COVID -19 a global pandemic that has brought all the greater global countries to a hook. The novel coronavirus (SARS-CoV-2) outbreak was first reported in Wuhan, China which then started spreading to different countries around the world. ACE2 receptors are present in various organs but the overexpression of ACE2 at lung epithelia makes them more vulnerable to respiratory symptoms. SARS-CoV-2 binds to ACE2 receptors for entry into host cells which may serve as potential target for future therapy.Repurposing of drugs are the present strategy undertaken as the SARS-CoV-2 shows similar respiratory distress symptoms as in the case of SARS and MERS. At present the antiviral medications and vaccines are at the early stages and may take few months to years, to achieve their complete efficacy to solve the public crisis. The technological advancements have brought passive immunisation, which is an anecdotal success, but the ideal approach to future outbreaks of SARS-CoV-2 is done by vaccines that are under clinical trials. There are a large percentage of population under psychological crisis either due to the fear of infection or stress from the quarantine lives. High levels of viral loads at the initial stages cause higher chances of transmission hence immediate isolations and screening methods must be undertaken. This review mainly focuses on the treatment strategies followed with no definitive approval from authorities. This is an attempt to gather all the materialistic evidences available for now. A novel strain of coronavirus (2019-CoV) was detected in Wuhan, Hubei province, China in December 2019. Coronavirus infects both humans and animals including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Southern China 2003 and Middle East respiratory syndrome–related coronavirus (MERS-CoV) in Saudi Arabia 2012 were two severe forms of infections out broken in the past. There are six coronavirus species well known to affect human, of which one species subdivided into two different strains making seven strains of human coronavirus. Out of this four strains  mostly cause common cold symptoms and three strains  cause severe acute respiratory syndromes. SARS-CoV and MERS-CoV can cause fatal respiratory diseases. As of now the magnitude of the outbreak exceeds the potentially available medical management capacities which make the scenario serious. Hence, the Nations worldwide are trying to control this havoc. The novel coronavirus will be referred as SARS-Cov-2, and has been labelled as a public health emergency of international concern as the pandemic curves are still on the rise. The coronavirus pandemic has led to severe global outbreak leading to socioeconomic disruption and has hence become a major public health issue. The infection has estimated to have mean incubation period of 5-6 days and a basic reproduction number of 2.24-3.58. COVID-19 had a case fatality rate ratio of 4% however recent reports suggests between 1 to 2 %. The novel coronavirus infection is called a super spreader as it can be spread from an individual patient to a large population of different countries which led the WHO characterise COVID-2019 as a pandemic crisis. The epidemiological studies suggest, the COVID -19 is known to be mostly fatal for elderly patients with comorbid conditions. The coronavirus are divided into four genera-alpha, beta, gamma and delta.SARS-CoV-2 belong to gene betacoronavirus wherein phylogenetic analysis revealed that the major reservoir of CoV infections are bats and bat-SL-CoVZC45, bat-SL-CoVZXC21 are two bat derived SARS like coronavirus which shows 79% similarity to SARS and 50% similarity to MERS. As there are many clinical trials undertaken by various countries to isolate and identify drugs and vaccines for COVID-19 some of the prevailing treatment strategies are discussed further which is not so far a standard protocol.The emergence of novel coronavirus disease 2019 (COVID-19) is the latest pandemic that is affecting human health and economy across the world.th December 2019, the first case of COVID-19 was reported in the Hubei province, Wuhan city, China. Four people from the street seafood market were admitted in the hospital and showed respiratory symptoms with fever. As a second outbreak, there were more human to human transmissions at a higher rate suggesting it to be an epidemic and viral infection. The cases reported included both immunosuppressed and normal people, with majority belonging to middle age and older citizens.On 29 The inclusion criteria also explains that the patients of age greater than 60 are at greater mortality risk therefore initiation of combination therapy can be preferred. The structure of the virus is spherical virion surrounded with projections, hence corona in Latin means crown. The genome size varies from 26 kb to 32 kb. The SARS-CoV -2 belongs to B-lineage of beta coronavirus. There are four major genes that encode the nucleocapsid-the spike protein (S), a membrane glycoprotein (M), a small membrane protein (SM), an additional membrane glycoprotein (HE). The reproduction number of COVID-19 is greater than SARS 1.77. The incubation period are expected to be an average of 7-14 days. The coronavirus exhibits zoonotic nature that includes respiratory, enteric, hepatic and neurological problems. The transmission is basically by droplet route, direct contact and aerosols route. As the patients diagnosed with SARS-CoV was found to have abdominal discomfort and diarrheal symptoms, the analysis opens a direct relation between angiotensin-converting enzyme 2 (ACE-2) receptors and coronavirus transmission. The SARS–CoV-2 encodes several proteins including structural proteins, on-structural proteins and auxiliary proteins. The spikes present on the external side of the virus binds to the ACE2 receptor. They contain amino acids with N- terminal S1 and C-terminal subunits. The S1 subunit has receptor binding domain (RBD) containing two subdomains. Out of it the external subdomain has two loops on the surface that binds to ACE2 receptor. This may explain the reason of entry of SARS-CovV-2 through receptors like ACE2 in respiratory tract. The ACE-2 receptors are present on small and large arteries, nasal-oral mucosa, nasopharynx, enterocytes of the small intestine but being abundant on the lung epithelia, pulmonary symptoms dominate in COVID-19 infections. Therefore, targeting the ACE-2 receptors, pneumonia-like symptoms along with pulmonary oedema and ARDS can be reduced. Coronavirus spike (S) protein is the major site responsible for viral attachment to the host ACE-2 receptors thus drugs carried by appropriate vector systems targeting viral S proteins can diminish the viral load at the target site.Coronaviruses are enveloped non-segmented single stranded positive sense RNA virus with a large size genome belonging to the family Coronaviridae, order Nidovirales and broadly infects humans and other animals.The most common symptoms of COVID-19 at onset are fever (90%), dyspnea, fatigue (70%), dry cough (60%), myalgia (44%) and less common symptoms are headache, dizziness, diarrhoea, nausea and vomiting. The elderly patients having underlying co-morbidities including hypertension, diabetes, and cardiovascular disease are at greater risk. The most common laboratory abnormalities among patients hospitalised with COVID-19 are marked lymphopenia, prolonged prothrombin time, elevated LDH, elevated D-dimer and these are close to the ones in MERS-CoV and SARS-CoV infections.The studies provide evidence that severe COVID-19 cases might have a cytokine storm syndrome. The cytokine storm is associated with the increase in cytokines like IL-2, IL-7 granulocyte colony stimulating factor, interferon-gamma, macrophage inflammatory protein 1-alfa and tumour necrosis factor-alfa. Viral infections and sepsis may trigger the secondary haemophagocytic lymphohistiocytosis (sHLH), which is characterised by unremitting fever, cytopenia’s, hyperferritinaemias, and acute respiratory distress syndrome (ARDS). Histological examination usually shows bilateral alveolar damage with cellular fibromyxoid exudates, shedding of pneumocytes and hyaline membrane formation indicating ARDS, pulmonary oedema, moderate microvesicular steatosis, levels of CD4 and CD8 were substantially reduced and high concentration of proinflammatory (CCR6 + Th17) CD4 T-cells showing viral cytopathic changes. Lymphopaenia is a critical factor associated with disease severity and mortality of COVID-19 patients. The COVID-19 infection primarily targets respiratory system causing severe pneumonia, and the epithelial cells of lungs are damaged.The dysregulated and exuberant immune responses due to coronavirus infections cause alveolar damage and respiratory failure leading to diminished survival rates. As cytokines and chemokines have a role in immunity and immunopathology the increase in cytokine levels  with reduction in IFN-gamma expression of CD4 T-cells are considered as indicators of severe COVID-19. There were some cases of interstitial thickening, moderate fibrosis, and presence of inflammatory cells. Dilation of airspaces and intra alveolar organisations of exudates, granulation of tissues in airways and airspaces, lesions of cellular components of histiocytes. The presence of large multinucleated pneumocytes were found from most post-mortem. The lymphoid infiltrate consisted of sparse T-cells and few B-cells but natural killer cells were absent. Most of the cells with atypical nuclei were positive for cytokeratin indicating the presence of pneumocytes. The viral like particles on pneumocytes depicts the presence of nucleocapsids and the surface of some had club like projections. There was also a ring moiety in some particles indicating the characteristics of helical nucleocapsid of coronaviruses. The pulmonary fibrosis found in patients largely points to the SARS infection. These interventions suggest that pneumocytes are the primary target for SARS-CoV infections. The pathogenesis involves proteolytic cleavage and membrane fusion mechanisms that serve their entry and spread. The virus once entered sheds its viral RNA genome in the cytoplasm that undergoes replication by post-translational events to produce viral glycoproteins. These get assembled in the endoplasmic reticulum and Golgi complex that enables the formation of vesicles of nucleocapsid proteins that fuse with the host plasma membrane to release new virions.The pulmonary pathological features of SARS-CoV from a post-mortem examination done in China explain pleural effusion causing pleural oedema and extensive consolidation. Majority of patients had diffuse alveolar damage (DAD), and hyaline membrane formation.Recent literatures have shown various extrapulmonary systemic involvement of disease articulation and virus transmission which included gastrointestinal tract, nervous system, cardiovascular system, renal system, eyes, and manifestations due to haematological abnormalities. Post COVID-19 complications include enduring damage to the heart muscle, even in those with only mild symptoms, increasing the risk of heart failure or other heart complications. Strokes, seizures, and Guillain-Barre syndrome that causes temporary paralysis. Possibilities of developing Parkinson’s and Alzheimer’s disease. Problems associated with blood cells like clotting leading do heart attacks, stroke has been studied. Heart damage caused by COVID-19 is believed to occur from exceedingly small clots that block capillaries in the heart muscle. Renal disorders, hypertension, hyperglycaemia, mood