Articles related to Treatment protocol of Covid-19

6 treatment.pdf

Discovery of new drug indications for COVID19: A drug repurposing approach

Priyanka KumariID1,2*, Bikram PradhanID3 , Maria KorominaID4 , George P. PatrinosID4,5,6, Kristel Van Steen1,7* 1 GIGA-R Medical Genomics - BIO3 Systems Genomics, University of Liège, Liège, Belgium, 2 Laboratory of Pharmaceutical Analytical Chemistry, CIRM, University of Liège, Liège, Belgium, 3 Indian Space Research Organisation (ISRO) Headquarters, Bengaluru, India, 4 University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece, 5 Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE, 6 Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, UAE, 7 Department of Human Genetics - BIO3 Systems Medicine, University of Leuven, Leuven, Belgium * priyanka@student.uliege.be (PK); kristel.vansteen@uliege.be (KVS)

Abstract

Motivation The outbreak of coronavirus health issues caused by COVID-19(SARS-CoV-2) creates a global threat to public health. Therefore, there is a need for effective remedial measures using existing and approved therapies with proven safety measures has several advantages. Dexamethasone (Pubchem ID: CID0000005743), baricitinib(Pubchem ID: CID44205240), remdesivir (PubchemID: CID121304016) are three generic drugs that have demonstrated in-vitro high antiviral activity against SARS-CoV-2. The present study aims to widen the search and explore the anti-SARS-CoV-2 properties of these potential drugs while looking for new drug indications with optimised benefits via in-silico research. Method Here, we designed a unique drug-similarity model to repurpose existing drugs against SARS-CoV-2, using the anti-Covid properties of dexamethasone, baricitinib, and remdesivir as references. Known chemical-chemical interactions of reference drugs help extract interactive compounds withimprovedanti-SARS-CoV-2 properties. Here, we calculated the likelihood of these drug compounds treating SARS-CoV-2 related symptoms using chemicalprotein interactions between the interactive compounds of the reference drugs and SARSCoV-2 target genes. In particular, we adopted a two-tier clustering approach to generate a drug similarity model for the final selection of potential anti-SARS-CoV-2 drug molecules. Tier-1 clustering was based on t-Distributed Stochastic Neighbor Embedding (t-SNE) and aimed to filter and discard outlier drugs. The tier-2 analysis incorporated two cluster analyses performed in parallel using Ordering Points To Identify the Clustering Structure (OPTICS) and Hierarchical Agglomerative Clustering (HAC). As a result, itidentified clusters of drugs with similar actions. In addition, we carried out a docking study for in-silico validation of top candidate drugs. Result Our drug similarity model highlighted ten drugs, including reference drugs that can act as potential therapeutics against SARS-CoV-2. The docking results suggested that doxorubicin showed the least binding energy compared to reference drugs. Their practical utility as anti-SARS-CoV-2 drugs, either individually or in combination, warrants further investigation.

5 treatment.pdf

Transcutaneous retrobulbar amphotericin-B (TRAMB) injection in orbital mucormycosis

Prabhakar Singh , Abhishek Gupta, Sravani Reddy Sanepalli, Amit Raj

SUMMARY

We aim to highlight the role of transcutaneous retrobulbar amphotericin-B (TRAMB) in cases of rhino-orbital mucormycosis. With the COVID-19 pandemic a rapid surge in the number of cases of rhino-orbital mucormycosis has been noted. The gold standard treatment for the progressive orbital disease is exenteration; however, organ salvage should be attempted, when possible. Here comes the role of TRAMB injection. We present a case of a man in his 70s, a known diabetic, who recovered from COVID-19 pneumonia but developed left-sided axial proptosis with orbital apex syndrome and ophthalmic artery occlusion secondary to rhino-orbital mucormycosis. The patient underwent debridement of paranasal sinuses and received intravenous liposomal amphotericin-B and three TRAMB injections. After three TRAMB injections significant improvement in extraocular movements, proptosis and ptosis was noted. An early intervention in orbital disease can avert a more radical procedure.

4 treatment.pdf

Infection control in the intensive care unit: expert consensus statements for SARS-CoV-2 using a Delphi method

Prashant Nasa, Elie Azoulay, Arunaloke Chakrabarti, Jigeeshu V Divatia, Ravi Jain, Camilla Rodrigues, Victor D Rosenthal, Waleed Alhazzani, Yaseen M Arabi, Jan Bakker, Matteo Bassetti, Jan De Waele, George Dimopoulos, Bin Du, Sharon Einav, Laura Evans, Simon Finfer, Claude Guérin, Naomi E Hammond, Samir Jaber, Ruth M Kleinpell, Younsuck Koh, Marin Kollef, Mitchell M Levy, Flavia R Machado, Jordi Mancebo, Ignacio Martin-Loeches, Mervyn Mer, Michael S Niederman, Paolo Pelosi, Anders Perner, John V Peter, Jason Phua, Lise Piquilloud, Mathias W Pletz, Andrew Rhodes, Marcus J Schultz, Mervyn Singer, Jéan-François Timsit, Balasubramanian Venkatesh, Jean-Louis Vincent, Tobias Welte, Sheila N Myatra

Summary

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

3 treatment.pdf

Efficacy of convalescent plasma therapy in the patient with COVID-19: a randomised control trial (COPLAII trial)

Meenu Bajpai,1 Ashish Maheshwari ,1 Vikas Dogra,2 Suresh Kumar,3 Ekta Gupta,4 Pratibha kale,5 Vandana Saluja,6 Sherin S Thomas,7 Nirupama Trehanpati,8 Chhagan Bihari,9 Reshu Agarwal,4 Praveen Bharti,3 Prabha Shankar,1 Javid Hussain ,2 Karan Chhabra,3 Amita Gupta,1 Ashad Narayanan,1 Sarika Agarwal,1 Shruti Jain,2 Ankit Bhardwaj,10 Guresh Kumar,10 Birendra Kumar Yadav,8 Shiv Kumar Sarin 1

ABSTRACT

Importance No proven treatment is available for severely ill COVID-19. Therapeutic use of COVID-19 convalescent plasma (COPLA) is under investigation. Objective To compare the efficacy of COPLA with standard medical therapy (SMT) alone in severe COVID-19 patients. Design, setting and participants A multicentric, openlabelled, phase-III randomised controlled trial conducted at two treatment centres with COPLA collected at the third dedicated centre in North-India, the coordinating centre during trial from June 2020 to December 2020. The study population comprised 400 participants in the ratio of 1:1 in each treatment group. Intervention One group received COPLA with SMT (n=200), and another group received SMT only (n=200). Main outcome measures Primary outcome was time to clinical improvement measured by a two-point reduction in the ordinal scale. Secondary outcomes included duration of O2 therapy, the proportion of patients on mechanical ventilation at day-7, mortality, SARS-CoV-2 antibody levels, cytokine levels and incidence of adverse events. Results The median time to a two-point reduction in the ordinal scale in both groups was 9days (IQR=7–13) (p=0.328). The median duration of O2 therapy was 8days (IQR=6–12) in COPLA and 10 days (IQR=6–12) in SMT group (p=0.64). The PaO2 /FiO2 ratio showed significant improvement at 7days in COPLA group(p=0.036). There was no difference in mortality till 28 days in both groups (p=0.62). However, if COPLA was given within 3days of hospital admission, a significant reduction in ordinal scale was observed (p=0.04). Neutralising antibody titres in COPLA group (80 (IQR 80–80)) were higher than SMT group (0 (IQR 0–80)) at 48 hours (p=0.001). COPLA therapy led to a significant reduction in TNF-α levels at 48 hours (p=0.048) and D-dimer at 7days (p=0.02). Mild allergic reactions were observed in 3 (1.5%) patients in COPLA group. Conclusion and relevance Convalescent plasma with adequate antibody titres should be transfused in COVID-19 patients along with SMT in the initial 3 days of hospitalisation for better clinical outcomes. Trial registration number NCT04425915.

