experiencing MACE versus those remaining symptomatically stable. Results: In March 2020, 35 patients were waitlisted for cardiac intervention (68.6% female, mean age 26.8 ± 9.4 yrs). Eighteen months later, 9 (25.7%) patients experienced definite MACE, comprising 3 sudden deaths and 14 admissions for decompensated heart failure. A further 10 patients (28.6%) had newly-disconnected phone numbers, implying possible additional deaths. 15 patients attended online telehealth clinics;7 (46.7%) had deteriorating NYHA scores. 14 patients (40.0%) were symptomatically stable. Patients experiencing MACE had been waitlisted a median of 30 months by August 2021 compared to 22 months for stable patients. Conclusions: At least one-quarter and possibly over half of a humanitarian charity’s patient list died or developed severe heart failure following eighteen months’ delay to cardiac intervention during international border closures from COVID-19. Patients attending online telehealth clinics reported high rates of morbidity and deteriorating symptoms. Abrupt border closures leaving a country without access to humanitarian surgery highlight the vulnerabilities of short-term medical mission models.

Neutralizing Antibody Response to Sarbecovirus Is Delayed in Sequential Heterologous Immunization.

Antigenic imprinting, which describes the bias of the antibody response due to previous immune history, can influence vaccine effectiveness. While this phenomenon has been reported for viruses such as influenza, there is little understanding of how prior immune history affects the antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting through immunization with two Sarbecoviruses, the subgenus that includes SARS-CoV-2. Mice were immunized subsequently with two antigenically distinct Sarbecovirus strains, namely SARS-CoV-1 and SARS-CoV-2. We found that sequential heterologous immunization induced cross-reactive binding antibodies for both viruses and delayed the emergence of neutralizing antibody responses against the booster strain. Our results provide fundamental knowledge about the immune response to Sarbecovirus and important insights into the development of pan-sarbecovirus vaccines and guiding therapeutic interventions.

Efficacy of a Novel Injection Lipolysis to Induce Targeted Adipocyte Apoptosis: A Randomized, Phase IIa Study of CBL-514 Injection on Abdominal Subcutaneous Fat Reduction.

BACKGROUND: CBL-514 is a novel injectable drug that may be safe and efficacious for localized abdominal subcutaneous fat reduction. OBJECTIVES: The aim of this study was to assess the safety and efficacy of CBL-514 in reducing abdominal subcutaneous fat volume and thickness. METHODS: This Phase IIa, open-label, random allocation study consisted of a 6-week treatment period and follow-up at 4 and 8 weeks following the last treatment. Participants were randomly allocated to receive 1.2 mg/cm2 (180 mg), 1.6 mg/cm2 (240 mg), or 2.0 mg/cm2 (300 mg) of CBL-514 with up to 4 treatments, each comprising 60 injections into the abdominal adipose layer. Changes in abdominal subcutaneous fat were assessed by ultrasound at follow-up visits. Treatment-emergent adverse events were recorded. RESULTS: Higher doses of CBL-514 (unit dose, 2.0 and 1.6 mg/cm2) significantly improved the absolute and percentage reduction in abdominal fat volume (P < 0.00001) and thickness (P < 0.0001) compared with baseline. Although the COVID-19 pandemic halted some participant recruitment and follow-ups, analysis was unaffected, even after sample size limitations. CONCLUSIONS: CBL-514 injection at multiple doses up to 300 mg with a unit dose of 2.0 mg/cm2 is safe, well-tolerated, and reduced abdominal fat volume and thickness by inducing adipocyte apoptosis. Although other procedures exist to treat abdominal fat, they have limitations and may cause complications. At a dose of 2.0 mg/cm2, CBL-514 safely and significantly reduced abdominal fat volume by 24.96%, making it a promising new treatment for routine, nonsurgical abdominal fat reduction in dermatologic clinics.