disorders, septic shock, extreme fatigue, and myalgia have been reported recently. Multisystem inflammatory syndrome is also said to occur in both elderly and paediatric groups.The epidemiological key parameter of COVID-19 is the incubation period which is determined with the help of epidemiological cases reporting. Incubation period of an infection is necessary factor to identify the quarantine periods. This also helps in identifying the contact tracings and screening purposes and transmission potential strength. Now the incubation periods are estimated with the data available from the reported travel histories and symptom onset dates. Accordingly, the mean incubation period ranges from 1-14 days with a median of 5-7 days, which may be chosen for the quarantine periods.The studies using stochastic method helped to estimate Ro of SARS to lie within 2 and 5 which is within the range of the mean Ro of COVID-19 also suggesting the reproduction number Ro of COVID-19 is greater than SARS coronavirus. The reproduction number helps to identify the transmission level and the incidence of new infections. The intervention that COVID-19 is more widespread than SARS makes it more transmissible. The review found that the mean average of Ro in case of COVID-19 is 3.28 with median of 2.79, and IQR of 1.16. Treatment basically focus on the management of patients. Additional intensive care with broad spectrum antibiotics, glucocorticoids, vasopressor and renal replacement therapy may be undertaken during SARS-CoV-2 therapy. Drug therapy monitoring is crucial in case of antiviral therapies and require continuous health surveillance as they are more likely to cause metabolic and haematological abnormalities.Currently there are no definitive proven treatments, thus multiple pharmacological options are being explored. The novel coronavirus prefers the ACE2 receptor for penetrating into the cells, therefore strategies used for blocking SARS are being tried out. Some of the trials initiated by using the undermentioned drugs showed improvement in patients and some animal models that led to further interest. A systematic review conducted on safety and efficacy of chloroquine by Chinese researchers using Vero E6 cells infected by SARS-CoV-2 demonstrated that chloroquine was highly effective in reducing viral replication with an effective concentration (EC) 90 of 6.9 µM that can be easily achieved with standard dosing due to its favourable penetration into the tissues and lungs. Similarly the early stage pre-clinical in vitro data suggests that hydroxychloroquine with EC 50 values 0.72 µM may be more potent than chloroquine with EC 50 values 5.47 µM. An open non randomised clinical trial conducted showed (70%) of hydroxychloroquine treated patients were cured when compared to the untreated control group. In the United States, the FDA issued an emergency use authorization (EUA) to allow the use of these agents in adolescent or adults hospitalized for COVID-19 when participation in clinical trials is not feasible. Although the initial single centred clinical trials showed CQ/HCQ has therapeutic efficacy on COVID-19 patients the further follow up on larger sample size population has come to a contrasting conclusion. Usually there are mild side effects like dizziness, gastrointestinal reactions, vomiting, and diarrhoea while the drugs when taken for longer period depicts toxic effects like retinopathy, conduction disorders and cardiomyopathy. The removal of the drug from the COVID-19 treatment strategy is mainly due to the abnormality of cardiac conduction system that provides higher chances of fatal arrhythmias. As CQ/HCQ are narrow therapeutic index drugs acute CQ poisoning is associated with potential life-threatening cardiovascular disease which made the long-term use conclusion futile. Hence regular monitoring of cardiac functions is necessary to rule out potential cardiac toxicity. There is still a need for potent evidences from multicentre clinical trials to clarify the safety and efficacy of CQ/HCQ in COVID-19 treatment trends. Even though the early stage treatment of HCQ to prevent viral replication was a success to an extent the patients must be cautioned while taking concomitant other antiviral QT prolonging drugs like azithromycin to avoid the pronounced side effect. The use of HCQ in healthy individuals and for a short period of time reduces the chances of life-threatening events. Monitor the QTc level of >500 ms (milliseconds) or an increase of 60 ms as they require immediate discontinuation of therapy and proper education counselling. The simple Vero cell models proves CQ and HCQ with appreciable antiviral properties but the more complex non-human primate models have no significant therapeutic benefit in SARS-COV-2 infections.Chloroquine, an antimalarial, has an in vitro activity against SARS-CoV-2 and may have immunomodulating properties. The drug mainly acts by increasing the endosomal pH that inhibits the fusion of viral particle and host cell membranes. Initially the pre-clinical data of in vitro studies suggests Chloroquine (CQ) had activity against SARS-CoV-2 and also reduce the exacerbations of pneumonia patients with COVID-19 infection. As COVID-19 is an emerging virus, an effective treatment has not been developed for the disease, the Indian Council of Medical Research (ICMR) has suggested off label emergency use of lopinavir/ritonavir combination for symptomatic COVID-19 patients. But according to recent sophisticated multi cantered clinical trial studies lopinavir/ritonavir combinations require several days to achieve the high concentration of drug therefore a loading dose is appropriate which may often show mild gastrointestinal disorders. The delayed treatment with standard doses of lopinavir/ritonavir are unlikely to have benefit for blockage of viral replication. The randomised controlled open labelled RECOVERY trials between March 19 and June 29, 2020 of lopinavir/ritonavir verses placebo trials at UK provided new results different from the previous findings of the drugs efficiency in COVID-19 patients. The limitations of the drug involve the uncertainty in the dose of lopinavir/ritonavir to achieve adequate SARS-COV-2 inhibitory concentration at lungs, their maximum effective concentration is limited probably due to their high protein binding >95%. Hence the monotherapy of lopinavir/ritonavir in patients with COVID-19 did not provide beneficiary reduction in hospital stay or mortality rates.Lopinavir and ritonavir are two HIV protease inhibitors that suppress the Mpro enzyme required for the coronavirus replication. Lopinavir is metabolised by CYP 3A isoenzyme in the liver, hence lopinavir is used with ritonavir as it helps to reduce the dose of lopinavir and ritonavir inhibits CYP3Aisoenzyme. The early stage data’s suggested that the adverse clinical outcomes like death and ARDS were lower in treatment groups when compared to control groups. Although earlier this year remdesivir was used under EUA, on 22nd October 2020 after three randomised controlled open labelled multi center clinical trial the antiviral drug (Veklury) Remdesivir from Gilead Science Incorporated has recently been approved by the USFDA as the first drug to get official approval for treatment of COVID-19 patients of 12 years and older of age with weighing at least 40 kg. They added to the knowledge that the drug achieved clinical recovery by five days faster and reduced the mortality rate of patients on ventilation support. They were instructed to be administered only in a hospital or healthcare setting comparable to inpatient hospital care. There must be benefit risk assessment to be followed to monitor the possible side effects like increased liver enzymes, allergic reactions, and nausea.Remdesivir (GS-5734) is an investigational nucleoside analogue, broad spectrum anti-viral with in vitro activity against SARS-CoV -2. It is a prodrug of remdesivir triphosphate that acts as an inhibitor of RNA-dependent RNA polymerase (RdRp) and interrupts proof reading causing a decrease viral RNA production. Remdesivir – triphosphate competes with adenosine-triphosphate for incorporation into nascent viral RNA chain, once incorporated this, then terminates RNA synthesis at position (i+3) and cause chain termination. The vitro studies conducted using Remdesivir is on the clinical phase, evaluating the efficacy and safety of the drug in 452 hospitalized adult patients with severe COVID-19 respiratory disease.Azithromycin - another agent which was tried, is a macrolide antibacterial, which has immunomodulating properties and decrease the exacerbations of cytokine production that normally occur during pulmonary respiratory disorders, reduce the chemotaxis of neutrophils to the lungs by inhibiting cytokines, IL-8, inhibiting neutrophil apoptosis, and blocking the activation of nuclear transcription factors.Tocilizumab: There have been evidences stating the use of tocilizumab has been useful to certain extent. The body temperatures have reached to normal in a single day, the clinical symptoms have reduced, there has been better oxygen saturation capacities, the percentage of lymphocytes and CRP levels have comer to normal values. Anecdotal reports have described good outcomes with the IL-6 receptor inhibitor tocilizumab but there are no published clinical data supporting its use. It is an IL-6 pathway inhibitor which is a monoclonal antibody, that acts by inhibiting the proinflammatory cytokines, T-cell activation, immunoglobulin secretion induction, haematopoietic precursor cell proliferation and differentiation stimulation. As the infection primarily causes chest tightness, shortness of breath, respiratory failure, the chest CT-shows opacities which was eventually decreased to a far extend by tocilizumab. This agent as well as sarilumab and siltuximab which also target the IL-6 pathway are being evaluated in clinical trial. There were notable difference in the discharge rates when patients received interferon beta 1-a in the early phase of disease with minor side effects like neuropsychiatric problems, agitation, mood swings, mild depression, hypersensitivity reactions, injection related problems  that were eventually tolerable and resolved during follow-ups. The recent studies demonstrates controversy in the use of interferon-I as treatment option in COVID-19 patients due to their activation of innate immune responses that promotes inflammatory cytokines production therefore the early use of interferon alpha decreased the mortality rates. There is future trial ongoing on IFN-III that exhibits antiviral activity without inflammatory efforts.Interferon beta 1-a: It has been under trials for its antiviral activity against SARS-CoV-2. The interferon therapy produces a cytopathic effect by reducing the infection and viral replication of coronavirus. The pre-treatment of interferon beta-1 b shows significant protection of post infection for 24-48 hours. The mechanism of action undertaken here is viral neutralisation. The sources of antibody for SARS-CoV-2 are human coalescent sera of recovered people, monoclonal antibodies, or preparations made in some animal hosts or engineered products that eventually produce human antibody. This procedure becomes a success only when there is an increase in potential donors quantitative. This treatment procedure is effective when used prophylactically rather than for treatment of disease. They neutralise the initial inoculums which is easier in the initial stages, they also work by modifying the inflammatory