2 treatmennt.pdf

COVID-19-related dynamic coagulation disturbances and anticoagulation strategies using conventional D-dimer and point-of-care Sonoclot tests: a prospective cohort study

Madhumita Premkumar ,1 Sekar Loganathan ,2 Kamal Kajal ,2 Amarjyoti Hazarika,2 Shiv Soni,2 Goverdhan Dutt Puri,2 Inderpaul Singh Sehgal,3 Vikas Suri,4 Pankaj Malhotra,5 Virendra Singh,1 Ajay Duseja,1 Ashish Bhalla,4 Jasmina Ahluwalia,6 Narender Kumar,6 Kushal Kekan,1 Sant Ram,7 Karan Singla,2 Varun Mahajan,2 Narayana Yaddanapudi2

ABSTRACT

Objectives Coagulation changes associated with COVID-19 suggest the presence of a hypercoagulable state with pulmonary microthrombosis and thromboembolic complications. We assessed the dynamic association of COVID-19-related coagulation abnormalities with respiratory failure and mortality. Design Single-centre, prospective cohort study with descriptive analysis and logistic regression. Setting Tertiary care hospital, North India. Participants Patients with COVID-19 pneumonia requiring intensive care unit (ICU) admission between August 2020 and November 2020. Primary and secondary outcome measures We compared the coagulation abnormalities using standard coagulation tests like prothrombin time, D-dimer, platelet count, etc and point-of-care global coagulation test, Sonoclot (glass beaded(gb) and heparinase-treated(h)). Incidence of thromboembolic or bleeding events and presence of endogenous heparinoids were assessed. Cox proportional Hazards test was used to assess the predictors of 28-day mortality. Measurement All patients underwent Sonoclot (glass beaded) test at admission apart from the routine investigations. In patients at risk of thromboembolic or bleeding phenomena, paired tests were performed at day 1 and 3 with Sonoclot. Activated clotting time (ACT) 75 units were used as the cutoff for hypercoagulable state. Presence of heparin-like effect (HLE) was defined by a correction of ACT ≥40 s in h-Sonoclot. Results Of 215 patients admitted to ICU, we included 74 treatment naive subjects. A procoagulant profile was seen in 45.5% (n=5), 32.4% (n=11) and 20.7% (n=6) in low-flow, high-flow and invasive ventilation groups. Paired Sonoclot assays in a subgroup of 33 patients demonstrated the presence of HLE in 17 (51.5%) and 20 (62.5%) at day 1 and 3, respectively. HLE (day 1) was noted in 59% of those who bled during the disease course. Mortality was observed only in the invasive ventilation group (16, 55.2%) with overall mortality of 21.6%. HLE predicted the need for mechanical ventilation (HR 1.2 CI 1.04 to 1.4 p=0.00). On multivariate analysis, the presence of HLE (HR 1.01; CI 1.006 to 1.030; p=0.025), increased C reactive protein (HR 1.040; CI 1.020 to 1.090; p=0.014), decreased platelet function (HR 0.901; CI 0.702 to 1.100 p=0.045) predicted mortality at 28days. Conclusion HLE contributed to hypocoagulable effect and associated with the need for invasive ventilation and mortality in patients with severe COVID-19 pneumonia. Trial registration NCT04668404; ClinicalTrials.gov. in. Available from https://clinicaltrials.gov/ct2/show/ NCT04668404.

1 treatment.pdf

A combination of potently neutralizing monoclonal antibodies isolated from an Indian convalescent donor protects against the SARS-CoV-2 Delta variant

Nitin Hingankar1, Suprit Deshpande1, Payel Das1 , Zaigham Abbas Rizvi2,3, Constantinos Kurt Wibmer4 , Poppy Mashilo4 , Mohammed Yousuf Ansari1 , Alison Burns5,6,7, Shawn Barman5,6,7, Fangzhu Zhao5,6,7, Sohini Mukherjee1,8,9, Jonathan L. Torres5,6,10, Souvick Chattopadhyay11, Farha Mehdi11, Jyoti Sutar1,8,9, Deepak Kumar Rathore3 , Kamal Pargai12, Janmejay Singh12, Sudipta Sonar11, Kamini Jakhar11, Jyotsna Dandotiya2,3, Sankar Bhattacharyya11, Shailendra Mani11, Sweety Samal11, Savita Singh11, Pallavi Kshetrapal11, Ramachandran Thiruvengadam11, Gaurav Batra11, Guruprasad Medigeshi11,12, Andrew B. Ward5,6,10, Shinjini Bhatnagar11, Amit Awasthi2,3, Devin Sok5,6,7,8*, Jayanta BhattacharyaID1,8,9*

Abstract

Although efficacious vaccines have significantly reduced the morbidity and mortality of COVID-19, there remains an unmet medical need for treatment options, which monoclonal antibodies (mAbs) can potentially fill. This unmet need is exacerbated by the emergence and spread of SARS-CoV-2 variants of concern (VOCs) that have shown some resistance to vaccine responses. Here we report the isolation of five neutralizing mAbs from an Indian convalescent donor, out of which two (THSC20.HVTR04 and THSC20.HVTR26) showed potent neutralization of SARS-CoV-2 VOCs at picomolar concentrations, including the Delta variant (B.1.617.2). One of these (THSC20.HVTR26) also retained activity against the Omicron variant. These two mAbs target non-overlapping epitopes on the receptor-binding domain (RBD) of the spike protein and prevent virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Furthermore, the mAb cocktail demonstrated protection against the Delta variant at low antibody doses when passively administered in the K18 hACE2 transgenic mice model, highlighting their potential as a cocktail for prophylactic and therapeutic applications. Developing the capacity to rapidly discover and develop mAbs effective against highly transmissible pathogens like coronaviruses at a local level, especially in a low- and middle-income country (LMIC) such as India, will enable prompt responses to future pandemics as an important component of global pandemic preparedness.

treatment1.pdf

Global access to existing and future antimicrobials and diagnostics: antimicrobial subscription and pooled procurement

Daniel Berman*, Sujith J Chandy, Oliver Cansdell, Krishnee Moodley, Balaji Veeraraghavan, Sabiha Y Essack*

Abstract:The COVID-19 pandemic has underlined the importance of an efficient and equitable supply of and access to essential health products. These factors are equally pertinent to the antimicrobial resistance pandemic, in which access to a portfolio of existing and pipeline antimicrobials plus complementary diagnostics is crucial. This Viewpoint focuses on market shaping in low-income and middle-income countries (LMICs), where the need for effective antimicrobials and complementary diagnostics is most acute. We propose the creation of a subscription and pooled procurement model that consolidates the growing demand for a portfolio of antimicrobials and diagnostics in LMICs. Anchored by regional market leaders, these pooling mechanisms would guarantee consistent private-sector and public-sector access in participating countries, while creating conditions for long-term best practice in stewardship. Supported by data from South Africa and India, this proposal sets out an innovative approach to tackle the antimicrobial resistance crisis in LMICs.