Serological response to the BNT162B2 mRNA or ChAdOx-nCOV-19 COVID-19 vaccine after first and second doses in plasma cell disorder patients: Influence of host and disease factors

Background Plasma cell disorders (PCD) are at risk of inadequate immune responses to COVID-19 vaccines due to recognised humoral and cellular immune dysfunction which is multi-factorial and related to host and disease factors. With an estimated risk of 33% mortality from contracting COVID-19 in this population, protection with an anti-SARS-CoV-2 vaccination is critical. Initial extension to vaccination intervals in the United Kingdom to 12 weeks in December 2020 led to concerns that PCD patients would be left vulnerable for an extended period. Methods A clinical audit was performed on measured serological responses in PCD patients after first and second doses of the BNT162b2 and ChAdOx-1 nCoV-19 vaccines. Antibody levels were measured using Elecsys Anti-SARS-CoV-2S assay (Roche) for quantitative detection of IgG Abs, specific for the SARS-CoV-2 spike-protein. Positive cut-off of 0.80 U/mL defined serological response. Testing was performed at (or closest to) 4 and 8-weeks post-dose. Baseline nucleocapsid Ab results were available from previous screening in a subset of patients. All patients on CIT underwent 4-weekly swabs. Clinical information was retrieved from medical records. Results 188 PCD patients (155 multiple myeloma, 18 amyloid, 10 SMM/MGUS, other 5 PCD), median age 64 (range 32-84), had serological assessment after both vaccine doses. Fourteen with previous COVID-19 infection were excluded. Of 174 patients, 112 were tested after first dose. 88% (153) were on chemo-immunotherapy treatment (CIT). Seropositive rate after first dose was 63% (71/112);of those with available negative baseline antibody test, 62% (31/50) seroconverted. After second dose, 89% (154/174) were seropositive;of those with negative baseline antibody, 90% (61/68) seroconverted. Expectedly, paired median titres after second dose were significantly higher than post first dose (n=112, 3.245 U/mL (IQR 0.4-25.55) vs 518 U/mL (IQR 29.40-2187) p<0.0001) (Figure 1A). Of 41 patients seronegative after first dose, 25 (61%) seroconverted after second, though with lower titres than those only requiring one dose (Figure 1B). Active CIT, disease response less than PR, >=4 lines therapy, light-chain disease, male gender and not responding to first dose were significant factors for not responding to two vaccine doses. We explored <400 U/mL as sub-optimal response (in keeping with upcoming booster study eligibility, OCTAVE-DUO(1), also encompassing the lower quartile of reported healthy controls(2)), which included 43% (75/174) patients. Age 70 years, male gender, >=4 lines of treatment were independent predictors of less-than-optimal response (anti-CD38 CIT of borderline significance). Importantly, vaccine dosing intervals classified as =<42 vs >42 days (Figure 1C) or 28 +/- 14 days vs 84 +/- 14 days (excluding n=66 in neither) (Figure 1D) did not show difference in both definitions of response, neither did vaccine type. Fourteen with previous COVID-19 infection responded to one vaccine dose, median titres 2121 U/mL (IQR 23.48- 2500)) rising to median 2500 U/mL (IQR 2500-2500) after second dose (Figure 1E), significantly higher than those without previous infection. Conclusion Serological response to COVID-19 vaccine is lower in PCD patients than reported healthy controls at 63% after first dose, rising to 89% after second dose, despite extended dosing intervals. PCD patients should be prioritised for shorter intervals, as we show that patients seronegative after first dose, respond after second dose. Further work in PCD is needed to understand how Ab levels correlate to neutralisation capability, cellular responses, protection from infection and how long seroconversion lasts to better define correlates of protection. A booster vaccination or prophylactic passive antibody strategy may be required for those identified at risk, shown not to have responded to two vaccine doses or to have less-than-optimal response. Results from these trials will be eagerly awaited. (Figure Presented).