responses which is also achieved during initial stages. After administration, the antibody circulates in blood, reaches tissues, and provide protection against diseases. There are also risks associated with passive administration of convalescent sera including TRALI (transfusion related acute lung injury) and ADE (antibody dependent enhancement) of infection, and chances of re-infections. Current data suggest the use of convalescent sera is safe in patients having a high chance of mortality, elderly and vulnerable groups where benefits outweighs risk. Convalescent sera can be used as a precautionary for members of the same family where caring for COVID-19 patients at home is required. It would be an expedient measure in the middle of current chaos.Convalescent plasma: A new drug application is the use of convalescent plasma for patients with life threatening COVID-19 infections has been undertaken by the United States. Convalescent plasma is collected from persons who have retrieved from COVID-19 infections that may contain antibodies to SARS-CoV-2. This is a type of passive antibody therapy that involves the administration of antibodies against a foreign agent present in the body of a susceptible individual for the purpose of preventing the infectious disease due to that agent. This is a means of providing immunity at the earliest to the susceptible persons.Favipiravir: It is an RNA polymerase inhibitor that is available in some Asian countries for treatment of influenza and is being evaluated in clinical trials for treatment of COVID -19, but the published clinical data is pending. Favipiravir is a new type of RNA-dependent RNA polymerase (RdRp) inhibitor, they block the replication of viral genome.Arbidol is orally administered at a dose of 200 mg 3 times/day. The duration of treatment is no longer than 10 days. Arbidol is an antiviral used to treat influenza virus. A study has revealed that Arbidol can effectively inhibit novel coronavirus infection in about a concentration of 10-30 μM in vitro. RECOVERY trials performed at UK suggests corticosteroids like dexamethasone and methylprednisone has a good bioavailability at lungs and works only at the early stages of infection. Their anti-inflammatory properties help to reduce the systemic inflammation and excessive fluid in lungs and further alveolar damage. The one major problem associated with steroid therapy is the inhibitory effect on immune response after long term use leads to decreased viral clearance. Corticosteroids are beneficial in reducing hospital stay in critically ill mechanically ventilated COVID-19 patients when compared to non-ventilated patients.Corticosteroids: The effect of early usage of corticosteroid treatment for SARS-CoV-2 is tried in treating immune-mediated pulmonary damage. There are clinical trials on hydrocortisone as well as methyl prednisone verses placebo are being checked for efficacy in reducing fever and decreasing the lung opacities are under trials. There are limitations to the therapy due to delayed viral clearances and immunosuppressive effects.Niclosamide - an anticestodal drug functions by inhibiting oxidative phosphorylation and stimulating adenosine triphosphate activity in mitochondria, it also has broad antiviral activities and acts in combating COVID-19. Niclosamide suppresses the cytopathic effect of SARS-CoV at a concentration as low as 1 µM and inhibited SARS-CoV replication with EC50 value of less than 0.1 µM. Drug repurposing is an attractive and readily available technique that uses the existing drugs for treating the unexpected sudden occurred challenging diseases thereby reduces the cost and timeline spent. On March 28th 2020 the FDA granted EUA for HCQ and Remdesivir on May 1, 2020 but however on 15th June FDA revoked the EUA of HCQ. Several drugs like remdesivir a monophosphate prodrug used for potential treatment of Ebola virus was approved by FDA under emergency situations in severely ill COVID-19 patients, mefuparib (CVL218) a poly (ADPribose) polymerase1 inhibitor shows antiviral activity against SARS-COV-2, toremifene selective estrogen receptor modulator l used in breast cancer also had the ability to block the interactions of virus in MERS, SARS and inhibits the non-structural proteins of SARS-COV-2. Even the host targeting strategies of baricitinib, melatonin and dexamethasone approved for various inflammatory and autoimmune conditions paved the way for reduction of mortality in COVID-19 patients. There are also combination drug therapies for boosting the host immune responses but are presently under theoretical analysis and not tested in preclinical trials. Glucocorticoids (dexamethasone) have proven to be effective in mechanic ventilation hospitalised patients by increasing the viral clearance and reducing the mortality rates of severely ill COVID-19 patients. Androgen receptor inhibitors like spironolactone, eplerenone are having extensive safety profile against hypertension and inhibits aldosterone actions, they also provide possible antiviral and anti-inflammatory actions that reduce lung injuries. Similarly, the 5 alpha reductase inhibitors –dutasteride and finasteride, inhibit the TMPRSS2 expression. Statins have anti-inflammatory, immunomodulatory, antioxidative, antiarrhythmic effects therefore reduce the severity of ARDS and lung injury. Vitamin D with calcium metabolites provides immunological protection from COVID-19 viral activity and neutralize effects on TMPRSS2. N-acetyl cysteine inhibits inflammatory pathways, improves T cells, and reduces lung injuries and prevent the pairing of ACE2 with SARS-COV-2 virus.There is a steeping increase in cases from day to day therefore the race to find appropriate treatment has accelerated a big challenge. Due to the urgent need even though some repurposed drugs gained attention at beginning due to the positive results from small scale studies the long term use shows there are drawbacks for every treatment. A joint research team of the Shanghai Institute of Material Medica and Shanghai Tech University, China performed drug screening in silicon and an enzyme activity test, and they reported 30 agents with potential antiviral activity against SARS-CoV-2 on January 25, 2020. The same study was done in Chinese herbal medicines to extract the active ingredient against SARS-CoV-2. There are temporary evidence on the drug Ivermectin which can inhibit the replication of SARS-CoV-2 virus. Ivermectin is an FDA approved anti parasitic agent which is presently showing a high reduction in the infection caused COVID-19 RNA virus within 48 hours and with no toxicity levels. Supplementary clinical trial on run may potentiate its use as an antiviral agent.SARS–CoV-2 enters lung alveoli by receptor mediated endocytosis, via angiotensin converting enzyme 2 receptors. Therefore drugs inhibiting the AP2-associated protein kinase 2 can prevent the viral entry to certain extend. Baricitinib is an AP2-associated protein kinase2 and JAK inhibitor is used to prevent viral replication. Further the drug leronlimab a humanised monoclonal antibody (chemokine receptor type 5) antagonist and a nucleoside RNA polymerase inhibitor Galidesivir shows better survival rates and is potentially tested for further efficacy. Even the use of interferons combined with lopinavir/ritonavir in severe COVID-19 cases caused worsening of tissue damage, CQ showing macular retinopathy and cardiomyopathy, favipiravir is teratogenic thus pregnancy confirmed or suspected woman must avoid its use. The optimum dosing schedule with appropriate monitoring of the repurposed drugs are important in order to have an efficient target concentration as the drugs were implemented for different treatment paradigms. The The challenges faced in drug repurposing are the difference in host environment of humans and cellular animal assays, lack of powerful clinical endpoints, few reproducible preclinical animal models, differences in sensitivity analysis, large heterogeneous populations, comorbid conditions variability, animal models with poor predictive efficacy, lack of monitoring parameters. Codagenix (CDX-005) from Serum Institute of India manufactures intranasal live attenuated vaccine candidate for SARS-CoV-2 which are expected to be more efficient and patient friendly. As the virus mechanism remains uncertain, it is extremely critical to develop first generation vaccine within short period of time. Various vaccine developed and under development for COVID-19 across globe is summarized in  Despite of the burst of coronavirus being sudden there are many pharmaceutical companies trying hard for the isolation, identification, and management of the COVID-19 and it might take another 10 years for composing an effective vaccine.Vaccines: The Bharat Biotech, the countries pandemic vaccine leaders are collaborating with virologist at the university of Wisconsin–Madison and the vaccine company FluGen, for the project of developing vaccine against corona. They are in a process of developing an intranasal vaccine for COVID-19 called CoroFlu. CoroFlu is in the animal testing phase in the US, and is expected to move to human trials in the next three months. The intranasal route is selected as flu, RSV and corona enter through the naso-region, and hence produce mucosal immunity when given by nasal drop . Bharat biotech has commercialised 16 vaccines including the one developed against the H1N1 flu that caused the pandemic in 2009. Kawaoka lab will insert gene sequence from SARS-CoV-2 which cause COVID-19 into M2SR (which is a self- limiting version that induces immunity response against the flu). So that the new vaccine will induce immunity against the coronavirus.There have been no effective antiviral therapies or vaccines approved so far for SARS-CoV-2. Vaccines for pandemic infections require rapid development and high production capacity. Many of the vaccine candidates are under developmental phase with a good number in clinical trial phase. An appropriate therapy requires the identification of surface structure of spike glycoproteins for the development of antiviral drug that still has multiple challenges. Clinical trials have been initiated in different countries to develop effective treatment options, but this may take several years to trace out a reliable treatment therapy for patients. Larger sample size studies are needed to investigate the effects of antiviral therapies for COVID-19 infections leading to a better endpoint. Currently many clinical studies have been reported worldwide and several drugs are repurposed to tackle the new health emergency of COVID-19. But there are no sufficient data to suggest the treatment eradication of COVID-19 as there is lack in comparative studies. Wide population of patients involved RCT opens the era for evaluating and reassuring the efficacy of drug repurposed for COVID-19. It is early to predict the safety and efficacy of drugs repurposed as they might have an alarming side effect in the future trials. As there is no pre-existing immunity against the new virus the exploration of intranasal delivery techniques with mucosal immunity may be an eye opener. It is also important to acknowledge that there are so far no proven data supporting the standard use of any of these agents for COVID-19.There are no ethical issues.Authors declare no conflict of interest in this study.We thank Dr. Shantikumar Nair, Dean of Research, Amrita Institute of Medical Science & Research Centre, and Dr. Sabitha M, Principal, Amrita School of Pharmacy for the facilities provided.