treatment2.pdf

Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma

Hyung Park, PhD, 1 Thaddeus Tarpey, PhD, 1 Mengling Liu, PhD, 1 , 2 Keith Goldfeld, DrPH, 1 Yinxiang Wu, MA, 3 Danni Wu, MS, 1 Yi Li, MS, 1 Jinchun Zhang, PhD, 4 Dipyaman Ganguly, MD, PhD, 5 Yogiraj Ray, MD, 6 , 7 Shekhar Ranjan Paul, MD, 6 Prasun Bhattacharya, MD, 8 Artur Belov, PhD, 9 Yin Huang, PhD, 9 Carlos Villa, MD, PhD, 9 Richard Forshee, PhD, 9 Nicole C. Verdun, MD, 10 Hyun ah Yoon, MD, 11 Anup Agarwal, MD, 12 Ventura Alejandro Simonovich, MD, 13 Paula Scibona, MD, 14 Leandro Burgos Pratx, MD, 15 Waldo Belloso, MD, 16 Cristina Avendaño-Solá, MD, 17 Katharine J Bar, MD, 18 Rafael F. Duarte, MD, PhD, 17 Priscilla Y. Hsue, MD, 19 Anne F. Luetkemeyer, MD, 19 Geert Meyfroidt, MD, PhD, 20 André M. Nicola, MD, PhD, 21 Aparna Mukherjee, MD, PhD, 12 Mila B. Ortigoza, MD, PhD, 22 Liise-anne Pirofski, MD, 11 Bart J. A. Rijnders, MD, PhD, 23 Andrea Troxel, ScD, 1 Elliott M. Antman, MD, 24 and Eva Petkova, PhD 1 , 25 , 26

Abstract:

Importance:

Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact.

Objective:

To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients’ baseline characteristics.

Design, Setting, and Participants:

This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants).

Exposure:

Receipt of CCP.

Main Outcomes and Measures:

World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI.

Results:

A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs.

Conclusions and Relevance:

The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

treatment3.pdf

Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19-A Meta-analysis

Andrea B. Troxel, ScD, 1 Eva Petkova, PhD, 1 , 2 , 3 Keith Goldfeld, DrPH, 1 Mengling Liu, PhD, 1 , 4 Thaddeus Tarpey, PhD, 1 Yinxiang Wu, MA, 5 Danni Wu, MS, 1 Anup Agarwal, MD, 6 Cristina Avendaño-Solá, MD, 7 Emma Bainbridge, MD, MPH, 8 Katherine J. Bar, MD, 9 Timothy Devos, MD, PhD, 10 Rafael F. Duarte, MD, PhD, 7 Arvind Gharbharan, MD, 11 Priscilla Y. Hsue, MD, 8 Gunjan Kumar, MD, 6 Annie F. Luetkemeyer, MD, 8 Geert Meyfroidt, MD, PhD, 12 André M. Nicola, MD, PhD, 13 Aparna Mukherjee, MD, PhD, 6 Mila B. Ortigoza, MD, PhD, 14 , 15 Liise-anne Pirofski, MD, 16 , 17 Bart J. A. Rijnders, MD, PhD, 11 Casper Rokx, MD, PhD, 11 Arantxa Sancho-Lopez, MD, 7 Pamela Shaw, PhD, 18 Pablo Tebas, MD, 9 Hyun-Ah Yoon, MD, 16 , 17 Corita Grudzen, MD, 1 , 19 Judith Hochman, MD, 20 and Elliott M. Antman, MD 21

Abstract

Importance:

COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing.

Objective:

To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP.

Data Sources:

From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly.

Study Selection:

Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally.

Data Extraction and Synthesis:

A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board.

Main Outcomes and Measures:

Prespecified coprimary end points—the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model—were assessed clinically at 14 days after randomization.

Results:

Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics.

Conclusions and Relevance:

This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.

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Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19- associated cytokine release syndrome (COVINTOC): an open label, multicentre, randomised, controlled, phase 3 trial

Arvinder S Soin, Kuldeep Kumar, Narendra S Choudhary, Pooja Sharma, Yatin Mehta, Sushila Kataria, Deepak Govil, Vikas Deswal, Dhruva Chaudhry, Pawan Kumar Singh, Ashish Gupta, Vikas Agarwal, Suresh Kumar, Shashikala A Sangle, Rajesh Chawla, Suneetha Narreddy, Rahul Pandit, Vipul Mishra, Manoj Goel, Athimalaipet V Ramanan

Summary

Background

Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country.

Methods

COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369).

Findings

180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference –3·71 [95% CI –18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study.

Interpretation

Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies.

Funding

Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.

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Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries

Ankit Bharat, Prof, MBBS,a,b,*,* Tiago N Machuca, MD,c,* Melissa Querrey, BS,a,b Chitaru Kurihara, MD,a Rafael Garza-Castillon, Jr, MD,a Samuel Kim, MD,a Adwaiy Manerikar, BS,a Andres Pelaez, MD,c Mauricio Pipkin, MD,c Abbas Shahmohammadi, MD,c Mindaugas Rackauskas, MD,c Suresh Rao KG, MD,d K R Balakrishnan, MD,d Apar Jindal, MD,d Lara Schaheen, MD,e Samad Hashimi, MD,e Bhuvin Buddhdev, MD,e Ashwini Arjuna, MBBS,e Lorenzo Rosso, MD,f Alessandro Palleschi, MD,f Christian Lang, MD,g Peter Jaksch, MD,g G R Scott Budinger, Prof, MD,a,b Mario Nosotti, Prof, MD,f,* and Konrad Hoetzenecker, Prof, MDg,*

Abstract

Background

Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications.

Methods

We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres—including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes—were collected by Northwestern University (Chicago, IL, USA) and analysed.

Findings

Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41–51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19.

Interpretation

The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients.

Funding

National Institutes of Health.

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Repurposing calcium channel blockers as antiviral drugs

Vijayashree Priyadharsini Jayaseelan and Arumugam Paramasivam

Abstract:

The current pandemic caused by the SARS-CoV-2 has claimed over a half a million lives within a very short span of time. A therapeutic drug which could prevent the entry and propagation of the virus is the need of the hour. Several lines of evidence collected from experimental studies older than three decades have pointed out the fact that inhibiting calcium entry into cells can affect vital steps in the lifecycle of viruses. Hence, calcium channel blockers may be considered as an effective measure in the containment of the viruses. This commentary throws light two scientific papers although with divergent facts converging at a point by suggesting a promising treatment option for CoVID-19 (Fang et al. Lancet Respir Med 8:e21, 2020; Straus et al. J Virol 94:e00426, 2020).

Keywords: CCB , Calcium homeostasis, Calcium channels, SARs, Virus, Verapamil

77.pdf

Guidance for Health Care Leaders During the Recovery Stage of the COVID-19 Pandemic A Consensus Statement

Jaason M. Geerts, PhD; Donna Kinnair, LLB/MA; Paul Taheri, MD; Ajit Abraham, MBBS; Joonmo Ahn, PhD; Rifat Atun, PhD; Lorena Barberia, PhD; Nigel J. Best, MA; Rakhi Dandona, PhD; Adeel Abbas Dhahri, MBBS; Louise Emilsson, MD, PhD; Julian R. Free, MA; Michael Gardam, MD; William H. Geerts, MD; Chikwe Ihekweazu, MBBS; Shanthi Johnson, PhD; Allison Kooijman, BA; Alika T. Lafontaine, MD; Eyal Leshem, MD; Caroline Lidstone-Jones, MIR; Erwin Loh, MBBS, PhD; Oscar Lyons, MBChB, DPhil; Khalid Ali Fouda Neel, MBBS; Peter S. Nyasulu, PhD; Oliver Razum, MD; Hélène Sabourin, MHA; Jackie Schleifer Taylor, PhD; Hamid Sharifi, PhD; Vicky Stergiopoulos, MD; Brett Sutton, MBBS; Zunyou Wu, PhD; Marc Bilodeau, MD

Abstract

Importance The COVID-19 pandemic is the greatest global test of health leadership of our generation. There is an urgent need to provide guidance for leaders at all levels during the unprecedented preresolution recovery stage.