Characteristics of SARS-CoV-2 RNA Viral Loads among Nursing Home Residents and Staff with Repeat Positive Tests ≥ 90 Days after Initial Infection: 5 US Jurisdictions, July 2020-March 2021

Background. Background. Understanding the viral load and potential infectivity of individuals in nursing homes (NH) with repeat positive SARS-CoV-2 tests ≥ 90 days after initial infection has important implications for safety related to transmission in this high-risk setting. Methods. Methods. We collected epidemiologic data by reviewing records of a convenience sample of NH residents and staff with respiratory specimens who had positive SARS-CoV-2 rRT-PCR test results from July 2020 through March 2021 and had a SARS-CoV-2 infection diagnosed ≥ 90 days prior. No fully vaccinated individuals were included. Each contributed one repeat positive specimen ≥ 90 days after initial, which was sent to CDC and retested using rRT-PCR. Specimens were assessed for replication-competent virus in cell culture if Cycle threshold (Ct) < 34 and sequenced if Ct < 30. Using Ct values as a proxy for viral RNA load, specimens were categorized as high (Ct < 30) or low (if Ct ≥ 30 or rRT-PCR negative at retesting). Continuous variables were compared using Wilcoxon signed-rank tests. Proportions were compared using Chi-squared or Fisher's exact tests. Results. Results. Of 64 unvaccinated individuals with specimens from 61 unique NHs, 14 (22%) were sent for culture and sequencing. Ten of 64 (16%) had a high viral RNA load, of which four (6%) were culture positive and none were known variants of interest or concern (Figure 1). Median days to repeat positive test result were 122 (Interquartile range (IQR): 103-229) and 201 (IQR: 139-254), respectively, for high versus low viral load specimens (p=0.13). More individuals with high viral loads (5/10, 50%) reported COVID-19 symptoms than with a low viral load (1/27, 4%, p=0.003). Most individuals (46/58, 79%) were tested following known or suspected exposures, with no significant differences between high and low viral load (p=0.18). Conclusion. In this study, nearly 1 in 6 NH residents and staff with repeat positive tests after 90 days demonstrated high viral RNA loads and viable virus, indicating possible infectivity. While individuals with high RNA viral load may be more likely to be symptomatic, distinguishing asymptomatic individuals who have high viral loads may be difficult with timing since initial infection, other test results, or exposure history alone.

Improved Clinic Attendance Rates With Introduction of Telehealth in a Tertiary Adult Congenital Heart Disease Clinic

Background: The COVID-19 pandemic has paved the way for the introduction of telehealth clinic consultations. Objectives: To examine the impact of the introduction of telehealth/telephone consultation in the COVID-19 era on clinic attendance rates in an adult congenital heart disease (ACHD) clinic. Methods: Single centre audit study to compare clinic attendance rates in a large tertiary ACHD clinic over a 12-month period immediately pre-telehealth/telephone (3/5/19-17/3/20) and post-telehealth/telephone (24/3/20-2/3/21). The overall fail to attend rate for the pre-telehealth/telephone and post-telehealth/telephone periods were compared using a chi-squared test. The ACHD clinic is held once a week except for one week per month. Patients receive lifelong follow-up and are reviewed on an annual basis, on average. Results: In the pre-telehealth/telephone period, there were 409 failures to attend for 1937 clinic bookings resulting in a 21.1% (409/1937) failure rate. In the post-telehealth/telephone period, there were 215 failures to attend for 1594 clinic bookings resulting in a 13.5% (215/1594) failure rate. There was a significant reduction in the fail to attend rate in the post-telehealth/telephone period compared with the pre-telehealth/telephone period (p<0.00001). Further research is currently underway to characterise (including geographical demographics) the patients now engaged due to telehealth/telephone consultation and those who still fail to attend. Conclusions: Clinic attendance rates in a tertiary adult congenital heart disease clinic significantly improved after introduction of telehealth/telephone consultation in the COVID-19 era. Further qualitative research is required to determine patient and clinician preferences for the use of telehealth in the ACHD clinic setting.