The design of rigid vortex generators (RVG) influences the thermal performance of various technologies. We employed Discrete Adjoint-Based Optimization to show the optimal development of vortex generators. Under turbulent flow conditions, different bi-objective functions on the RVG design were examined. Specifically, we aimed at an optimal RVG shape that minimizes the pressure drop and maximizes the local heat transfer in a rectangular channel. We show that an optimal design of an RVG can be obtained using computational fluid dynamics in conjunction with the Pareto Front at a computational cost of the order ~ However, the bi-objective optimization of conjugated heat transfer in channel flows of compact HEXs remains a computational challenge. Employing computational fluid dynamics (CFD) to identify a well-defined Pareto Front for optimal designs of fluid and thermo-fluid components is a time-demanding computational task because the design space is vast. The numerical studies usually compare variants of methods, e.g., adjoint versus adjoint-free parametric and shape optimization3 and topology optimization4. Thermo-fluid optimization in channels requires minimizing the overall pressure drop and maximizing the heat transfer.Many industrial and engineering applications include conjugated heat transfer in complex fluid flow geometries such as multi-functional heat exchangers (HEX’s)5, which can be classified as active, passive, and dynamic. Active techniques depend on external power sources, such as vibrations, oscillations or electromagnetic fields, aiming to perturb the flow locally. On the other hand, passive methods are more efficient and robust. They depend not on external sources, but local surfaces, such as deformation-induced perturbation, such as rigid vortex generators (RVGs)6. Finally, dynamic techniques for enhancing heat transfer employ elastically-deformed surfaces such as flexible vortex generators (FVGs)8.Researchers developed different methods for enhancing heat transfer with vortex streets9. During the last decade, progress in optimization methods and computational resources, e.g., cloud and high-performance computing, opened new perspectives of optimization in CFD. For example, adjoint-based optimization (ABO) methods10 employ adjacent variables to the state variable to estimate the objective function’s sensitivity field concerning the design variables. The sensitivity maps enter into a gradient-based optimization algorithm coupled with the CFD solver to find the overall objective function, e.g., employing a local deformation of the surface immersed in or surrounding the fluid flow.The optimal design of RVGs is an active research topic11 investigated the post-formation evolution of a laminar vortex ring. Sun et al.12 studied the wake structure of a micro-ramp vortex generator in hypersonic flows. Tian et al.13 investigated different types of longitudinal RVGs in a flat plate channel flow to increase the heat transfer through the Nusselt number and reduce the pumping power through the friction factor. Moreover, researchers conducted numerical investigations of RVG designs like annular winglet; wave-element RVG15; curved winglet RVG with or without local perforations17; twisted and helical RVGs19; wavy-fins and oval-tube-bank with mounted RVGs21 and longitudinal vorticity RVGs22.Several researchers in the past performed computational modelling of vortical structures. For example, Danaila and Hélie23 tried experimentally controlling an axisymmetric jet by using vortex generators. Behfard and Sohankar24 characterized the local flow structures for a fluid flow in the presence of delta winglet pair (DWP) in a finned circular heat exchanger under a turbulent regime with a steady SST 26 investigated the influence of a new RVG design as an inclined-projected-winglet-pair (IPWP) on the heat transfer enhancement under a turbulent flow regime. Finally, Hamidouche et al.27 conducted flow characteristics downstream delta-winglet vortex generator experiments using the stereoscopic particle image velocimetry (PIV) technique in a rectangular channel but without heat transfer. Experimental measurements of RVGs with coupled fluid flow and heat transfer are scarce in the literature, and the last works go back to the 1990s by Fiebig and Tiggelbeck29. The difficulty is to cover a wide range of operating conditions, such as different Reynolds and Prandtl numbers, RVG designs and angles of attack.Zaman et al.30 realized shape optimization of dimples RVGs in a rectangular channel by employing a Surface Response Optimization (SRO) method. Song et al.31 developed an advanced optimization technique in CFD using a Surrogate-Based Algorithm (SBA) for designing a heat sink. Recently, Karkaba et al.3 presented multi-objective function optimization through a large space exploration design developed to find optimal RVG design. They defined seven different design variables to draw/find the shape of the optimal RVG. A new enhanced RVG design was found recently by3 through parametric shape optimization. The optimal design3 led to a substantial increase in the thermal enhancement factor, though at the expense of computational costs. Moreover, Oh and Kim32 studied the thermal and flow characteristics of the rectangular-winglet (RW); delta-winglet-upstream (DWU); and delta winglet-downstream (DWD) curved vortex generators (CVGs). These designs varied regarding the position angle and the radial distance in the fin-tube heat exchanger configuration. Most of their results suggested that conventional VGs are superior in performance compared to curved vortex generator CVGs. Carpio and Valencia33 investigated the effect of introducing longitudinal vortex generators (LVGs) in arrays consisting of 9 alternating, 18 alternating, 18 aligned, 27 alternating and 39 alternating LVGs. Results show that the design with the best thermal performance corresponds to geometry with 39 LVG, with a 34 adopted artificial neural networks (ANNs) for predicting the efficiency of a double-pipe heat exchanger which employs T-W tape inserts with different wing-width ratios. The ANNs predicted with high accuracy thermal parameters such as the friction factor, the Nusselt number and the thermal performance factor (TPF) of a double pipe heat exchanger. More recently, Khan et al.35 used ANN to optimise the performance of a double pipe heat exchanger, i.e., to obtain better heat transfer enhancement with a low-pressure drop penalty. They found a maximum value of TPF equal to 1.44 by varying five input parameters related to wing-width ratio, pitch ratio, attack angle, Reynolds number, and tube length (L).The optimization of thermofluid components by employing advanced optimization techniques in CFD, e.g., heat transfer enhancement, pressure drop, and overall weight/mass reduction, has emerged as a topic of research and development. For example, Kim and Choi37 but also have great potential for heat exchangers technology. The present work chooses the Adjoint method for several reasons. To the author’s knowledge, Adjoints have not been used in conjunction with vortex generators in current literature. Still, they can be powerful and efficient tools in developing vortex generator-based heat exchangers. Furthermore, popular CFD codes such as ANSYS Fluent have an Adjoint solver already implemented so that the methods developed here are widely accessible to the general CFD/Thermal engineering community working on vortex generators. This will increase the impact of this research and shed more light on the Adjoint method’s applicability to heat enhancement techniques based on the vortex generator technology.As seen in the research mentioned above, the design method for vortex generators typically revolves around a set of geometrical parameters such as the angle of attack, inclination angle, span, height, and different shapes such as delta wing and rectangular wing. Since the parametric space is ample, it becomes a tedious task to define a concrete parametric optimization problem without considering that designing vortex generators within these parameters is somewhat restrictive. Optimization processes typically require extensive CFD calculations to explore the variations of just a few parameters. Therefore, effective optimization techniques are needed to rapidly advance the development of vortex generators’ performance. To this end, gradient-based optimization methods aim to find ’sensitivity gradients’ from the solution of the flow field. These will indicate how the performance will change by modifying the vortex generator’s geometry. Such advanced techniques, therefore, minimize the computational cost of the optimization process. Gradient-based methods have been developed mainly for aerospace applications to enhance lift and reduce drag for airfoils geometriesIn this study, we employ an adjoint-based shape optimization method in conjunction with CFD for the optimal and rapid design of RVGs in a turbulent flow regime. We define a bi-objective Adjoint-Based Optimization problem to compute the sensitivity maps by: (1) locally morphing the mesh and deforming the RVG surface topology in a controlled volume sub-domain; (2) creating the overall optimization algorithm to act in an enhanced and more rapid optimal line-search direction using the steepest descent algorithm, thus reducing the overall computational time of the Pareto Front by an order ~TPF above one, even by a small percentage of TPF value, e.g., The Pareto Front for the RVG designs fits well with a Pareto function Fig. . The solt}f2 Eq.  while th}f1 Eqs. , 9. The The RVG’s shape evolution during the ABO process  is reduced by In conclusion, we employed the Discrete ABO method coupled with advanced CFD to optimise a DWP RVG under a turbulent flow regime at 29. The distance from the inlet to the RVG tip is denoted by h and has the following dimensions: The computational three-dimensional (3D) domain is made of a channel of a rectangular form see Fig.  of heigh25. The conjugated fluid dynamics and heat transfer are solved through the following consecutive mass, momentum and energy conservation equations:T the temperature, Cp the specific heat, Pr and The fluid flow is incompressible and turbulent inside the rectangular channel at a Reynolds number of 39 are employed to solve for the turbulent flow field. The SST model includes two additional partial differential equations coupled to k and the turbulent dissipation rate 26.The Reynolds averaged Navier–Stokes (RANS) in conjunction with the mentclass2pt{minimInlet: A constant temperature Upper and lower channel surfaces: a constant temperature Left and right channel surfaces: a symmetry boundary condition.VG surface: adiabatic wall with zero heat flux.Outlet: a zero-pressure Neumann boundary condition.The boundary conditions Fig.  are set The flow chart of the adjoint-based optimization (ABO) algorithm is shown in Fig. 3. Moreover, adjoint-based methods can produce better engineering designs at an overall reduced cost. Compared to the continuous adjoint method, the discrete approach computes the sensitivity field more accurately, especially in turbulent flow conditions.Adjoint optimization methods require no parameterization of the geometry, which is the case in other methods, such as in parametric optimization techniques in CFDa and b such that Two mathematical problems of adjoint-based optimization are formulated and solved by minimizing two different global bi-objective functions (BOF) h and k is the thermal conductivity of the flowing fluid.The global Nusselt number is calculated using the logarithmic mean temperature difference method as follows:LMTD is calculated using the following equation:The log mean temperature difference Moreover, the global friction factor ) of Eq.  is givenz/h in the flow direction:To analyze the optimized RVGs performance, the local Nusselt number inside the channel is computed as a function of the dimensionless local position The local friction factor (or fanning friction factor) in the channel Finally, the Reynolds number is calculated based on the hydraulic diameter of the channel as follows:F such that F with respect to F. A mesh morphing algorithm guarantees the quality of the morphed mesh through local control of the positive volume of each finite volume cell. The steepest descent algorithm guarantees the convergence of the optimization problem toward a local minimum of F in the design space. The second term F due to a change in the position at a given cell center. The final term F due to the sensitivity of the flow solution to changes in the local position of the RVG. R is also known as the Residuals vector/matrix of the flow solution, and For computing the shape sensitivity of the RVG concerning the objective function see Fig.  envelopiPolyhedral cells are generated in the computational domain employing a local mesh refinement method and a volume control imposed in the VG design space zone. The automatic local refinement algorithm ensures that the value of the dimensionless wall distance 40 validated with the experimental DWP design of Tiggelbeck et al.29 at same Reynolds number 29 with an error that is less than Several polyhedral grids have been generated to choose the appropriate mesh size in a mesh sensitivity analysis procedure. The grid-convergence index (GCI) chooses the appropriate initial mesh size. A polyhedral mesh which contains entclass1pt{minima41 for the evaluation of the global Nusselt number and the correlation of Blasius42 for the assessment of the global friction factor. The CFD results for an empty channel compared to the empirical correlations show an error of less than 2% for both the global Nusselt number and the friction factor.Another approach to verify the choice of a numerical model and mesh size is the validation with fully developed turbulent flow in an empty channel. The numerical results are compared with the correlation of Dittus–Boelterf and Nusselt number (Nu) stability versus sub-iterations.In each ABO inner loop, the convergence of the CFD solvers is verified by looking at the friction factor A mesh strategy in each ABO outer loop is set as follows: a control volume ain Fig.  for the see Fig. .Supplementary Information.