Objective To create an evidence- and expertise-informed framework of leadership imperatives to serve as a resource to guide health and public health leaders during the postemergency stage of the pandemic.

Evidence review A literature search in PubMed, MEDLINE, and Embase revealed 10 910 articles published between 2000 and 2021 that included the terms leadership and variations of emergency, crisis, disaster, pandemic, COVID-19, or public health. Using the Standards for Quality Improvement Reporting Excellence reporting guideline for consensus statement development, this assessment adopted a 6-round modified Delphi approach involving 32 expert coauthors from 17 countries who participated in creating and validating a framework outlining essential leadership imperatives.

Findings The 10 imperatives in the framework are: (1) acknowledge staff and celebrate successes; (2) provide support for staff well-being; (3) develop a clear understanding of the current local and global context, along with informed projections; (4) prepare for future emergencies (personnel, resources, protocols, contingency plans, coalitions, and training); (5) reassess priorities explicitly and regularly and provide purpose, meaning, and direction; (6) maximize team, organizational, and system performance and discuss enhancements; (7) manage the backlog of paused services and consider improvements while avoiding burnout and moral distress; (8) sustain learning, innovations, and collaborations, and imagine future possibilities; (9) provide regular communication and engender trust; and (10) in consultation with public health and fellow leaders, provide safety information and recommendations to government, other organizations, staff, and the community to improve equitable and integrated care and emergency preparedness systemwide.

Conclusions and relevance Leaders who most effectively implement these imperatives are ideally positioned to address urgent needs and inequalities in health systems and to cocreate with their organizations a future that best serves stakeholders and communities.

81.pdf

Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results

WHO Solidarity Trial Consortium

Abstract

Background

World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).

Methods

We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.

Results

At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.

Conclusions

These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)

83.pdf

Stability Indicating LC Method Development for Hydroxychloroquine Sulfate Impurities as Available for Treatment of COVID-19 and Evaluation of Risk Assessment Prior to Method Validation by Quality by Design Approach

Thirupathi Dongala, Naresh Kumar Katari, [...], and Vishnu Murthy Marisetti

Abstract

A quality by design-based stability indicating HPLC method has been developed for hydroxychloroquine sulfate impurities. The optimized HPLC method can detect and quantify the hydroxychloroquine sulfate and related organic impurities in pharmaceutical solid oral dosage forms. Nowadays, for the quantification of impurities in drug products demands more comprehensive way of analytical method development. The quality by design approach allows the assessment of different analytical parameters and their effects with minimum number of experiments. A highly sensitive and stability indicating RP-HPLC method was developed and evaluated the risk assessment prior to method validation. The chromatographic separation was achieved with X-terra phenyl column (250 × 4.6 mm, 5 µm) using phosphate buffer (0.3 M and pH 2.5). The gradient method flow rate was 1.5 mL min−1 and UV detection was made at 220 nm. The calibration curve of hydroxychloroquine sulfate and related impurities were linear from LOQ to 150% and correlation coefficient was found more than 0.999. The precision and intermediate precision % RSD values were found less than 2.0. In all forced degradation conditions, the purity angle of HCQ was found less than purity threshold. The optimized method found to be specific, accurate, rugged, and robust for determination of hydroxychloroquine sulfate impurities in the solid oral dosage forms. Finally, the method was applied successfully in quality control lab for stability analysis.

Keywords: Hydroxychloroquine sulfate, Quality by design, Design of experiments, HPLC, Validation

84.pdf

SARS-CoV-2 attachment to host cells is possibly mediated via RGD-integrin interaction in a calcium-dependent manner and suggests pulmonary EDTA chelation therapy as a novel treatment for COVID 19

Tikam Chand Dakal

Abstract

SARS-CoV-2 is a highly contagious virus that has caused serious health crisis world-wide resulting into a pandemic situation. As per the literature, the SARS-CoV-2 is known to exploit humanACE2 receptors (similar toprevious SARS-CoV-1) for gaining entry into the host cell for invasion, infection, multiplication and pathogenesis. However, considering the higher infectivity of SARS-CoV-2 along with the complex etiology and pathophysiological outcomes seen in COVID-19 patients, it seems that there may be an alternate receptor for SARS-CoV-2. I performed comparative protein sequence analysis, database based gene expression profiling, bioinformatics based molecular docking using authentic tools and techniques for unveiling the molecular basis of high infectivity of SARS-CoV-2 as compared to previous known coronaviruses. My study revealed that SARS-CoV-2 (previously known as 2019-nCoV) harbors a RGD motif in its receptor binding domain (RBD) and the motif is absent in all other previously known SARS-CoVs. The RGD motif is well known for its role in cell-attachment and cell-adhesion. My hypothesis is that the SARS-CoV-2 may be (via RGD) exploiting integrins, that have high expression in lungs and all other vital organs, for invading host cells. However, an experimental verification is required. The expression of ACE2, which is a known receptor for SARS-CoV-2, was found to be negligible in lungs. I assume that higher infectivity of SARS-CoV-2 could be due to this RGD-integrin mediated acquired cell-adhesive property. Gene expression profiling revealed that expression of integrins is significantly high in lung cells, in particular αvβ6, α5β1, αvβ8 and an ECM protein, ICAM1. The molecular docking experiment showed the RBD of spike protein binds with integrins precisely at RGD motif in a similar manner as a synthetic RGD peptide binds to integrins as found by other researchers. SARS-CoV-2 spike protein has a number of phosphorylation sites that can induce cAMP, PKC, Tyr signaling pathways. These pathways either activate calcium ion channels or get activated by calcium. In fact, integrins have calcium & metal binding sites that were predicted around and in vicinity of RGD-integrin docking site in our analysis which suggests that RGD-integrins interaction possibly occurs in calcium-dependent manner. The higher expression of integrins in lungs along with their previously known high binding affinity (~KD = 4.0 nM) for virus RGD motif could serve as a possible explanation for high infectivity of SARS-CoV-2. On the contrary, human ACE2 has lower expression in lungs and its high binding affinity (~KD = 15 nM) for spike RBD alone could not manifest significant virus-host attachment. This suggests that besides human ACE2, an additional or alternate receptor for SARS-CoV-2 is likely to exist. A highly relevant evidence never reported earlier which corroborate in favor of RGD-integrins mediated virus-host attachment is an unleashed cytokine storm which causes due to activation of TNF-α and IL-6 activation; and integrins role in their activation is also well established. Altogether, the current study has highlighted possible role of calcium and other divalent ions in RGD-integrins interaction for virus invasion into host cells and suggested that lowering divalent ion in lungs could avert virus-host cells attachment.

