The Covid Response in the GCC: Making a Durable Economic Policy Agenda

Given the trauma of the Covid-19 pandemic, the Gulf states realized a major success in the containment of the virus, a roll-out of a vaccination campaign and choosing to continue a general shift toward economic reform that began after the decline in oil prices in late 2014. It has been a heavy order for state capacity, and the GCC states have largely demonstrated that their control over population mobility and their tools for management of public health systems have demonstrated competent public service delivery. The reward for that success may be a sharp U-turn in the direction of oil prices by late 2021 that would help with fiscal spending buffers but will also tempt governments to limit their commitment to subsidy reform, taxation, and reduction of the public sector wage bill. However, the economic reform agenda underway in efforts to increase new forms of non-oil government revenue and to reduce government spending on subsidies and public sector wages seems to be held in place. In general terms, the Covid crisis also highlighted the limits of public sector-driven economic growth. The ability to direct support to workers and private sector businesses was comparatively weaker in the Gulf than in OECD and advanced economies. This chapter highlights the surprising durability of the economic reform policies already underway when the twin crises of the oil price declines (in both late 2014 and again as a shock in spring 2020) and the Covid-19 pandemic. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023, corrected publication 2023.

GCC Hydrocarbon Economies and COVID: Old Trends, New Realities

The book considers the impact of COVID-19 on the GCC member states through the prism of challenges faced by their hydrocarbon sector. Yet, the publication's discourse is not solely focused on the problems experienced by the oil and gas industries of the GCC member states after the beginning of the COVID pandemic. Instead, the contributors will analyze how these challenges and subsequent response to them affected other aspects of the GCC socio-economic and political development, from direct impact of the COVID on the energy sector of the GCC to socio-economic consequences of the oil market crisis for the region and its potential fallouts for the international relations of the Gulf. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023, corrected publication 2023.

Immune response enhancement with GLS-5310 DNA primary vaccine against SARS-CoV-2 followed by administration of an mRNA vaccine heterologous boost.

Heterologous boost regimens are being increasingly considered against SARS-CoV-2. We report results for the 32 of 45 participants in the Phase 1 CoV2-001 clinical trial (Kim et al., Int J Iinfect Dis 2023, 128:112-120) who elected to receive an EUA-approved SARS-CoV-2 mRNA vaccine 6 to 8 months following a two-dose primary vaccination with the GLS-5310 bi-cistronic DNA vaccine given intradermally and followed by application of suction using the GeneDerm device. Receipt of EUA-approved mRNA vaccines after GLS-5310 vaccination was well-tolerated, with no reported adverse events. Immune responses were enhanced such that binding antibody titers, neutralizing antibody titers, and T-cell responses increased 1,187-fold, 110-fold, and 2.9-fold, respectively. This paper is the first description of the immune responses following heterologous vaccination with a DNA primary series and mRNA boost.

The Effect Of Rhabdomyomas On Underlying Cardiomyopathy: A Case Report

Case Presentation: Term male infant born to SARS-CoV-2 positive mother with infant testing negative. ECG for perinatal bradycardia revealed ventricular pre-excitation. Echocardiogram showed asymmetric LV hypertrophy with prominent trabeculations, subaortic narrowing with no pressure gradient, and normal biventricular systolic function. Rapid increase in RV pressure estimates and NT-proBNP in first week if life concerning for diastolic dysfunction. Anti-arrhythmic therapy initiated for SVT with subsequent resolution. Later, developed progressive LV dilation and systolic dysfunction. Myocardium showed regions resembling non-compaction and others concerning for infiltrative process. Cardiac MRI showed no obvious tumors, but rhabdomyomas could not be ruled out given similar appearance to myocardium. Due to worsening heart failure, everolimus therapy initiated to target potential rhabdomyomas while awaiting genetic testing for tuberous sclerosis. Subaortic narrowing and LV hypertrophy improved within days, and LV appearance became more consistent with non-compaction. Genetic testing revealed a TSC2 gene variant consistent with tuberous sclerosis. Systolic function improved, and patient discharged on afterload reduction. Echocardiogram 6 months post-discharge shows continued LV dilation and mild systolic dysfunction. Discussion(s): Although outflow obstruction and arrhythmias are common with cardiac rhabdomyomas and can cause dysfunction, our patient developed progressive dysfunction in the absence of outflow tract gradient or prolonged arrhythmia. As rhabdomyomas subsided, it became clearer that he had an underlying cardiomyopathy. We suspect that rhabdomyomas in the setting of abnormal myocardium led to abnormalities in myocardial contractility and compliance causing combined systolic and diastolic dysfunction. After complete resolution of rhabdomyomas, cardiac function has improved. However, he continues to have ventricular dilation and mild dysfunction attributable to cardiomyopathy. It is unlikely that mother's SARS-CoV-2 infection played a role as infant tested negative and clinical picture was not consistent with myocarditis.