On the staggering emergence of the Omicron variant, numerous questions arose about the evolution of virulence and transmissibility in microbes.The trade-off hypothesis has long speculated the exchange of virulence for the sake of superior transmissibility in a wide array of pathogens. While this certainly applies to the case of the Omicron variant, along with influenza virus, various reports have been allocated for an array of pathogens such as human immunodeficiency virus (HIV), malaria, hepatitis B virus (HBV) and tuberculosis (TB). The latter abide to another form of trade-off, the invasion–persistence trade-off. In this study, we aim to explore the molecular mechanisms and mutations of different obligate intracellular pathogens that attenuated their more morbid characters, virulence in acute infections and invasion in chronic infections.Recognizing the mutations that attenuate the most morbid characters of pathogens such as virulence or persistence can help in tailoring new therapies for such pathogens. Targeting macrophage tropism of HIV by carbohydrate-binding agents, or targeting the TMPRSS2 receptors to prevent pulmonary infiltrates of COVID-19 is an example of how important is to recognize such genetic mechanisms. After the discovery of the SARS-CoV-2 variant, Omicron, that sporadically arose in November 2021, it was compared to the Delta variant that was discovered in May 2021 in terms of virulence and transmissibility. While Omicron has shown higher rates of transmission than the other variants, it showed less virulent symptoms with relatively mild disease. The Delta variant, however, has been associated with high virulence causing severe lower respiratory tract symptoms and reduced transmission rate  a compromised level of virulence must be reached. This could be explained by the fact that a pathogen’s ability to spread is directly proportional to its ability to induce symptoms that favor the pathogen’s spread such as coughing and sneezing . However, up to a certain degree of virulence, a reduction in the spread of the pathogen could occur by the reduction in the duration of the infectious period or reducing contact between the host and other potential hosts. This could be seen with a reduction in the host’s physical level of activity or their death. Therefore, it is predicted that compromised moderate levels of virulence should be in sync with the pathogen’s evolution , considered p, the contact rate with other carriers of the disease, c with infectiousness duration d, virulence v can impact the three latter factors in various ways. This all gives the proportionality equation:Hence, an equation was reached based on the multiple factors that are thought to affect transmission potential. Transmission potential, The trade-off of virulence to transmissibility can explain the evolution of acute infections but falls short when addressing chronic infections. Strains with shorter infectious periods and higher transmission rates tend to spread at a faster rate than strains with longer infectious periods and lower transmission rates. However, such strains are more prone to extinction as their population is very liable to severe fluctuations. This indicates the need for a larger community size to overcome such fluctuations and decrease the risk of extinction. As such, the persistence of these highly transmissible strains is harder than those with lower transmission rates which require a smaller community size to persist  has provided beneficial mechanisms in combating the HIV-1 replication, for instance, hindering the disease progression, decreasing the viral load and boosting T cell immune function. In addition to the previous mechanisms, c-ART effectively prevents transmission to uninfected individuals. Before the ART era, the benefits of latency were not fully understood but now during ART, we can say that latency has a substantial role in avoiding the extinction of HIV  and T cell tropic (T-tropic), targeting memory CD4 T cells throughout acute and chronic infections. However, viruses can expand into different cell variants. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect phagocytes, that have solely low levels of surface CD4. In comparison with T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on an average of 28-fold more efficiently, have exaggerated sensitivity to soluble CD4 (sCD4), and have proficient usage of low-density CD4 with more sensitivity to CD4 binding website antibodies. In addition to the prior findings, we tend to postulate that low-density CD4 usage and sensitivity to soluble CD4 (sCD4) are distinct criteria for macrophage reaction. Furthermore, CD4 entry phenotypes are more reproducible than the relative infection of monocyte-derived macrophages (MDMs) Arrildt .Another example of pathogen evolution under the combined pressure of host immune responses and antimicrobials is the mutated strains of falciparum malaria. The escalation of artemisinin resistance due to mutations in Plasmodium falciparum K13 has weakened antimalarial efficacy and burdens the global antimalarial elimination campaign. Mutation of the PfK13 propeller domain plays a role in artemisinin resistance; also, it includes divergent mechanisms based on a quiescence state leading to parasite rejuvenation as soon as drug pressure is removed. Transcription analysis demonstrated an evident downregulation for 10 genes following exposure to DHA, but continued transcription of 2 genes encoding mitochondrial and apicoplast proteins. Transcription of various genes encoding mitochondrial and apicoplast proteins, especially genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also preserved. Supplementing inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways have slowed down the rehabilitation of stagnant parasites by 6 and 4 days, respectively, following DHA treatment. The results portray that majority of metabolic pathways are downregulated in DHA-induced dormant parasites. In opposition, pyruvate and fatty acid metabolic pathways remain functioning Mok .One of the viruses that are also subject to the same type of viral trade-off is the hepatitis B virus. The high error rate of HBV reverse transcriptase (RT) was associated with developing several mutations. Although these mutants have errors in the replication or infectivity of the virus compared to wild-type HBV, they can turn out to be the dominant species due to their different response to the antiviral immune response or therapy. HBV genotypes, sub-genotypes and mutations in certain regions of the HBV genome have been found to influence many aspects of the virtual infection. Some of the adverse outcomes are linked to alterations in the pre-S/S region, for instance, occult HBV infection, vaccine malfunction and the occurrence of hepatocellular carcinoma (HCC). Moreover, mutations in the P region may cause the drug resistance to NA antivirals. Mutations in the pre-C/C region are related to HBeAg negativity, immune escape and persistent hepatitis (El-Mokhtar Variants within the HBV surface antigens are correlated with occult HBV infection (OBI) which is defined as the presence of HBV DNA in the liver tissue of HBsAg-negative individuals.Deletions in the pre-S region can lead to decreased expression of HbsAg, hence its absence in the serum. It also aids in viral persistence by removing HLA-restricted B cell and T cell epitopes. The overlapping between the genes encoding reverse transcriptase (RT) and HBsAg causes differences in the major hydrophilic region of HBsAg that reduce the binding affinity of neutralizing antibodies, including those induced by HBV vaccine. Immune-associated escape mutations lead to harder HBsAg recognition by vaccine-induced antibodies. In addition to this, immune-associated escape mutations can lessen HBsAg binding to antibodies used in diagnostic assays for HBsAg detection and quantification which therefore results in false negativity or an underestimation of HBsAg levels  enzyme. Mutations in RT can result in drug resistance after long-term use of nucleotide analogues (NA). Antiviral drug resistance can be related to the selection of adaptive mutations which decreases the sensitivity of the mutants to the inhibitory effects of a drug.In addition to NA-induced escape mutations, 29 immune-associated escape mutations were found in the major hydrophilic region of HBsAg. Studies show that certain circulating HBV strains have a higher number of immune-associated escape mutations than others; for instance, genotype D has more mutations than A  mutation terminates HBeAg expression at the translational level. Despite the previous common belief that HbeAg acts as tolerogen and helps the immune escapism of HBV, it is now increasingly recognized that it acts as an immunogen, enhancing the immune clearance of HBV. The HBeAg-negative cases who undergo HBeAg seroconversion demonstrate a recurrence of high HBV DNA levels unlike HBeAg-positive cases, where seroconversion is accompanied by decreased HBV DNA levels. This renders HBeAg-negative cases to exhibit unsuccessful immune clearance. Consequently, HBeAg-negative chronic hepatitis B is currently the leading type worldwide as well as the most difficult in treatment regarding achieving sustained virological response. Mutations in HBcAg may result in the formation of immune escape variants, leading to the persistence of HBV. The core protein HBcAg of HBV is a potent immune stimulator, stimulating a strong neutralizing immune response mainly in the form of the HBV-specific CD8 + T lymphocytes (CTL)-mediated immune response. The more conserved the HBV core protein (HBc), the stronger the CTL responses. This suggests that the HBc-specific T cell response may play a leading role in viral control and clearance  lineage rebounded from O2 deprivation, but strains belonging to others did not  Tizzano .This peculiar ability of L4 is due to the upregulation of the dormancy survival regulator gene (DosR). The DosR regulon allows the pathogen to withstand hypoxia. Transcriptomic analysis for the experimented lineages showed upregulation of DosR genes in L4. This explains its survival during oxygen deprivation. Four hundred seventy-one genes were upregulated and 483 downregulated with a fold change of at least 2, including 36 induced (out of 48) DosR regulon genes. The Beijing (L2) strain had a different expression pattern than H37Rv (L4) , a surface glycoprotein, initiates influenza infection. It binds and fuses viral and endosomal membranes using sialic acid-containing molecules as receptors. In an experiment, all human influenza virus strains readily attached and decorated ciliated epithelial and goblet cells from human upper respiratory tract tissues, such as the nasal septum, concha and nasopharynx  hospital deaths during the Omicron wave, compared to 847 (21.3%) deaths during the Delta wave; it also showed that hospital admissions were 1% of cases during the Omicron wave and 4.3% during previous ones; the duration of hospital stay itself was also shorter in the Omicron wave (4 days) than in previous waves (8.8 days)  and 116 (2.2%) Delta patients were hospitalized. There were no confirmed deaths in matched Omicron-infected patients, but 7 (0.3%) deaths in Delta-infected patients. In addition, the risk of hospitalization or death was 68% lower in Omicron cases than in Delta cases. The risk of hospitalization or death was also 54% lower in vaccinated Omicron cases than in vaccinated Delta cases though more infected patients , the N-terminal domain (NTD) and other regions such as the proteolytic cleavage site and the fusion machinery  protein and the angiotensin-converting enzyme II (ACE2). This binding leads to either the endolysosomal (endocytic) or the TMPRSS2-mediated entry. The endocytic route is pH-sensitive. The acidic endosomal pH activates the virions, which then fuses the viral and endosomal membranes and releases the viral genome into the cytosol. The endocytic pathway also includes caveolae-dependent endocytosis, macropinocytosis and Clathrin-dependent endocytosis   –persistence trade-off in chronic infections. These mutations can be a great potential for drug development. Several new drugs are under development, that are a good illustration of the exploitation of these molecular targets. For chronic infections, targeting cyclin-dependent kinases that mediate dormancy in malaria, or the use of ethoxzolamide in TB is under trial. Blocking HIV entry into macrophages by aromatase inhibitors has been recently FDA-approved. Inhibitors of viral proteases mediating lung entry of SARS-CoV-2 and influenza attachment to sialic acid are also new potential targets for drug development (Aspatwar et al.