Multistate Outbreak of Melioidosis Associated with Imported Aromatherapy Spray.

Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an uncommon infection that is typically associated with exposure to soil and water in tropical and subtropical environments. It is rarely diagnosed in the continental United States. Patients with melioidosis in the United States commonly report travel to regions where melioidosis is endemic. We report a cluster of four non-travel-associated cases of melioidosis in Georgia, Kansas, Minnesota, and Texas. These cases were caused by the same strain of B. pseudomallei that was linked to an aromatherapy spray product imported from a melioidosis-endemic area.

Hope is No Plan: Uncovering Actively Missing Transition-Aged Youth with Congenital Heart Disease

Studies describing gaps in care for youth with congenital heart disease (CHD), focus on those who have returned to care, but rarely those actively missing from care. Our objective was to determine barriers for young adults with CHD actively missing from cardiac care and to re-engage them in care. Retrospective single-center cohort study of cardiology clinic patients ages 15–21 years with CHD between 2012 and 2019 for patients actively missing from care (≥ 12 months beyond requested clinic follow-up). We conducted prospective interviews, offered clinic scheduling information, and recorded cardiac follow-up. Data analyzed using descriptive statistics, univariable, and multivariable logistic regression. Of 1053 CHD patients, 33% (n = 349) were actively missing. Of those missing, 58% were male and median age was 17 years (IQR 16–19). Forty-six percent were Non-Hispanic White, 33% Hispanic, and 9% Black. Moderately complex CHD was in 71%, and 62% had private insurance. Patients with simple CHD, older age at last encounter (18–21), and scheduled follow-up > 12 months from last encounter were more likely to be actively missing. Interviews were completed by 125 patients/parents (36%). Lack of cardiac care was reported in 52%, and common barriers included: insurance (33%), appointment scheduling (26%), and unknown ACHD center care (15%). Roughly half (55%) accepted appointment information, yet only 3% successfully returned. Many patients require assistance beyond CHD knowledge to maintain and re-engage in care. Future interventions should include scheduling assistance, focused insurance maintenance, understanding where to obtain ACHD care, and educating on need for lifelong care.

Incidence of cardiac complications during index hospitalisation with covid-19 in Australia: Aus-covid study

Introduction: Cardiac complications of COVID-19 include acute cardiac injury, myopericarditis, cardiomyopathy and arrhythmias. This study aimed to describe the incidence of cardiac complications in patients admitted to hospital with COVID-19 in Australia. Methods: AUS-COVID is a multicentre observational cohort study across 21 Australian hospitals including all index hospitalisations with laboratory-proven COVID-19 in patients aged 18 years or older. All consecutive patients entered in the AUS-COVID Registry by 28 January 2021 were included in the present study. Results: Six hundred and forty-four hospitalised patients (62.5 ± 20.1 years old, 51.1% male) with COVID-19 were enrolled in the study. Overall in-hospital mortality was 14.3%. Twenty (3.6%) patients developed new atrial fibrillation or flutter during admission and 9 (1.6%) patients were diagnosed with new heart failure or cardiomyopathy. Three (0.5%) patients developed high grade atrioventricular (AV) block. Two (0.3%) patients were clinically diagnosed with pericarditis or myopericarditis. Among the 295 (45.8%) patients with at least one troponin measurement, 99 (33.6%) had a peak troponin above the upper limit of normal (ULN). In-hospital mortality was higher in patients with raised troponin (32.3% vs 6.1%, p<.001). New onset atrial fibrillation or flutter (6.4% vs 1.0%, p=.001) and troponin elevation above the ULN (50.3% vs 16.4%, p<.001) were more common in patients 65 years and older. There was no significant difference in the rate of cardiac complications between males and females. Conclusions: Among patients with COVID-19 requiring hospitalisation in Australia, troponin elevation was common but clinical cardiac sequelae were uncommon. The incidence of atrial arrhythmias and troponin elevation was greatest in patients 65 years and older.