85.pdf

Silver-Based Nanomaterials as Therapeutic Agents Against Coronaviruses: A Review

Chanchal Das, Subha Sankar Paul, [...], and Goutam Biswas

Abstract

Since the identification of the first human coronavirus in the 1960s, a total of six coronaviruses that are known to affect humans have been identified: 229E, OC43, severe acute respiratory syndrome coronavirus (SARS-CoV), NL63, HKU1, and Middle East respiratory syndrome coronavirus (MERS-CoV). Presently, the human world is affected by a novel version of the coronavirus family known as SARS-CoV-2, which has an extremely high contagion rate. Although the infection fatality rate (IFR) of this rapidly spreading virus is not high (ranging from 0.00% to 1.54% across 51 different locations), the increasing number of infections and deaths has created a worldwide pandemic situation. To provide therapy to severely infected patients, instant therapeutic support is urgently needed and the repurposing of already approved drugs is presently in progress. In this regard, the development of nanoparticles as effective transporters for therapeutic drugs or as alternative medicines is highly encouraged and currently needed. The size range of the viruses is within 60–140 nm, which is slightly larger than the diameters of nanoparticles, making nanomaterials efficacious tools with antiviral properties. Silver-based nanomaterials (AgNMs) demonstrate antimicrobial and disinfectant effects mostly by generating reactive oxygen species (ROS) and are presently considered as a versatile tool for the treatment of COVID-19 patients. Other metal-based nanoparticles have been primarily reported as delivery agents or surface modifying agents, vaccine adjuvant against coronavirus. The present review summarizes and discusses the possible effectiveness of various surface-modified AgNMs against animal coronaviruses and presents a concept for AgNM-based therapeutic treatment of SARS-CoV-2 in the near future.

Keywords: silver nanomaterials, coronavirus, silver nanocomposites, antiviral, SARS-CoV

88.pdf

Pharmacological insight into potential therapeutic agents for the deadly Covid-19 pandemic

Ranjana Bhandari, Garima Khanna, and Anurag Kuhad

Abstract

Coronaviruses are pleomorphic, enveloped, or spherical viruses, which have a size ranging from 80 to 120 nm. These viruses act on receptors that cause the triggering of fusion. Coronaviruses were first described after cultivation from patients with common colds by Tyrell and Bynoe in 1966. There are various subtypes of coronavirus, 7 out of these can cause infection in human beings. The Alpha subtype is responsible for mild infection showing symptoms or infection without any prevailing symptoms. On the other hand, the beta subtype is responsible for very serious diseases leading to fatality. The lineage of this novel SARS-CoV-2 falls under the beta lineage of the beta coronavirus which has been observed to have a relation to the MERS and SARS coronavirus. In the Huanan market selling seafood, the transition of this novel virus in humans from animals has occurred. It has the potential to be the cause of widespread fatality amongst the people of the globe. On August 16, 2020, the World Health Organisation had reported 2,1294,845 cases which are confirmed to date out of which 413,372 deaths have occurred. Currently, no targeted antiviral vaccines or drugs to fight against COVID-19 infection have been approved for use in humans. This pandemic is fast emerging and drug repurposing is the only ray of hope which can ensure quick availability. Vaccine development is progressing each day with various platforms such as DNA, Live Attenuated Virus, Non-Replicating Viral Vector, Protein Subunit, and RNA, being utilized for the development. COVID-19 attacks the immune system of the host & this can result in a cytokine storm. As a result, various herbal agents both acting as antivirals and immunomodulatory can also be used. Convalescent Plasma Therapy and Mesenchymal Stem Cell therapy are also being explored as a plausible therapeutic. There remains a considerable unmet need for therapeutics to be addressed. The development and availability of accessible and efficient therapy are essential for the treatment of patients. This review discusses the epidemiology, pathogenesis, the tale of origin, and transmission of COVID-19 or Sars-Cov2 virus and gives evidence of potential therapeutic agents that can be explored to cast away this pandemic.

Keywords: Coronavirus, COVID-19, SARS-COV2, Drug repurposing, Vaccines, Convalescent plasma therapy and mesenchymal stem cell therapy

89.pdf

1,2,4 triazolo[1,5-a] pyrimidin-7-ones as novel SARS-CoV-2 Main protease inhibitors: In silico screening and molecular dynamics simulation of potential COVID-19 drug candidates

Kuppuswamy Kavitha, Subramaniam Sivakumar, and Balasubramanian Ramesh

Abstract

Discovery of a potent SARS-CoV-2 main protease (Mpro) inhibitor is the need of the hour to combat COVID-19. A total of 1000 protease-inhibitor-like compounds available in the ZINC database were screened by molecular docking with SARS-CoV-2 Mpro and the top 2 lead compounds based on binding affinity were found to be 1,2,4 triazolo[1,5-a] pyrimidin-7-one compounds. We report these two compounds (ZINC000621278586 and ZINC000621285995) as potent SARS-CoV-2 Mpro inhibitors with high affinity (<−9 kCal/mol) and less toxicity than Lopinavir and Nelfinavir positive controls. Both the lead compounds effectively interacted with the crucial active site amino acid residues His41, Cys145 and Glu166. The lead compounds satisfied all of the druglikeness rules and devoid of toxicity or mutagenicity. Molecular dynamics simulations showed that both lead 1 and lead 2 formed stable complexes with SARS-CoV-2 Mpro as evidenced by the highly stable root mean square deviation (<0.23 nm), root mean square fluctuations (0.12 nm) and radius of gyration (2.2 nm) values. Molecular mechanics Poisson-Boltzmann surface area calculation revealed thermodynamically stable binding energies of −129.266 ± 2.428 kJ/mol and − 116.478 ± 3.502 kJ/mol for lead1 and lead2 with SARS-CoV-2 Mpro, respectively.

Keywords: COVID-19, SARS-CoV-2 Main protease inhibitor, Molecular docking, Molecular dynamics simulation, Novel antiviral compound, 1,2,4 triazolo[1,5-a] pyrimidin-7-one

97.pdf

BRD4 targeting nanotherapy prevents lipopolysaccharide induced acute respiratory distress syndrome

Venkatesh Pooladanda, Sowjanya Thatikonda, [...], and Chandraiah Godugu

Keywords: ARDS, BRD4, Lipoplexes, Cytokine storm, p65, STAT3 nuclear translocation

Abstract

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory disease associated with pulmonary edema, alveolar dysfunction, hypoxia, and inflammatory cell accumulation. The most contagious form of COVID-19 associated with ARDS caused by SARS-CoV-2. SARS-CoV-2 majorly produces the cytokine storm and severe lung inflammation and ultimately leads to respiratory failure. ARDS is a complex disease and there is no proper therapeutics for effective therapy. Still, there is a huge scope to identify novel targets to combat respiratory illness. In the current study, we have identified the epigenetic regulating protein BRD4 and developed siRNA based nanomedicine to treat the ARDS. The liposomes were prepared by thin-film hydration method, where BRD4 siRNA complexed with cationic lipid and exhibited 96.24 ± 18.01 nm size and stable even in the presence of RNase. BRD4 siRNA lipoplexes (BRD4-siRNA-LP) inhibited inflammatory cells in lungs and suppressed the lipopolysaccharide (LPS) induced the neutrophil infiltration and mast cell accumulation. Also, BRD4 siRNA based nanomedicine significantly reduced the LPS induced cytokine storm followed by inflammatory signaling pathways. Interestingly, BRD4-siRNA-LP suppressed the LPS-induced p65 and STAT3 nuclear translocation and ameliorated the lung inflammation. Thus, BRD4-siRNA-LP could be a plausible therapeutic option for treating ARDS and might be useful for combating the COVID-19 associated respiratory illness.