Natural products are structurally highly diverse and exhibit a wide array of biological activities. As a result, they serve as an important source of new drug leads. Traditionally, natural products have been discovered by bioactivity-guided fractionation. The advent of genome sequencing technology has resulted in the introduction of an alternative approach towards novel natural product scaffolds: Genome mining. Genome mining is an in-silico natural product discovery strategy in which sequenced genomes are analyzed for the potential of the associated organism to produce natural products. Seemingly universal biosynthetic principles have been deciphered for most natural product classes that are used to detect natural product biosynthetic gene clusters using pathway-encoded conserved key enzymes, domains, or motifs as bait. Several generations of highly sophisticated tools have been developed for the biosynthetic rule-based identification of natural product gene clusters. Apart from these hard-coded algorithms, multiple tools that use machine learning-based approaches have been designed to complement the existing genome mining tool set and focus on natural product gene clusters that lack genes with conserved signature sequences. In this perspective, we take a closer look at state-of-the-art genome mining tools that are based on either hard-coded rules or machine learning algorithms, with an emphasis on the confidence of their predictions and potential to identify non-canonical natural product biosynthetic gene clusters. We highlight the genome mining pipelines' current strengths and limitations by contrasting their advantages and disadvantages. Moreover, we introduce two indirect biosynthetic gene cluster identification strategies that complement current workflows. The combination of all genome mining approaches will pave the way towards a more comprehensive understanding of the full biosynthetic repertoire encoded in microbial genome sequences. Streptomyces coelicolor A3(2) . Th. Th21].  (NRPSs)  25–26].–26.cis-as-AT PKS ), or ket systems ,27). Mor systems . trans-A domains ,22. As aructures . Insteadion rule . All comrule [7) )) 28]..cis-acyl8) . . 8) . BL. BL42]. cis-AT PKSs vs >150 in trans-AT PKSs ..AspergilStreptomyces) to find non-syntenic blocks that might code for NP BGCs. Comparable to the genome-wide characterization of all clustered genes concept, CGA focuses on BGC detection independently of signature sequences and known NP families to expand the known NP chemical space via the identification of non-canonical pathways.CGA aims at scaling this approach and comparing all sequenced strains of one genus (e.g., The first step of CGA consists of the homogenous functional annotation of all genes of the selected genomes to reduce false positive rates of non-syntenic blocks due to different annotations of genes using different annotation algorithms. Subsequently, all annotated genes are clustered based on sequence similarity to improve functional annotations . The obtWhole genome alignments are performed to detect single diverging gene loci that are subsequently expanded by their genomic neighborhood to detect genomic islands. Therefore, the genomic neighborhoods of the identified genes are analyzed for differences in their synteny to detect HGT regions composed of multiple genes. In addition, these regions are analyzed for genetic characteristics like promoters or transposase genes to identify operon-like structures. Single gene duplication events are filtered out and all known BGCs are excluded in a similar fashion as in the gcBGC approach. The presence of prototypical tailoring enzymes ubiquitously distributed in secondary metabolism might serve as an additional line of evidence for a functional NP BGC. This approach is computationally expensive yet feasible with the availability of high-performance computer clusters but requires excellent quality of the analyzed genomes. This method has the advantage over simpler approaches to detect HGT events, like for example comparing GC contents of different regions, that it can be used to detect HGT events from closely related strains.The development of next-generation sequencing technologies  and the


Participants performed a forward hop followed by a 45° unanticipated diagonal hop either in a medial (UMDH) or lateral direction (ULDH). Medial and lateral quadriceps and hamstrings EMG were recorded for one leg (injured/non-dominant). Quadriceps-to-Hamstring (Q:H) ratio, lateral and medial Q:H co-contraction indices (CCIs), and medial-to-lateral Q:H co-contraction ratio  were calculated for three phases  of landing. We found greater activity of the quadriceps than the hamstrings during the IC and deceleration phases of UMDH/ULDH across groups. However, higher co-contraction of medial rather than lateral thigh muscles during the deceleration phase of landing was found; if such co-contraction patterns cause knee adduction, a putative mechanism to decrease ACL injury risk, during the deceleration phase of landing across groups warrants further investigation.Efficient neuromuscular coordination of the thigh muscles is crucial in maintaining dynamic knee stability and thus reducing anterior cruciate ligament (ACL) injury/re-injury risk. This cross-sectional study measured electromyographic (EMG) thigh muscle co-contraction patterns during a novel one-leg double-hop test among individuals with ACL reconstruction (ACLR;  The age at which individuals commonly suffer an ACL injury ranges from 5 to 64 years3 and most ACL injuries occur in sporting activities4. Following injury, risk of a secondary ACL tear increases by > 20%5. ACL injuries often result in long rehabilitation periods and might be career-ending or cause a long time lay-off from sports participation for athletes8. For sportspeople, only 30% of ACL injuries occur due to direct contact, while the remaining 70% occur in non-contact mechanisms11. Non-contact ACL injuries most often occur shortly after the initial foot contact (~ first 50 ms) during one and/or two-leg landing with relatively low knee (< 40°) flexion and multiplanar loading with frequent knee abduction17.Anterior cruciate ligament (ACL) tear is a common orthopedic injury19. Such tests determine an individual’s ability to integrate joint stability, neuromotor control, flexibility, muscle strength, power, proprioception, agility, or balance into a functional task, mimicking a sports situation19. One-leg hop tests can be quantified using biomechanical tools such as motion capture systems to identify potential asymmetries between injured and uninjured legs in persons with a unilateral ACL injury, and can thereby be used to determine progress in rehabilitation, as well as assess ACL (re)injury risk21. There is however a lack of consensus as to the most optimal design of one-leg hop test best suited for such purposes. One-leg lateral22 and medial hops23 in particular emulate the movement patterns and forces occurring during side-step and crossover cutting maneuvers, respectively, to some extent. Moreover, medial hop tests with added visual-cognitive tasks have been reported to be reliable and, at the same time, challenge hop performance in healthy individuals24. When cutting maneuvers are performed in an unanticipated manner compared to pre-planned maneuvers, the time available for making optimal postural adjustments before task performance is decreased. Such maneuvers emulate sports-specific scenarios and have ecological validity25. This may further add to the ACL strain due to an increase in internal/external rotation and varus/valgus movement in the knee27. Aberrant motion patterns of the lower limb relating to ACL injury risk are often investigated during the deceleration phase of one-leg landing 29. Knee abduction and internal rotation angles and  moments have been reported to be increased during the unanticipated one-leg cutting maneuvers compared to the anticipated counterparts30. Therefore, we have previously designed a novel one-leg double-hop test consisting of a forward hop followed by an unanticipated diagonal hop in a medial or lateral direction involving cutting maneuvers. Our test requires movement control and full loading with the leg being tested and prevents compensation from the contralateral leg during the land-and-cut maneuver. This might help to quantify/discriminate dynamic limb motion asymmetries in individuals with ACL injury/reconstruction and healthy-knee controls. Moreover, the test is easy to administer , less time-consuming, requires very little space compared to a run-and-cut task and allows knee-challenging unanticipated change of direction with one-leg landing. This test has been found to reliably capture hip and knee angles and moments in healthy individuals31 and in those with ACL reconstruction (ACLR)32. In the current paper, we further investigate our unanticipated double hop test by determining thigh muscle co-contraction patterns during the pre-landing, initial (foot) contact (IC), and deceleration phases, as the latter two are the most vulnerable phases for non-contact ACL injuries. We hypothesized that thigh muscle activation patterns augmenting or mitigating ACL injury risk are evident during the one-leg double-hop test with an unanticipated change of direction.Incorporation of functional physical performance tests such as one-leg landing and/or cutting, mimicking sporting activities, is necessary in the assessment and training of ACL-injured persons. Functional physical performance tests are quantitative measures that emulate certain components of sporting activities. They have been shown to predict the risk of acquiring lower limb (sport) injuries and determine a player’s preparedness to return-to-play33 during dynamic tasks. An increased electromyographic (EMG) activity of the quadriceps compared to that of the hamstrings has been reported during one-legged landing in healthy athletes34 which results in an anterior translation of the tibia relative to the femur and increases ACL strain36. Thus, a balanced co-contraction of the quadriceps and hamstrings prior to one-leg landing is crucial in order to prepare for landing37. Conversely, quadriceps activation failure 38 and weakness39 have been demonstrated in individuals with a unilateral ACLR or deficiency (managed conservatively) compared to healthy controls. Increased coactivation of the hamstrings during maximal or submaximal isometric knee extension in individuals with ACLR or ACL deficiency compared to healthy controls might restrict anterior tibial translation and improve joint stability40. This further reflects a protective strategy, based on an ACL-hamstring synergy 40, adopted by these individuals to mitigate ACL injury risk. A recent systematic review found no