POLYFUNCTIONAL SARS-CoV-2-SPECIFIC T CELLS PERSIST IN TISSUE OF COVID-19 CONVALESCENTS

Background: T cells play an essential role in SARS-CoV-2 immunity, including in defense against severe COVID-19. However, most studies analyzing SARSCoV- 2-specific T cells have been limited to analysis of blood. Furthermore, the role of T cells in SARS-CoV-2 immunity in pregnant women, which are at disproportionately higher risk of severe COVID-19, is poorly understood. Method(s): Here, we quantitated and deeply phenotyped SARS-CoV-2-specific T cells from convalescent women (n=12) that had mild (non-hospitalized) COVID-19 during pregnancy. Endometrial, maternal blood, and fetal cord blood specimens were procured at term, which ranged from 3 days to 5 months post-infection. SARS-CoV-2-specific T cells were deeply analyzed by CyTOF using a tailored phenotyping panel designed to assess the effector functions, differentiation states, and homing properties of the cells. Result(s): SARS-CoV-2-specific T cells were more abundant in the endometrium than in maternal or fetal cord blood. In a particularly striking example, in one donor sampled 5 months after infection, SARS-CoV-2-specific CD8+ T cells comprised 4.8% of total endometrial CD8+ T cells, while it only reached 1.4% in blood. Endometrial SARS-CoV-2-specific T cells were more frequently of the memory phenotype relative to their counterparts in maternal and fetal cord blood, which harbored higher frequencies of naive T cells. Relative to their counterparts in blood, endometrial SARS-CoV-2-specific T cells exhibited unique phenotypic features, including preferential expression of the T resident memory marker CD69, inflammatory tissue-homing receptor CXCR4, and the activation marker 4-1BB. Endometrial T cells were highly polyfunctional, and could secrete IFNg, TNFa, MIP1b, IL2, and/or IL4 in response to spike peptide stimulation. By contrast, their counterparts in blood preferentially produced the cytolytic effectors perforin and granzyme B. Conclusion(s): Polyfunctional SARS-CoV-2-specific T cells primed by prior exposure to the virus are abundant and persist in endometrial tissue for months after infection. These cells exhibit unique phenotypic features including preferential expression of select chemokine receptors and activation molecules. Compared to their blood counterparts, the effector functions of these cells are more cytokine-driven and less cytolytic. The long-term persistence of these cells in the endometrium may help protect future pregnancies from SARS-CoV-2 re-infection.

Safety and immunogenicity of the bi-cistronic GLS-5310 COVID-19 DNA vaccine delivered with the GeneDerm suction device.

OBJECTIVES: The CoV2-001 phase I randomized trial evaluated the safety and immunogenicity of the GLS-5310 bi-cistronic DNA vaccine through 48 weeks of follow-up. DESIGN: A total of 45 vaccine-naïve participants were recruited between December 31, 2020, and March 30, 2021. GLS-5310, encoding for the SARS-CoV-2 spike and open reading frame 3a (ORF3a) proteins, was administered intradermally at 0.6 mg or 1.2 mg per dose, followed by application of the GeneDerm suction device as part of a two-dose regimen spaced either 8 or 12 weeks between vaccinations. RESULTS: GLS-5310 was well tolerated with no serious adverse events reported. Antibody and T cell responses were dose-independent. Anti-spike antibodies were induced in 95.5% of participants with an average geometric mean titer of ∼480 four weeks after vaccination and declined minimally through 48 weeks. Neutralizing antibodies were induced in 55.5% of participants with post-vaccination geometric mean titer of 28.4. T cell responses were induced in 97.8% of participants, averaging 716 site forming units/106 cells four weeks after vaccination, increasing to 1248 at week 24, and remaining greater than 1000 through 48 weeks. CONCLUSION: GLS-5310 administered with the GeneDerm suction device was well tolerated and induced high levels of binding antibodies and T-cell responses. Antibody responses were similar to other DNA vaccines, whereas T cell responses were many-fold greater than DNA and non-DNA vaccines.