98.pdf

Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis

Shalja Verma and Anand Kumar Pandey

Abstract

SARS-CoV-2 main protease (Mpro) cleaves the viral polypeptide 1a and 1ab in a site-specific ((L-Q|(S, A, G)) manner and produce functional enzymes for mediating viral replication. Numerous studies have reported synthetic competitive inhibitors against this target enzyme but increase in substrate concentration often reduces the effectiveness of such inhibitors. Allosteric inhibition by natural compound can provide safe and effective treatment by alleviating this limitation. Present study deals with in silico allosteric inhibition analysis of quercetin, against SARS-CoV-2-Mpro. Molecular docking of quercetin with Mpro revealed consistent binding of quercetin at a site other than active site in multiple runs, with the highest binding energy of − 8.31 kcal/mol, forming 6 H-bonds with residues Gln127, Cys128, Lys137, Asp289 and Glu290. Molecular dynamic simulation of 50 ns revealed high stability of Mpro-quercetin complex with RMSD values ranging from 0.1 to 0.25 nm. Moreover, native-Mpro and Mpro-quercetin complex conformations extracted at different time points from simulation trajectories were subjected to active site-specific docking with modelled substrate peptide (AVLQSGFR) by ZDOCK server. Results displayed site-specific cleavage of peptide when docked with native-Mpro. While substrate peptide remained intact when docked with Mpro-quercetin complex, also the binding energy of peptide reduced from 785 to 86 from 1 to 50 ns as quercetin induced alterations in the active site cavity reducing its affinity for the substrate. Further, no interactions were noticed between peptide and active site residues of Mpro-quercetin complex conformations at 40 and 50 ns. Hence, quercetin displayed effective allosteric inhibition potential against SARS-CoV-2 Mpro, and can be developed into an efficient treatment for COVID-19.

Keywords: Allosteric inhibition, Quercetin, SARS-CoV-2 main protease (Mpro), Molecular docking, Molecular dynamic simulation

99.pdf

In vitro Dissolution Profile at Different Biological pH Conditions of Hydroxychloroquine Sulfate Tablets Is Available for the Treatment of COVID-19

Thirupathi Dongala, Naresh Kumar Katari, [...], and Kamal Dua

Abstract

Hydroxychloroquine sulfate is one of an extensive series of 4-aminoquinolines with antimalarial activity. Moreover, it is used for the treatment of rheumatoid arthritis. Sometimes, hydroxychloroquine sulfate is beneficial for the treatment of autoimmune diseases. Based on recent clinical experiments, it is exploited for the treatment of COVID-19, coronavirus across the globe. The chromatogram separation was achieved by using Agilent, Zorbax C8, 250 mm × 4.6 mm i.d., column. The buffer consists of 0.01 M of 1-pentane sulfonic acid and 0.02% of orthophosphoric acid in purified water. Mixed buffer, acetonitrile, and methanol (800:100:100 v/v). The flow rate was 1.0 ml min−1, and injection volume was 10 μl. Detection was made at 254 nm by using a dual absorbance detector (DAD). The reversed-phase high-performance liquid chromatography (RP-HPLC) method has been developed and validated as per the current International Conference on Harmonization (ICH) guidelines to estimate hydroxychloroquine sulfate tablets. As part of method validation, specificity, linearity, precision, and recovery parameters were verified. The concentration and area relationships were linear (R2 > 0.999) over the concentration range of 25–300 μg ml−1 for hydroxychloroquine (HCQ). The relative standard deviations for precision and intermediate precision were <1.5%. The proposed RP-HPLC generic method was applied successfully to evaluate the in vitro dissolution profile with different pH conditions such as 0.1 N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffers as US-marketed reference products.

Keywords: coronavirus disease 2019, hydroxychloroquine sulfate, dissolution, validation, pH

101.pdf

Efficacy of convalescent plasma therapy for COVID‐19: A systematic review and meta‐analysis

Charan T. R. Vegivinti, John M. Pederson, [...], and Ameer E. Hassan

Abstract

The purpose of this systematic review and meta‐analysis was to examine clinical outcomes associated with convalescent plasma therapy in COVID‐19 patients. We performed a literature search on PubMed, medRxiv, Web of Science, and Scopus to identify studies published up to December 10th, 2020 that examined the efficacy of convalescent plasma treatment for COVID‐19. The primary endpoints were mortality, clinical improvement, and hospital length of stay. We screened 859 studies that met the search criteria, performed full‐text reviews of 56 articles, and identified 15 articles that fulfilled inclusion criteria for meta‐analysis. The odds of mortality were significantly lower in the convalescent plasma group compared to the control group (OR = 0.59 [95% CI = 0.44; 0.78], P < .001), although results from two key randomized controlled trials did not support the mortality benefit. The odds of clinical improvement were significantly higher in the convalescent plasma group compared to the control group (OR = 2.02 [95% CI = 1.54; 2.65], P < .001). There was no difference in hospital length of stay between the convalescent plasma group and the control group (MD = −0.49 days [95% CI = −3.11; 2.12], P= .713). In all, these data indicate that a mortality benefit with convalescent plasma is unclear, although there remain benefits with convalescent plasma therapy for COVID‐19.

Keywords: convalescent plasma, coronavirus, COVID‐19, meta‐analysis

102.pdf

Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E

Ram Kumar, Mohammad Afsar, [...], and Naveen Kumar

Abstract

Emetine is a FDA-approved drug for the treatment of amebiasis. Previously we demonstrated the antiviral efficacy of emetine against some RNA and DNA viruses. In this study, we evaluated the in vitro antiviral efficacy of emetine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and found it to be a low nanomolar (nM) inhibitor. Interestingly, emetine exhibited protective efficacy against lethal challenge with infectious bronchitis virus (IBV; a chicken coronavirus) in the embryonated chicken egg infection model. Emetine treatment led to a decrease in viral RNA and protein synthesis without affecting other steps of viral life cycle such as attachment, entry and budding. In a chromatin immunoprecipitation (CHIP) assay, emetine was shown to disrupt the binding of SARS-CoV-2 mRNA with eIF4E (eukaryotic translation initiation factor 4E, a cellular cap-binding protein required for initiation of protein translation). Further, molecular docking and molecular dynamics simulation studies suggested that emetine may bind to the cap-binding pocket of eIF4E, in a similar conformation as m7-GTP binds. Additionally, SARS-CoV-2 was shown to exploit ERK/MNK1/eIF4E signalling pathway for its effective replication in the target cells. Collectively our results suggest that further detailed evaluation of emetine as a potential treatment for COVID-19 may be warranted.

Keywords: Emetine, Antiviral efficacy, SARS-CoV-2, IBV, eIF4E, In silico binding

103.pdf

Performance study of a sterilization box using a combination of heat and ultraviolet light irradiation for the prevention of COVID-19

Nilkamal Mahanta, Varun Saxena, [...], and U.S. Dixit

Abstract

SARS-CoV-2 virus and other pathogenic microbes are transmitted to the environment through contacting surfaces, which need to be sterilized for the prevention of COVID-19 and related diseases. In this study, a prototype of a cost-effective sterilization box is developed to disinfect small items. The box utilizes ultra violet (UV) radiation with heat. For performance assessment, two studies were performed. First, IgG (glycoprotein, a model protein similar to that of spike glycoprotein of SARS-COV-2) was incubated under UV and heat sterilization. An incubation with UV at 70 °C for 15 min was found to be effective in unfolding and aggregation of the protein. At optimized condition, the hydrodynamic size of the protein increased to ~171 nm from ~5 nm of the native protein. Similarly, the OD280 values also increased from 0.17 to 0.78 indicating the exposure of more aromatic moieties and unfolding of the protein. The unfolding and aggregation of the protein were further confirmed by the intrinsic fluorescence measurement and FTIR studies, showing a 70% increase in the β-sheets and a 22% decrease in the α-helixes of the protein. The designed box was effective in damaging the protein's native structure indicating the effective inactivation of the SARS-COV-2. Furthermore, the incubation at 70 °C for 15 min inside the chamber resulted in 100% antibacterial efficacy for the clinically relevant E.coli bacteria as well as for bacteria collected from daily use items. It is the first detailed performance study on the efficacy of using UV irradiation and heat together for disinfection from virus and bacteria.

