Hesitancy and reactogenicity to mRNA-based COVID-19 vaccines-Early experience with vaccine rollout in a multi-site healthcare system.

BACKGROUND: Hesitancy and incomplete vaccination against coronavirus disease 2019 (COVID-19) remains an obstacle to achieving herd immunity. Because of fear of vaccine reactions, patients with medical and allergic co-morbidities express heightened hesitancy. Limited information is available to guide these patients. We sought to identify factors associated with mRNA-based COVID-19 vaccines hesitancy and reactogenicity. METHODS: We surveyed employees of a multi-site health system in central Pennsylvania who were offered the COVID-19 vaccine (N = 18,740) inquiring about their experience with the Moderna and Pfizer-BioNTech mRNA-based vaccines. The survey was administered online using the REDCap platform. We used multivariable regression analysis to determine whether a particular factor(s) (e.g., demographics, selected co-morbid allergic and medical conditions, vaccine brand, and prior COVID-19) were associated with vaccine reactogenicity including the occurrence and severity of local and systemic reactions. We also explored factors and reasons associated with vaccine hesitancy. RESULTS: Of the 5709 who completed the survey (response rate, 30.4%), 369 (6.5%) did not receive the vaccine. Black race and allergy to other vaccines were associated with vaccine hesitancy. Reaction intensity following the first vaccine dose and allergic co-morbidities were associated with incomplete vaccination. Older individuals (>60 years) experienced less reactogenicity. Females had higher odds of local and systemic reactions and reported more severe reactions. Asians reported more severe reactions. As compared to Pfizer-BioNTech, the Moderna vaccine was associated with higher odds of vaccine reactions of higher severity. Prior COVID-19 resulted in more severe reactions following the first dose, but less severe reactions following the second dose. CONCLUSIONS: Targeted campaigns to enhance vaccination acceptance should focus on Black individuals, females, and those with allergic co-morbidities. Prior COVID-19 caused more severe reactions after the first but not the second vaccine dose. Moderna vaccine caused more vaccine reactions. Lessons learned from the early rollout of COVID-19 vaccine may serve to inform future novel vaccine experiences.

Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial).

BACKGROUND: Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. METHODS: In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. RESULTS: The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41-2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27-1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. CONCLUSIONS: Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 ( http://ctri.nic.in ; registered on 25/07/2020).

Primer for Designing Main Protease (Mpro) Inhibitors of SARS-CoV-2.

The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure-activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (Mpro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four "rules" for designing potent Mpro inhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as Mpro inhibitors. Experimental examination of our own previously reported inhibitors using the four "rules" identified a potential lead compound, the cathepsin inhibitor GB111-NH2, that was 2.3 times more potent than SARS-CoV-2 Mpro inhibitor N3.

Triumvirate to treat mucormycosis: Interplay of pH, metal ions and antifungal drugs

Mucormycosis is a rare fungal infection mainly affecting immunocompromised patients. Recently, an alarming rise in cases of mucormycosis was observed in patients undergoing COVID-19 treatment. Commonly, this fungal infection is caused by Rhizopus spp., Mucor spp., and Lichtheimia spp., although the genera of other Mucorales such as Saksenaea, Rhizomucor, Cunninghamella, and Apophysomyces may also be involved. A number of factors such as high concentration of zinc, iron and hypoxia induced acidosis promote the growth of fungi, thereby increasing the risk of mucormycosis multiple folds. Iron chelators (deferasirox and deferiprone) and zinc chelators (clioquinol, phenanthroline and N,N,N′,N′-tetrakis-(2-pyridylmethyl)ethane-1,2-diamine) have been reported to inhibit the growth of fungi in a number of in vitro and animal studies. Correction of metabolic acidosis by administration of bicarbonate or glycine reduces the susceptibility of patients to the invasion by fungal species. However, these factors have largely been ignored while deciding the treatment strategy for mucormycosis and first line treatment for the management of mucormycosis continues to be the expensive lipid based formulation of amphotericin B. Treatment with isavuconazole which is proposed as the second choice is reported to be more cost effective. Therefore, it is proposed that a combination of antifungal agent (isavuconazole) with zinc and iron chelators (deferasirox and clioquinol respectively) along with alkalizer (glycine buffer) could be an effective and multi-target approach for the treatment of mucormycosis while being cost effective also.

Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19.

In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC50 of 1.81 ± 0.04 µM and inhibit SARS-CoV-2 viral infection in cells with an EC50 of 71.6 µM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.

Orthopaedics Practice in a Rural Hospital During the COVID-19 Pandemic: A Descriptive Cross-Sectional Study.

INTRODUCTION: The coronavirus disease 2019  pandemic is one of the biggest public health challenges that we have faced, and has had a significant impact on the delivery of essential healthcare worldwide. Trauma and orthopaedic surgery was one of the most severely affected specialties as all non-emergency surgical cases were cancelled. With the possibility of future peak of corona virus, knowing the impact of Covid on orthopaedics would enable us to manage trauma patient in an effective manner and will help us to resume normal schedule of the trauma care. METHODS: This is a descriptive cross-sectional study. We studied the details of total number of patient at Orthopaedic and trauma outpatient, inpatient and operation theatre of Karnali Academy of Health Sciences from 14th March 2020 to 16 September 2020 as compared with the patient data from the same time period in 2019. RESULTS: There were 2288 patients during the non-Covid period who visited to the orthopaedic outpatient in comparison to 1618 during Covid period. Only 5 implant removals were performed in comparison to 50 removals (90% reduction) in elective cases. But the number of surgical cases was almost similar (204 vs 207 respectively). Total number of hospital stay had significantly reduced in the non-COVID period (average 4 days vs 6 days).There were 181 in-patient admissions during the COVID period while 241 admission during the non-COVID period. CONCLUSIONS: There is reduction in number of orthopaedic and trauma cases during COVID 19 with marked reduction in number of elective cases. Alternative methods of treatment like telemedicine and small scale health camps at peripheral districts should be conducted to treat non-urgent orthopaedic conditions during lockdown.