PRIMARY LUNG MALIGNANCY PRESENTING AS RARE CUTANEOUS METASTASIS TO EYELID

SESSION TITLE: Unusual Cancer Cases SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 09:15 am - 10:15 am INTRODUCTION: Cutaneous lesions may present as a clue to an internal malignancy and provide an easily accessible site for tissue confirmation. We present a case of an eyelid metastatic lesion presenting as an initial sign of primary pulmonary malignancy. CASE PRESENTATION: A 67-year-old woman with past medical history of SARS-COVID-2 pneumonia six months ago and reformed smoker (26 pack year) who quit 27 years ago, presented to the primary care physician's office with a chief complaint of a small right upper eyelid margin (base of eyelashes) lesion (Figure 1A), and ongoing nonproductive cough and fatigue since diagnosis of SARS-COVID-2 pneumonia. The eyelid lesion appeared two weeks prior and had quickly grown in size. The lesion was associated with mild itching, but without any associated pain, discharge, or bleeding. She also complained of left elbow and foot pain but denied fever, chills, rigors, hemoptysis, pleurisy, and weight loss. Physical examination was negative for lymphadenopathy. Chest x-ray revealed a hazy left upper lobe opacity. Urine antigen for blastomycoses and histoplasma were negative. Rheumatoid factor, erythrocyte sedimentation rate, C reactive protein, QuantiFERON TB gold and anti-nuclear and cyclic citrullinated peptide antibodies were negative. Computed tomography of chest revealed a left upper lobe 3.7 x 5.4 x 5.6 cm mass, numerous bilateral ground glass opacities, and scattered (less than 5 mm) nodules (Figure 1B). Simultaneously, the patient was evaluated by an ophthalmologist for excision of the eyelid lesion. Histopathological evaluation revealed malignancy compatible with metastatic lung adenocarcinoma (Figure 1C) DISCUSSION: While an uncommon presentation, this case highlights the importance of a through history and examination in a patient presenting with pulmonary symptoms with risk factors for a lung malignancy. While she did have imaging that demonstrated lung masses, the diagnosis of lung cancer came not from invasive sampling of these masses, but rather from excision and histopathological evaluation of an eyelid soft tissue mass. Lung cancer is prone to metastasis, however cutaneous manifestations of lung cancer are relatively rare and are more common in the advanced stages of disease, making cutaneous metastasis a poor prognostic factor. In terms of cutaneous metastases, ocular metastases are one of the rarest locations making this a unique presentation. In a patient presenting with pulmonary masses, any concurrent development of new and/or growing skin lesions should be evaluated to rule out metastasis and potentially yield diagnosis. CONCLUSIONS: In patients presenting with concern for a malignant lung process, a skin exam should be completed, and suspicious skin lesions should be biopsied. Although rare, lung malignancies do metastasize to ocular cutaneous tissues and are a marker of more advanced stage of the malignancy. Reference #1: Hidaka T, Ishii Y, Kitamura S. Clinical features of skin metastasis from lung cancer. Intern Med. 1996;35:459-462. Reference #2: Marcoval J, Penin RM, Llatjos R, Martinez-Ballarin, I. Cutaneous metastasis from lung cancer: retrospective analysis of 30 patients. Australas J Dermatol. 2012;53(4):288-290. Reference #3: Abdeen Y, Amireh S, Patel A, Al-Halawani M, Shaaban H, Miller R. Cutaneous metastasis as a first presentation for lung adenocarcinoma. N Am J Med Sci. 2016;8(5): 222-225. DISCLOSURES: No relevant relationships by Gregory Griepentrog No relevant relationships by Chinmay Jani No relevant relationships by Bailey Ray No relevant relationships by Harpreet Singh No relevant relationships by Amit Taneja No relevant relationships by Kara Young