Association of hypertension with mortality in patients hospitalised with covid-19

Introduction: To assess whether hypertension is an independent risk factor for mortality amongst patients hospitalised with COVID-19 and to evaluate the impact of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) on mortality in patients with a background of hypertension. Methods: This observational cohort study included all consecutive index hospitalisations with laboratory proven COVID-19 aged 18 years or older across 21 Australian hospitals entered in the AUS-COVID Registry by 22nd January 2021. Patients were excluded if their past medical or medication history was not available or if they were transferred to another hospital in which case mortality outcomes were not available. Registry data were analysed for in-hospital mortality in patients with comorbidities including hypertension, and baseline treatment with ACE inhibitors or ARBs.Results: 546 consecutive patients (62.9±19.8 years old, 51.8% male) hospitalised with COVID-19 were enrolled. In the multivariable model, significant predictors of mortality were age (aOR 1.09, 95% CI 1.07-1.12, p<.001), heart failure or cardiomyopathy (aOR 2.71, 95% CI 1.13-6.53, p=.026), chronic kidney disease (aOR 2.33, 95% CI 1.02-5.32, p=.044) and chronic obstructive pulmonary disease (aOR 2.27, 95% CI 1.06-4.85, p=.035) (Figure 1). Hypertension was the most prevalent comorbidity (49.5%) but was not independently associated with increased mortality (aOR 0.92, 95% CI 0.48-1.77, p=.81). Amongst patients with hypertension, ACE inhibitors (aOR 1.37, 95% CI 0.61-3.08, p=.61) and ARBs (aOR 0.64, 95% CI 0.27-1.49, p=.30) did not affect mortality. Conclusions: In patients hospitalised with COVID-19, pre-existing hypertension was the most prevalent comorbidity but was not independently associated with mortality. Similarly, the baseline use of ACE inhibitors or ARBs had no independent association with in-hospital mortality.

Evaluating COVID-19 Associated Coagulopathy with Thromboelastogram-Experience from South India

Introduction: Coagulopathy in COVID-19 progresses from initialpulmonary microthrombi without systemic coagulation activation to asystemic hypercoagulable stage with widespread activation of coagulation and then to a hypocoagulable picture seen in later phases ofthe disease.Aims &Objectives: We decided to conduct this study because of thesevere infections in 2021 compared to 2020 to understand theCoagulopathy in COVID-19 among our population using Thromboelastography (TEG) and V curve.Materials &Methods: All adult patients with a confirmed COVID-19 and TEG report were recruited in the study and followed up fortwo months. Citrated Kaolin TEG parameters included were R and Ktime, alpha angle, maximum amplitude, clotting index, lysis 30. Thefirst-degree velocity curve of (V curve) TEG which extrapolatesthrombin generation potential with maximum rate of thrombin generation and time as well as thrombin generated. Comparison betweensurvivors and thromboembolisms were made with TEG parameters.Result: Study included 43 patients after excluding three patients.Average age was 58.34 (± 15.35) and majority of them were males(34/43). TEG as well as V-curve were hypercoagulable compared toage matched reference range. Systemic hypercoagulable stage (34/43)and interestingly 13/34 patients had secondary fibrinolysis activity.Mortality rate and thrombotic incidents was 32.56% and 30.23%respectively. Risk factors for mortality were MA, LY 30, TG,Hypercoagulable TEG (OR-7.36), D Dimer (OR-1.40) and Thrombosis (OR-1.37). Incidents of Thrombosis in decreasing order wasacute coronary syndrome (n = 10), DVT with PTE (n = 2) and MCAinfarction (n-1). LY 30 was associated with an increased thromboticrisk (OR-15.3, r = 0.122, Correlation-0.40, P = 0.02). Repeat TEGwas performed in 11 patients which was consistent with a hypercoagulable picture even after 5 days of thromboprophylaxis.Conclusions: TEG is useful in diagnosing and categorizing Coagulopathy associated with COVID-19.