Keywords: SARS-CoV-2, COVID-19, Sterilization, UV radiation, Heat treatment, Bacteria

104.pdf

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (Mpro) of SARS-CoV-2

Arabinda Ghosh, Monoswi Chakraborty, [...], and Mohamad Parvez Alam

Abstract

The spread of novel coronavirus SARS-CoV-2 has directed to a state of an unprecedented global pandemic. Many synthetic compounds and FDA-approved drugs have been significantly inhibitory against the virus, but no SARS-CoV-2 solution has been identified. However, small molecule fragment–based derivatives of potent phytocompounds may serve as promising inhibitors against SARS-CoV-2. In the pursuit of exploring novel SARS-CoV-2 inhibitors, we generated small molecule fragment derivatives from potent phytocompounds using neural networking and machine learning–based tools, which can cover unexplored regions of the chemical space that still retain lead-like properties. Out of 300 derivative molecules from withaferin-A, hesperidin, and baicalin, 30 were screened out with synthetic accessibility scores > 4 having the best ADME properties. The withaferin-A derivative molecules 61 and 64 exhibited a significant binding affinity of − 7.84 kcal/mol and − 7.94 kcal/mol. The docking study reveals that withaferin-A mol 61 forms 5 polar H-bonds with the Mpro where amino acids involved are GLU166, THR190, CYS145, MET165, and GLN152 and upon QSAR analysis showed a minimal predicted IC50 value of 7762.47 nM. Furthermore, the in silico cytotoxicity predictions, pharmacophore modeling, and molecular dynamics simulation studies have resulted in predicting the highly potent small molecule derivative from withaferin-A (phytocompound from Withania somnifera) to be the potential inhibitor of SARS-CoV 2 protease (Mpro) and a promising future lead candidate against COVID-19. The rationale of choosing withaferin-A from Withania somnifera(Ashwagandha) was propelled by the innumerous applications of Ashwagandha for the treatment of various antiviral diseases, common cold, and fever since time immemorial.

105.pdf

Nano-formulation of herbo-mineral alternative medicine from linga chenduram and evaluation of antiviral efficacy

Mysoon M. Al-Ansari, A.J.A. Ranjit Singh, [...], and J.S. Michael

Abstract

Traditional medicine is becoming a primary source of health care in many countries in recent years. The current study proposes a new dimension of understanding a traditional origin treatment, using herbo-mineral preparations in nanoform. The herbo-mineral preparation, Linga chenduram [HMLC], was prepared according to the ancient palm script protocol dates back to 1000 years. In search of alternative therapy for the coronavirus, an attempt was made to determine this ethnic medicine formulation's therapeutic potential for viral hepatitis infection. The Hepatitis C virus [HCV] has several genomic similarities with SARS-CoV-2 viruses. The herbo-mineral formulation (HMLC) were analyzed using UV–vis, EDAX, FTIR, XRD, SEM, and TEM studies. SEM images confirmed the ' presence of nanoparticles with agglomerated conditions having an average grain size of 18 to 25 nm. EDAX studies showed the presence of metallic components in oxide or sulfide form in HMLC. The HCV inhibitory effects of HMLC indicated a good response. The cytotoxicity of this preparation against the Huh-7 human hepatoma cellline was significant. The HMLC showed a strong inhibitory effect on HCV replication in a dose-dependent manner. The genomic component of HCV is similar to COVID −19 virus. The Hepatitis C virus (HCV) NS3/4A protease has a striking three-dimensional structural similarity to the SARS-CoV2 Mpro protease, particularly in the arrangement of key active site residues. So HMLC can be tried to treat coronavirus infection. At higher concentrations, HMLC exhibited over 100-fold inhibition. In the MTT assay, HMLC did not show any apparent cytotoxic effect on cell viability at the concentrations 1–100 µg. Histological studies indicated that the liver and kidney did not experience any toxicity by 7 and 15 consecutive days of administration of HMLC on experimental Wistar rats. Hence, the HMLC can be tried as a therapy for COVID −19 infections using the preparations strictly according to ethnopharmacological protocol and optimum doses.

Keywords: Lingachenduram, Ethnopharmacology, Herbo-mineral nanomedicines, SARS-CoV2, HCV

107.pdf

Identification of potential plant-based inhibitor against viral proteases of SARS-CoV-2 through molecular docking, MM-PBSA binding energy calculations and molecular dynamics simulation

Bhaskarjyoti Gogoi, Purvita Chowdhury, [...], and Pratap Jyoti Handique

Abstract

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, SARS-CoV-2, has recently emerged as a pandemic. Here, an attempt has been made through in-silico high throughput screening to explore the antiviral compounds from traditionally used plants for antiviral treatments in India namely, Tea, Neem and Turmeric, as potential inhibitors of two widely studied viral proteases, main protease (Mpro) and papain-like protease (PLpro) of the SARS-CoV-2. Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (−)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the selected receptors, with the lowest CDocker energy − 46.22 kcal mol−1 for SARS-CoV-2 Mpro and CDocker energy − 44.72 kcal mol−1 for SARS-CoV-2 PLpro, respectively. The SARS-CoV-2 Mpro complexed with (−)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 Mpro–Co-crystal ligand (N3) and SARS-CoV-2 Mpro- (−)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (−)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC50 of 0.3281 nM against SARS-CoV-2 Mpro. Overall, (−)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment.

Keywords: COVID-19, SARS-CoV-2, Main protease, Papain-Like protease (−)–epicatechin-3-O-gallate, Molecular Dynamics, QSAR

diabetic foot.pdf

Managing diabetic foot in times of COVID-19: time to put the best ‘foot’ forward

Avica Atri, Chaithanya Murthy Kocherlakota, and Riddhi Dasgupta

Abstract

Introduction

The COVID-19 pandemic has had an unparalleled impact on the socio-economic and healthcare structure of India. Due to our large populations of diabetic patients, who have an increased risk of worse outcomes with COVID-19 infection, it is of utmost public health importance to analyse the relationship between the two. The aim of our review was to analyse the possible relationship between COVID-19 infection and DFUs, which are a fairly common, yet serious complication in diabetic patients, as well as their management, under the given changing circumstances.

Methodology

An extensive review of related educational articles was analysed from various databases.

Results

The two main pathogenic mechanisms described in COVID-19 infection are a cytokine storm (causing ARDS) as well as an acquired coagulopathy, with widespread thrombosis. DFUs are associated with an underlying peripheral neuropathy, a chronic low-grade inflammatory state and peripheral arterial disease, which lead to chronic non-healing ulcers. Similarities seen in the pathogenic mechanisms of these two conditions make a bidirectional relationship highly plausible.

Conclusion

Due to the disruptions in the healthcare system brought on by the COVID-19 pandemic, changes in practice to a telehealth-driven approach, with emphasis on homecare and community clinics, need to be adopted, to ensure best possible care to patients with DFUs, in order to reduce their risk of DFU-related complications and need for hospitalization.