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

EFFECTS OF DELAYED ENDOSCOPIES IN INFLAMMATORY BOWEL DISEASE PATIENTS DURING THE COVID-19 PANDEMIC

Objectives: Care for many chronic conditions was altered during the COVID-19 pandemic. For patients with Inflammatory Bowel Disease (IBD), routine maintenance including endoscopies were postponed. The effects of delaying endoscopies on IBD outcomes are currently unknown. This study aimed to evaluate effects of delays of maintenance endoscopies on patients with IBD during the COVID-19 pandemic. Methods: This was a retrospective review of all IBD patients scheduled for routine endoscopy at Northwestern Memorial Hospital March 13, 2020 through May 31, 2020. All endoscopic examination were canceled in this period due to COVID-19. Patients were divided between those whose endoscopies were rescheduled promptly (on-time) or postponed (delayed) after August 31, 2020. Patient outcomes were examined one year after cancellation. Primary outcomes included hospital and emergency room admissions. Secondary outcomes included need for surgery and medication changes. Results: 100 patients were included in the delayed group and 150 in the on-time group, with a mean age of 47.5 and 42.8 years respectively. 59.2% had Crohn's disease (CD), 39.2% had Ulcerative Colitis (UC) and 1.2% had indeterminate colitis. Both groups had a similar initial severity scores as measured by the Harvey-Bradshaw Index in CD and the Simple Clinical Colitis Activity Index in UC. On average, the on-time group endoscopy was re-scheduled 2.8 months after closure compared to 9.1 months for the delayed group. There was no difference in the number of emergency room visits or hospital admissions during the delay. At one-year post-endoscopy, there was no difference in the number of emergency room visits between the on-time group (n=10, 6.7%) and the delayed group (n= 3, 3%), p= 0.17. One-year post-endoscopy there were significantly more hospitalizations in the on-time group (n=14, 9.3%) compared to the delayed group (n=3, 3%), p=0.03. There was one malignancy in the on-time group and two in the delayed group which did not reach statistical significance. Although clinical severity scores were similar at 1 year, there were more IBD related surgeries in the on-time group (16) compared to the delayed group (4), p=0.03. Discussion: Patients with delayed endoscopies due to COVID-19 did not experience worse outcomes compared to patients whose endoscopies remained on-time. There was a trend towards increased malignancies in the delayed group, but higher number of admissions and operations in the on-time group despite similar degree of inflammation on endoscopy. Retrospective nature of this review did not allow us to evaluate all the factors that may have influenced the decision for admission and surgery. Conclusions: Controlled delay in colonoscopies in patients with IBD with closely monitored re-scheduling efforts is safe and can be utilized in times of emergencies without compromising patient outcomes.

In people with type 2 diabetes most risk factors for covid-19 mortality are shared with pneumonia, however ethnicity related risk is very different

Aims: Previous UK population research identified multiple risk factors for increased covid-19 mortality in people with type 2 diabetes but it is unclear if these are general to respiratory infections or specific to covid-19. We aimed to compare risk factors associated with death from covid-19 (pre-vaccination roll-out) and pneumonia. Methods: In UK routine primary care data (CPRD), we followed adults with type 2 diabetes from 01/09/2019-31/ 01/2020 (pneumonia mortality cohort n = 609,079) and 01/02/2020-31/ 10/2020 (covid-19 mortality cohort n = 587,933). Multivariable Cox proportional hazards models were used to identify risk factors in each cohort. Results: We observed 2,690 deaths (0.5%) due to covid- 19, and 1,612 deaths due to pneumonia (0.3%). For covid- 19 mortality, we replicated previously reported risk factor associations for male sex, older age, higher deprivation, higher BMI, renal impairment, previous stroke and cardiovascular disease. These features were also associated with higher pneumonia mortality. A differential effect was observed for ethnicity: compared to people of white ethnicity, black and south Asian groups had higher covid-19 mortality (adjusted hazard ratio [aHR] 2.07 [95%CI 1.81-2.38], p < 0.001, and 1.50 [1.33-1.70], p < 0.001 respectively), but lower pneumonia mortality (aHR 0.43 [95%CI 0.31-0.60], p < 0.001, and 0.54 [0.43-0.68], p < 0.001 respectively). Higher HbA1c was a stronger risk factor for covid-19 mortality than pneumonia mortality (aHRs [95%CI] HbA1c >86 vs 48-53 mmol: 1.30 [1.09-1.54], p = 0.004 for covid- 19, 1.10 [0.86-1.42], p = 0.442 for pneumonia). Conclusions: In type 2 diabetes, clinical risk factors for covid-19 and pneumonia mortality are largely similar, but non-white ethnicities have disproportionately higher risk of covid-19 mortality compared to lower risk of pneumonia mortality, which needs further exploration.

Effects of delayed endoscopies in inflammatory bowel disease patients during the COVID-19 pandemic