differences in quadriceps and hamstrings activity onset prior to one-leg landing or decelerating tasks between individuals with ACL injury or ACLR and healthy controls41. However, the included studies (n = 5) in that review were of poor to moderate quality41 and the outcomes of such studies must be interpreted cautiously.Neuromuscular control of the thigh muscles alters knee stability by controlling motion and loading of the knee joint43 and persons with knee osteoarthritis44. A discordant co-contraction between the medial and lateral thigh muscles, where the medial muscles show lower co-contraction than the lateral group, limits the ability to resist abduction load and eventually abducts the knee and increases ACL strain46. Neuromuscular training has been reported to increase medial hamstring activation and might help in preventing the knee from excessive abduction47, a mechanism to lower the risk of ACL injury.A differential recruitment of medial versus lateral thigh muscles has been reported during different tasks in healthy individuals48. Moreover, previous studies have indicated differences in neuromuscular contributions (EMG-moment relationships) to dynamic knee stability49 and altered thigh muscle co-activation patterns during knee joint positions tests50 between individuals with and without ACL injury. We expected that our participants with ACLR would have different physical activity levels (light labor to competitive sports based on Tegner scores). Whether differences in physical activity levels and ACL injury status affect thigh muscle co-contraction patterns during our novel test with an unanticipated change of direction need further investigation. Therefore, the aim of this study was to examine EMG co-contraction patterns of the hamstrings and quadriceps muscles during our unanticipated one-leg double-hop test. Specifically, the study aimed to determine whether co-contractions of these muscle groups differ during the pre-landing and deceleration phases of the land-and-cut maneuver in three groups  of mixed or different physical activity levels (sedentary to competitive sports). Our hypotheses were three-fold: (1) all groups would present with high Quadriceps-to-Hamstring (Q:H) ratios in the pre-landing phase and low Q:H ratios in the IC and deceleration phases of unanticipated medial diagonal hop (UMDH) or unanticipated lateral diagonal hop (ULDH) which would emulate an ACL injury risk situation; (2) there would be a significant interaction between groups and phases of landing for medial and lateral Q:H co-contraction indices (CCI) for UMDH/ULDH; (3) all groups would present with a low medial-to-lateral Q:H co-contraction ratio  for the pre-landing phase and a high medial-to-lateral Q:H CCR for the IC and deceleration phases for UMDH/ULDH.Activity level, rather than ACL injury, might be a contributing factor for proprioceptive deficitsThis cross-sectional study was conducted at the U-motion laboratory, Department of Community Medicine and Rehabilitation, Umeå University, Sweden. The study was ethically approved by the Regional Ethical Review Board in Umeå (reference: 2015/67–31). All participants provided their prior written informed consent.n = 80) aged between 17 and 34 years were recruited for this study: (1.) 34 individuals  who had undergone unilateral ACLR 33.7 ± 32.2 months prior, (2.) 22 asymptomatic elite athletes  who were regularly involved in neuromuscular training of the knee and actively playing in the highest or second highest league in their respective sport, and (3.) 24 asymptomatic non-athletic controls  who were not performing any specific knee-demanding activities, resistance exercises or participating in group training activities were considered acceptable. All groups were recruited through convenience sampling via adverts posted around the university campus, emails, and word of mouth. Individuals with ACLR were recruited, regardless of their physical activity level, if they were at the end phase of rehabilitation or had completed rehabilitation and were able to perform hops on the ACLR leg without any pain or discomfort. Participants with any history of hip, knee or ankle injuries within the past 6 months (other than ACL injury for ACLR participants) or diagnosed with any ongoing musculoskeletal, rheumatic, or neurological diseases were excluded. Each participant was examined by an experienced physiotherapist prior to the test sessions to ensure their eligibility.Three groups of participants , Tegner score, International Physical Activity Questionnaire (IPAQ)—short form, and the International Knee Documentation Committee (IKDC) form. In addition, quadriceps and hamstring isometric strength was assessed using the Kin-Com® dynamometer .32.A Noraxon TeleMyo™ Direct Transmission System (DTS) Belt Receiver , four DTS EMG transmitters, adhesive disposable silver/silver chloride surface electrodes, a 3-dimensional motion analysis system  with eight high-speed cameras, and two floor-embedded force plates  were used. The details of marker set configuration (56 retroreflective markers) and motion analysis are elaborated in our previous reliability studies on the one-leg double-hop testRelevant demographic and anthropometric data were collected before testing. Each participant’s self-preferred leg to kick a ball was noted as their dominant leg. All the participants performed the tests barefoot and wore a sports bra and/or tight training shorts.51. Participants’ skin over the recording site was shaved, abraded with sandpaper and swabbed with antiseptic wipes . Then Ag/AgCL surface electrodes were placed at an inter-electrode distance of 2 cm on the biceps femoris, medial hamstring, vastus lateralis and vastus medialis  using QTM software .The recommendations from the Surface Electromyography for the Non-Invasive Assessment of Muscles (SENIAM) committee were followed for recording muscle activity32. Following two practice trials for each leg, participants were required to perform a minimum of 12 successful unanticipated diagonal hops . Inclusion of three trials for functional tests has been recommended by the IKDC56.The procedure was verbally explained to the participants at the start of the test session. Our one-leg double-hop test comprised of a forward hop followed by an immediate diagonal hop 45° to the medial or lateral direction in an unanticipated manner  behind their lower back. They hopped forward onto the second force plate, and then performed a cutting maneuver  in either the medial or the lateral direction at an angle of 45°57 Fig.  over a pAs for unpredictability of the hop direction, a projector mounted in the ceiling provided the visual cue (illumination of rectangles on the floor at a distance of 25% of their body height) upon initiation of the hop, to indicate whether the participant should attempt to land in a position medial or lateral to the direction of the forward hop. The order of direction was pseudorandomized. The visual cue was triggered as soon as vertical ground reaction force (VGRF) on the first force plate fell below 80% of its peak value during the push-off phase of the forward hop. Participants were required to perform the cutting maneuvers as quick as possible after receiving the visual cue indicating the hop direction. While hopping with the right leg, cutting done to the right side was named as ULDH and the left side as UMDH.58, touched the force plate with the contralateral foot upon landing, landed outside the target (illuminated) areas, had extra hops upon landing or hands let go of the rope. Participants were allowed repeat the test till a minimum of three successful trails was achieved.The trials were declared successful by an assessor during testing and then verified afterwards by another assessor using video analysis and Qualisys data. A ULDH or UMDH was considered successful if the participants hopped in the appropriate direction, covered the required distance and maintained balance and control upon landing without touching down their other foot. The trials were declared unsuccessful if the participants hopped in the opposite direction (performed UMDH instead of ULDH or vice versa), pausedTwo events based on vertical ground reaction force (VGRF) on the second force plate were used to define the stance phase of landing and for extraction of EMG data during the timeframe of interest: IC, defined by an increase in VGRF by 20 N for the first time, to toe-off, marked by a fall in the VGRF below 20 N. EMG and force data were synchronized through a square wave transmitted by the Qualisys system.59 to generate a linear envelope. Thigh muscles EMG activity of the hopping leg on the second force plate , first 50 ms of foot contact61 (IC), and IC to peak knee flexion62 (deceleration phase) of the land-and-cut maneuver.EMG data were band-pass filtered between 20 and 500 Hz through a fourth order Butterworth filter and then Root Mean Square (RMS) filtered with a 20 ms sliding windowate Fig.  was aver46, i.e., between the pre-landing and the end of the land-and-cut maneuver was used to normalize linear envelopes at each phase of interest. An average of three successful trials for each participant (with the shortest stance time on the second force plate) was included in the analysis.The peak EMG value observed during landingS/EMGL*(EMGS + EMGL)63 where EMGS is the EMG magnitude of the less active muscle and EMGL is the EMG magnitude of the more active muscle. This equation was applied for each data sample and the resulting curve was integrated for the (three) phases of interest63. A high CCI can be interpreted as a high level of muscle activity in both muscles while low CCI would imply either low activity in both muscles or that one of the muscles has high activity and the other has a low activity63. CCIs were calculated for the three landing phases of interest for the following muscle pairs: vastus lateralis and biceps femoris , and vastus medialis and medial hamstrings . To determine whether CCIs were balanced between the medial and lateral sides, the medial-to-lateral Q:H co-contraction ratio (CCR) was calculated by dividing the medial Q∶H CCI by the lateral Q∶H CCI42.Mean EMG activity of the vastus lateralis and vastus medialis was divided by that of the medial hamstrings and biceps femoris muscles to calculate Q:H ratio. In addition, muscle CCI was defined as the concurrent activation of two muscle groups: EMGp < 0.05. For all statistical analyses, the Statistical Package for the Social Sciences  was used.Data were tested for normal distribution using the Shapiro–Wilks tests. Skewed data were log-transformed and subjected to parametric analysis given that the log-transformed data followed normal distribution. Multiple 3 (groups) × 3 (phases) mixed analysis of variance models (ANOVAs) were used with group as a between-subject factor and phase of landing as a within-subjects factor for each hop direction (UMDH/ULDH). Kruskal–Wallis tests were used to test between-group mean differences in participant characteristics as those data were skewed, except for normally distributed thigh muscle strength values subjected to one-way ANOVA. Post hoc multiple tests were adjusted with a Bonferroni correction. The level of significance was set at p = 0.020) where athletes were slightly younger than those with ACLR. Also, individuals with ACLR had greater knee laxity (p < 0.001) than controls and athletes when measured with KT1000 arthrometer  as estimated by IPAQ. Individuals with ACLR had a median Tegner score of 6 (range: 3–9) at the time of our study but their median pre-injury score was 9 (range: 3–10). All three groups differed significantly in activity level (athletes > ACLR > controls) according to the Tegner scores at the time of data collection. All but one person with ACLR were injured during sports participation and 23/34 (68%) had injured their dominant leg  for Q:H ratio ; however, post hoc tests did not reveal significant differences between groups for any of the phases. Even so, there was an increase in the mean  scores of the groups through the phases, more so for individuals with ACLR and athletes. The deceleration phase had the highest Q:H CCI value amongst the phases of interest , all groups demonstrated a low CCI in the pre-landing phase with gradually increasing CCIs for the IC and deceleration phases. However, there was a significant interaction between groups and phases for medial and lateral Q:H CCIs for UMDH (st Table . No intep < 0.001) which implied that the landing phases were different regardless of the group. The IC and deceleration phases had a higher value  compared to the pre-landing phase for ACLR and control groups (Table p = 0.019), post hoc comparisons did not reveal significant differences between phases (p > 0.050). Nevertheless, a trend similar to UMDH was observed for the phases of land-and-cut maneuver. No significant interaction between groups was found for the medial-to-lateral Q:H CCRs of UMDH and ULDH.A significant main effect of phases (but not of groups) was found for UMDH . Increased thigh muscle (quadriceps or hamstrings) activity in the pre-landing phase implies preparation for landing66 owing to feed-forward control67 associated with anticipation of variations in joint movements and forces required for task-specific landing68. However, the preferential activation of quadriceps with landing from an increased drop height might be due to increased demand of the task on the knee joint65. EMG activity patterns seem to be individual- and task-specific with different recruitment strategies. A recent systematic review did not find significant differences in quadriceps and hamstrings activity onset prior to one-leg landing or decelerating tasks between individuals with ACL injury/ACLR and asymptomatic controls41. There might be a lack of difference in EMG onset between thigh muscles during certain tasks which involve deceleration41 which warrants further investigation in relation to UMDH/ULDH. However, in the current study, we did not investigate EMG onsets, and the magnitude of activity differed between thigh muscles prior to and during the land-and-cut maneuver of UMDH and ULDH.Discordant with our findings, a study by Ford et al. (2011) reported greater quadriceps  activity compared with the hamstrings (biceps femoris and semitendinosus) in the pre-landing phase for healthy athletes while performing a bilateral drop-vertical jump from a height of 45 cm66 which could be mediated by feed-forward control67 in anticipation of joint movements and loads associated with landing68. Even so, similar to our findings, quadriceps activity has been reported to be higher than the hamstrings during the deceleration phase of side-step cutting69 and jump landing maneuvers70. Increased quadriceps activity could increase anterior tibial translation and strain the ACL from 0° to 45° of knee flexion71. However, clinicians and also individuals with ACLR should note that sagittal translation of the tibia remains lower in closed kinetic chain exercises compared to open kinetic chain exercises72 incorporated in rehabilitation.For UMDH and ULDH, the medial and lateral Q:H CCIs gradually increased from the pre-landing phase to the deceleration phase Table . This re64 during the IC and deceleration phases. These findings seem to be concordant with the observed knee adduction angles during the deceleration phase . However, we found weak insignificant Pearson correlations  between medial-to-lateral Q:H CCR and knee adduction angles for the deceleration phase of the land-and-cut maneuver for all three groups for both  direction of hops. Although these correlations addressed the frontal plane mechanics, it is important to consider the relationship between multiplanar movement combinations and CCIs/CCRs of the knee in subsequent studies. Whether medial-to-lateral Q:H CCR, medial Q:H CCI or medial quadriceps and hamstring EMG amplitudes would be associated with a significant variation in the frontal plane knee angles, and external or internal moments during different phases of landing warrant further detailed investigation in the future studies. We recommend incorporating various covariates  while analyzing the relationship between multiplanar knee angles/moments and thigh muscle CCIs/CCRs or temporal parameters (EMG onsets and duration of co-contraction of muscle pairs).The medial-to-lateral Q:H CCRs were not significantly different between groups. The IC and deceleration phases had a higher value than the pre-landing phase for ACLR and control groups. The medial-to-lateral Q:H CCRs Table  indicate42. Nevertheless, there is a lack of consensus regarding an optimal neuromuscular training to be implemented following ACLR73. Zebis et al. found that neuromuscular training aimed at preventing non-contact ACL injuries might help to increase selective activation of the medial hamstrings to decrease external rotation and abduction of the knee during instep and side-cutting maneuvers47. In the current study, we documented only the current physical activity levels of the healthy controls based on the IPAQ and Tegner scores; therefore, their prior experience with cutting maneuvers or knee demanding activities was not fully explored. It cannot be ruled out whether all three groups  may have experienced some form of training that resulted in a lack of difference between groups.Prior training might help with neuromotor planning and anticipatory contraction of the lower limb muscles that control and stabilize the kneeSome methodological considerations pinpointing limitations of the study are summarized below. Performing UMDH and ULDH in a controlled laboratory environment will not exactly emulate sports-specific cutting maneuvers endangering ACL integrity. Though our participants were asked to perform UMDH/ULDH as quickly as possible by reacting to the visual cue, this may still have taken a longer time than that to perform a cutting maneuver in a real sporting situation.We assumed that a difference in males:females ratio  might not affect between-group comparisons owing to that the proportion was similar in all groups. Despite a statistically significant difference in age of participants (ACLR vs. athletes), they were not expected to have any age-related changes of physical attributes affecting thigh muscle activity. Participants (aged 17–34 years) in all groups were screened for musculoskeletal impairments by an experienced physiotherapist prior to data collection.75 could result in a more proximal insertion of the distal tendon (⁓4 cm) and a decreased muscle moment arm. This might lead to an increase in EMG activity of the medial hamstring because of an increased motor unit activation to produce more force to match an equal amount of muscle torque76. Individuals with ACLR had the surgery 7 to 129 months (median 18 months) prior to their participation in the study and the extent of regeneration of the semitendinosus tendon and associated changes in EMG co-contraction patterns might be variable among the participants . A longitudinal prospective cohort study thoroughly addressing the influence of time aspect on such outcomes is warranted.As we have included participants with a hamstring graft in the ACLR group, whether it would adversely affect medial hamstring activity remains ambiguous. Following a semitendinosus graft the regeneration of the semitendinosus tendon after 1–3 years77. Our knee-challenging one-leg double-hop test might be even more suitable to investigate objective measures of movement coordination in relation to fear of re-injury, which is one of the major reasons preventing return to sports78.A novel standardized rebound side-hop recently demonstrated that individuals with ACLR with a high fear of re-injury display significantly higher thigh muscle co-contraction when compared to ACLR individuals with a low fear of re-injury and asymptomatic controls79. We recommend recording gastrocnemius (an antagonist of the ACL)80 activity along with the thigh muscles and analyze the relationship of EMG to knee angles and moments in the future studies. Comparing unanticipated hops with pre-planned hops is further warranted.Future studies can also compare variations in our double-hop test and subsequent changes in EMG co-contraction patterns of individuals with and without ACL injuries; for instance, incorporating penultimate contact with the non-dominant foot followed by final foot contact with the dominant foot or vice versa at varying angles of direction change An increased quadriceps activity compared to that of the hamstrings, accounting for a higher Q:H ratio, was found during the IC and deceleration phases compared to the pre-landing phase of the land-and-cut maneuver (UMDH/ULDH) for all groups. All groups, irrespective of ACL injury or physical activity level, showed a relatively low imbalance in the medial and lateral Q:H CCIs for the pre-landing phase compared to the IC and deceleration phases of landing. However, controls took a longer time to complete the task compared to individuals with ACLR and elite athletes. Overall, the findings indicate predominant co-contraction of the medial thigh muscles over the lateral group; if such co-contraction patterns cause knee adduction during the deceleration phases of the land-and-cut maneuver needs further substantiation. Our study results would be useful for clinicians and researchers investigating the role of thigh muscle activation patterns in augmenting or mitigating ACL injury risk during unanticipated one-leg landing tasks.Supplementary Information.