Orthopaedic services during COVID-19 lockdown at Patan Hospital, Nepal

Introduction: The COVID-19 pandemic has paralyzed the world, including elective health care services. To prevent the spread of infection, most countries have gone into lockdown and adjustments have been made to provide urgent medical care, including Orthopaedic services. In accordance with the guidelines from worst affected countries and neighboring India, Patan Hospital followed instructions from Ministry of Health and Population to provide only urgent and semi-urgent Orthopaedic services. This study aims to audit the patient profile during lockdown so as to have a clearer picture, which will enable us to be prepared for similar epidemic in the future. Method: All patients admitted to the Orthopaedic ward of Patan hospital from 24 March to 27 April 2020, during the lockdown, were included. Clinical profile, including cause of admission, management, hospital stay were descriptively analyzed. Ethical approval was obtained. Result: Out of 44 admissions, there were male 27 and female 17. Trauma cases were 38, and 18 were in age group 20-26 years. Admission due to infections were four. Conservative management were done in seven while 33 were treated surgically, out of which 30 accounted for trauma. Average 6.14 days hospital stay, range 1-22 days. Conclusion: Trauma comprised of major bulk of patients seeking urgent Orthopaedic care. Hospital needs to be prepared with necessary measures to ensure safety of health care workers and yet provide urgent Orthopaedic services. Keyword: COVID-19, lockdown, orthopaedics

Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To assess the impact of adding statin (atorvastatin) and/or aspirin on clinical deterioration in patients infected with SARS-CoV-2 who require hospitalisation. The safety of these drugs in COVID-19 patients will also be evaluated. TRIAL DESIGN: This is a single-centre, prospective, four-arm parallel design, open-label, randomized control trial. PARTICIPANTS: The study will be conducted at National Cancer Institute (NCI), Jhajjar, Haryana, which is a part of All India Institute of Medical Sciences (AIIMS), New Delhi, and has been converted into a dedicated COVID-19 management centre since the outbreak of the pandemic. All RT-PCR confirmed cases of SARS-CoV-2 infection with age ≥ 40 years and < 75 years requiring hospital admission (patients with WHO clinical improvement ordinal score 3 to 5) will be included in the trial. Written informed consent will be taken for all recruited patients. Patients with a critical illness (WHO clinical improvement ordinal score > 5), documented significant liver disease/dysfunction (aspartate transaminase [AST] / alanine aminotransferase [ALT] > 240), myopathy and rhabdomyolysis (creatine phosphokinase [CPK] > 5x normal), allergy or intolerance to statins or aspirin, prior statin or aspirin use within 30 days, history of active gastrointestinal bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, or inability to take oral or nasogastric medications will be excluded. Patients refusing to give written consent and taking drugs that are known to have a significant drug interaction with statin or aspirin [including cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor, telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole), clarithromycin and colchicine] will also be excluded from the trial. INTERVENTION AND COMPARATOR: In this study, the benefit and safety of atorvastatin (statin) and/or aspirin as adjuvant therapy will be compared with the control group receiving usual care for management of COVID-19. Atorvastatin will be prescribed as 40 mg oral tablets once daily for ten days or until discharge, whichever is earlier. The dose of aspirin will be 75 mg once daily for ten days or until discharge, whichever is earlier. All other therapies will be administered according to the institute's COVID-19 treatment protocol and the treating physician's clinical judgment. MAIN OUTCOMES: All study participants will be prospectively followed up for ten days or until hospital discharge, whichever is longer for outcomes. The primary outcome will be clinical deterioration characterized by progression to WHO clinical improvement ordinal score ≥ 6 (i.e., endotracheal intubation, non-invasive mechanical ventilation, pressor agents, renal replacement therapy, ECMO requirement, and mortality). The secondary outcomes will be change in serum inflammatory markers (C-reactive protein and Interleukin-6), Troponin I, and creatine phosphokinase (CPK) from time zero to 5th day of study enrolment or 7th day after symptom onset, whichever is later. Other clinical outcomes that will be assessed include progression to Acute Respiratory Distress Syndrome (ARDS), shock, ICU admission, length of ICU admission, length of hospital admission, and in-hospital mortality. Adverse drug effects like myalgia, myopathy, rhabdomyolysis, hepatotoxicity, and bleeding will also be examined in the trial to assess the safety of the interventions. RANDOMISATION: The study will use a four-arm parallel-group design. A computer-generated permuted block randomization with mixed block size will be used to randomize the participants in a 1:1:1:1 ratio to group A (atorvastatin with conventional therapy), group B (aspirin with conventional therapy), group C (aspirin + atorvastatin with conventional therapy), and group D (control; only conventional therapy). BLINDING (MASKING): The study will be an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): As there is no existing study that has evaluated the role of aspirin and atorvastatin in COVID-19 patients, formal sample size calculation has not been done. Patients satisfying the inclusion and exclusion criteria will be recruited during six months of study period. Once the first 200 patients are included in each arm (i.e., total 800 patients), the final sample size calculation will be done on the basis of the interim analysis of the collected data. TRIAL STATUS: The institutional ethical committee has approved the study protocol (Protocol version 3.0 [June 2020]). Participant recruitment starting date: 28th July 2020 Participant recruitment ending date: 27th January 2021 Trial duration: 6 months TRIAL REGISTRATION: The trial has been prospectively registered in Clinical Trial Registry - India (ICMR- NIMS): Reference no. CTRI/2020/07/026791 (registered on 25 July 2020)]. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.