OBJECTIVES: Care for many chronic conditions was altered during the COVID-19 pandemic. For patients with Inflammatory Bowel Disease (IBD), routine maintenance including endoscopies were postponed. The effects of delaying endoscopies on IBD outcomes are currently unknown. This study aimed to evaluate effects of delays of maintenance endoscopies on patients with IBD during the COVID-19 pandemic. METHODS: This was a retrospective review of all IBD patients scheduled for routine endoscopy at Northwestern Memorial Hospital March 13, 2020 through May 31, 2020. All endoscopic examinations were canceled in this period due to COVID-19. Patients were divided between those whose endoscopies were rescheduled promptly (ontime) or postponed (delayed) after August 31, 2020. Patient outcomes were examined one year after cancellation. Primary outcomes included hospital and emergency room admissions. Secondary outcomes included need for surgery and medication changes. RESULTS: 100 patients were included in the delayed group and 150 in the on-time group, with a mean age of 47.5 and 42.8 years respectively. 59.2% had Crohn's disease (CD), 39.2% had Ulcerative Colitis (UC) and 1.2% had indeterminate colitis. Both groups had similar initial severity scores as measured by the Harvey-Bradshaw Index in CD and the Simple Clinical Colitis Activity Index in UC. On average, the on-time group endoscopy was rescheduled 2.8 months after closure compared to 9.1 months for the delayed group. There was no difference in the number of emergency room visits or hospital admissions during the delay. At one-year post-endoscopy, there was no difference in the number of emergency room visits between the on-time group (n=10, 6.7%) and the delayed group (n=3, 3%), p= 0.17. One-year post-endoscopy there were significantly more hospitalizations in the on-time group (n=14, 9.3%) compared to the delayed group (n=3, 3%), p=0.03. There was one malignancy in the on-time group and two in the delayed group which did not reach statistical significance. Although clinical severity scores were similar at 1 year, there were more IBD related surgeries in the ontime group (16) compared to the delayed group (4), p=0.03. DISCUSSION: Patients with delayed endoscopies due to COVID-19 did not experience worse outcomes compared to patients whose endoscopies remained on-time. There was a trend towards increased malignancies in the delayed group, but higher number of admissions and operations in the on-time group despite similar degree of inflammation on endoscopy. Retrospective nature of this review did not allow us to evaluate all factors that may have influenced the decision for admission and surgery. CONCLUSIONS: Controlled delay in endoscopies in patients with IBD with closely monitored re-scheduling efforts is safe and can be utilized in times of emergencies without compromising patient outcomes.

Longitudinal myocardial mechanics in covid19 survivors with normal left ventricular ejection fraction, a single center study

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods &Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40;p value <0.0001), SRs was similar (-0.97 s-1±0.10 vs. -0.98 s-1±0.02, p value 0.2528) and SRe was lower (0.85 s-1±0.0 vs. 1.05 s-1±0.02;p value <0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p<0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs &SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.

Nano-triciribine reduces sars-cov-2 infection by sequestering ace2 and the novel host factor LDLR

Introduction: People with previous CVD hospitalized for COVID-19 have elevated death rate. We reported that patients with diabetes and HF higher protein levels of the low density lipoprotein receptor (LDLR). We hypothesized that LDLR is a novel host factor for the SARS-CoV-2-Spike (S2S) protein that may be regulated by the Akt inhibitor Triciribine (TCN), a drug being tested in Phase III studies for breast cancer. We also hypothesized that nano-formulation of Triciribine (NanoTriciribine;NTCN) would enhance its efficacy and allow for intranasal delivery. Methods: Interactions between the recombinant proteins Spike-RBD (receptor binding domain), ACE2, LDLR and its ectodomains (EGFA-EFFB, C2-C5 and C2) were analyzed by binding assays and co-IP in HepG2, HK2, and 293T cells. Viral entry assays were performed with 2 S2S pseudoviruses using 293T cells + hACE2 and TMPRSS2 or Furin protease. The effect of NTCN or the LXR agonist GW-3965 on viral uptake (pseudotyped VSVΔG-GFP∗S2S or chimera VSV-S2SeGFP virus) was assessed. Akt, pAkt, ACE2, and LDLR levels were determined in 293T+hACE2 by flow cytometry. Assays were done in triplicates and 1-way-ANOVA with Tukey's correction was used for statistics. Results: RBD protein binds modestly to the human LDLR (EC50:10μM) and its C2-C5 ectodomain (EC50:13.8μM). Co-IP revealed a novel and strong LDLR-ACE2 interaction in several human cell lines. LDLR overexpression in human cells increased the uptake of VSVΔG-GFP∗S2S (FC=2.32;p<0.001) and chimera virus (FC=.33;p<.0001). NTCN and TCN each reduced pAkt/Akt ratio. 1μM TCN or NTCN reduced LDLR (7.2%;p<.01 &15.6%;p<0.0001) and ACE2 (32%;p<0.05 &44.7%;p<.01) cell surface expression, respectively. 1μM NTCN or GW-3965 reduced S2S viral entry by 64.2% (p<.0001) and 40.7% (p<.01), respectively, confirming a role for LDLR in S2S infection. In hACE2tg mice, chimera VSV-S2S caused significant lung infection as measured by qPCR, GFP expression in proximal and distal lung airway epithelial cells, and electron microscopy. Intranasal delivery of NTCN was well tolerated. Conclusions: LDLR enhanced S2S viral entry supporting the elevated COVID-19 susceptibility seen in patients with heart disease. NTCN is a promising candidate for prophylactic treatment against COVID-19.