Keywords: COVID-19, Diabetic peripheral neuropathy (DPN), Diabetic foot ulcers (DFU), Cytokine storm, Ischemia

115.pdf

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

Anup Agarwal,1 Aparna Mukherjee,1 Gunjan Kumar,1 Pranab Chatterjee,1 Tarun Bhatnagar,2 Pankaj Malhotra,3 on behalf of the PLACID Trial Collaborators

ABSTRACT

OBJECTIVE To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. DESIGN Open label, parallel arm, phase II, multicentre, randomised controlled trial. SETTING 39 public and private hospitals across India. PARTICIPANTS 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO2 /FiO2 ) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). INTERVENTIONS Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. MAIN OUTCOME MEASURE Composite of progression to severe disease (PaO2 / FiO2 <100 mm Hg) or all cause mortality at 28 days post enrolment. RESULTS Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). CONCLUSION Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. TRIAL REGISTRATION Clinical Trial Registry of India CTRI/2020/04/024775.

121.pdf

How to rapidly design and operationalise PPE donning and doffing areas for a COVID-19 care facility: quality improvement initiative

LaxmiTej Wundavalli, Sheetal Singh, Angel Rajan Singh, and Sidhartha Satpathy

Abstract

Introduction

Effective implementation of standard precautions specific to COVID-19 is a challenge for hospitals within the existing constraints of time and resources.

Aim

To rapidly design and operationalise personal protective equipment (PPE) donning and doffing areas required for a COVID-19 care facility.

Methods

Literature review was done to identify all issues pertaining to donning and doffing in terms of Donabedian’s structure, process and outcome. Training on donning and doffing was given to hospital staff. Donning and doffing mock drills were held. 5S was used as a tool to set up donning and doffing areas. Instances of donning and doffing were observed for protocol deviations and errors. Plan–do–study–act cycles were conducted every alternate day for 4 weeks. The initiative was reported using Standards for QUality Improvement Reporting Excellence (SQUIRE) guidelines.

Results

Best practices in donning and doffing were described. Our study recommends a minimum area of 16 m2 each for donning and doffing rooms. Verbally assisted doffing was found most useful than visual prompts.

Discussion

Challenges included sustaining the structure and process of donning and doffing, varied supplies of PPE which altered sequencing of donning and/or doffing, and training non-healthcare workers such as plumbers, electricians and drivers who were required during emergencies in the facility.

Conclusion

Our study used evidence-based literature and quality improvement (QI) tools to design and operationalise donning and doffing areas with focus on people, task and environment. Our QI will enable healthcare facilities to rapidly prototype donning and doffing areas in a systematic way.

Keywords: checklists, continuous quality improvement, healthcare quality improvement, infection control, PDSA

131.pdf

Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis

Surjit Singh,#1 Daisy Khera,#2 Ankita Chugh, #3 Pushpinder Singh Khera,4 and Vinay Kumar Chugh3

Abstract

Objectives

Evaluation of remdesivir, an RNA polymerase inhibitor, for effectiveness in adults with COVID-19.

Data sources

Electronic search for eligible articles of PubMed, Cochrane Central and clinicaltrials.gov was performed on 20 September 2020.

Participants and study eligibility criteria

Only randomised controlled trials (RCTs) evaluating efficacy of remdesivir in COVID-19 were included for meta-analysis.

Interventions

Remdesivir was compared with standard of care.

Primary and secondary outcomes

Primary outcome was mortality and secondary outcomes were time to clinical improvement and safety outcomes like serious adverse events, respiratory failure.

Study appraisal and synthesis methods

Data synthesis was done with Cochrane review manager 5 (RevMan) V.5.3. Cochrane risk of bias V.2.0 tool was used for methodological quality assessment. The GRADE pro GDT was applied for overall quality of evidence.

Results

52 RCTs were screened and 4 studies were included in analysis, with total of 7324 patients. No mortality benefit was observed with remdesivir versus control group (OR=0.92 (95% CI 0.79 to 1.07), p=0.30, moderate quality evidence). Significantly higher rates of clinical improvement (OR=1.52 (95% CI 1.24 to 1.87), p<0.0001, low quality) and faster time to clinical improvement (HR=1.28 (95% CI 1.12 to 1.46), p=0.0002, very low quality) was observed with remdesivir versus control group. Significant decrease was found in the risk of serious adverse events (RR=0.75 (95% CI 0.62 to 0.90), p=0.0003, low quality); however, no difference was found in the risk of respiratory failure (RR=0.85 (95% CI 0.41 to 1.77), p=0.67, very low quality evidence) with remdesivir.

Conclusions

As per the evidence from current review, remdesivir has shown no mortality benefit (moderate quality evidence) in the treatment of COVID-19. From a cost–benefit perspective, it is our personal opinion that it should not be recommended for use, especially in low and lower middle income countries.

Trial registration number

PROSPERO registration number: CRD42020189517.

Keywords: COVID-19, immunology, clinical pharmacology, respiratory infections

132.pdf

When technology precedes regulation: the challenges and opportunities of e-pharmacy in low-income and middle-income countries

Rosalind Miller, 1 Francis Wafula,2 Chima A Onoka,3 Prasanna Saligram,4 Anita Musiega,2 Dosila Ogira,2 Ikedichi Okpani,5 Ufuoma Ejughemre,6 Shrutika Murthy,4 Surekha Garimella,4 Marie Sanderson,7 Stefanie Ettelt,7 Pauline Allen,7 Devaki Nambiar,4 Abdul Salam,4 Emmanuel Kweyu,8 Kara Hanson,1 and Catherine Goodman1

Abstract:

The recent growth of medicine sales online represents a major disruption to pharmacy markets, with COVID-19 encouraging this trend further. While e-pharmacy businesses were initially the preserve of high-income countries, in the past decade they have been growing rapidly in low-income and middle-income countries (LMICs). Public health concerns associated with e-pharmacy include the sale of prescription-only medicines without a prescription and the sale of substandard and falsified medicines. There are also non-health-related risks such as consumer fraud and lack of data privacy. However, e-pharmacy may also have the potential to improve access to medicines. Drawing on existing literature and a set of key informant interviews in Kenya, Nigeria and India, we examine the e-pharmacy regulatory systems in LMICs. None of the study countries had yet enacted a regulatory framework specific to e-pharmacy. Key regulatory challenges included the lack of consensus on regulatory models, lack of regulatory capacity, regulating sales across borders and risks of over-regulation. However, e-pharmacy also presents opportunities to enhance medicine regulation—through consolidation in the sector, and the traceability and transparency that online records offer. The regulatory process needs to be adapted to keep pace with this dynamic landscape and exploit these possibilities. This will require exploration of a range of innovative regulatory options, collaboration with larger, more compliant businesses, and engagement with global regulatory bodies. A key first step must be ensuring that national regulators are equipped with the necessary awareness and technical expertise to actively oversee this e-pharmacy activity.

Keywords: health systems, public health, qualitative study, health policy

150.pdf

Steroid harms if given early in COVID-19 viraemia

Kanupriya Arora and Prasan Kumar Panda

Abstract:

COVID-19 is a biphasic illness with an initial viraemia phase and later effective adaptive immune phase, except in a minority of people who develop severe disease. Immune regulation is the key target to treat COVID illness. In anticipation, an elderly man self-medicated himself with dexamethasone on the day of symptom onset of a flu-like illness, took other symptomatic measures and was tested positive for SARS-CoV-2. His condition deteriorated with each passing day resulting in hospitalisation. He demanded oxygen and declared as severe COVID. With supportive treatment, he recovered after the 20th day of illness. Immunosuppression and anti-inflammation are likely to benefit when the immune response is dysregulated and turning into a cytokine storm. A medication that has saved many could be the one predisposing to severity if taken as a preventive measure, too early in the disease course, especially the viraemia phase.

Keywords: COVID-19, general practice / family medicine, global health, infectious diseases