Delayed diagnosis of homocystinuria presenting with coronavirus disease 2019 in a 17-year-old boy.

Homocystinuria is a treatable autosomal recessive inherited disorder. This condition may cause life-threatening complications such as thromboembolic events. Coronavirus disease 2019 (COVID-19) is associated with an increased risk of venous thromboembolic events. Here, we report a case of late diagnosis of homocystinuria presenting with deep venous thrombosis and COVID-19. This study highlights a sustained high index of suspicion for homocystinuria to prevent severe thromboembolic complications.

Bleeding In Head And Neck Malignancy : Institution Based Management And Review (preprint)

Introduction:Squamous cell carcinoma constitutes for >90% of head and neck cancers. Acute rupture of irradiated, large vessels is life-threatening complication. The distribution of bleeding foci is diverse and can range from internal or common carotid arteries to branches of the external carotid artery. We intend to assess the management of patients presented in our institution with such acute bleeding episodes and also review the management of carotid blowout syndrome which is an oncological emergency.Methods:Retrospective observational study of 27 cases presented in our institution with acute bleeding due to head and neck cancer for period of two years. After resuscitation and necessary consents, emergency open tracheostomy was done with universal precautions. ECA/CCA ligation was done. All the patients were started on low molecular weight heparin 8 hours post surgery. Therapeutic outcomes were assessed based on simple frequencies and proportions.Results:Of the 27 cases presented in our institution, 19 of them underwent ECA ligation while 8 of them CCA ligation for the control of active bleeding. 12 of 27 patients were receiving definitive chemoradiation of which 7 of them were ongoing. Remaining 15 patients were receiving adjuvant radiotherapy following surgery.19 patients who underwent ECA ligation, had no further bleeding episodes. 8 patients who underwent CCA ligation, had only wound related complications and none of them had neurological deficits. 11 patients were operated during covid-19 period. 4 patients turned out covid positive. None of the medical personnel contacted the infection.Conclusion:Radiotherapy is one the major contributor for CBS. Endovascular procedures can be used for local tumour bleed, threatened, impending and stable acute CBS. Surgical CCA ligation done in bleeds unsuccessful by endovascular procedure and in acute unstable CBS. ECA ligation is safe and effective method to control local tumor bleed. Surgical finesse, careful planning, adherence to universal precautions and institutional protocol can reduce Covid-19 transmission to medical personnel in this testing times.

Profiling Molecular Simulations of SARS-CoV-2 Main Protease (Mpro) Binding to Repurposed Drugs Using Neural Network Force Fields (preprint)

With the current pandemic situation caused by a novel coronavirus disease (COVID-19), there is an urgent call to develop a working therapeutic against it. Efficient computations can minimize the efforts by identifying a subset of drugs that can potentially bind to the COVID-19 main protease or target protein (M PRO ). The results of computations are accompanied by an evaluation of their accuracy, which depends on the details described by the model used. Neural network models trained on millions of points and with unmatched accuracies are the best approach to employ in this process. In this work, I first identified and described the interaction sites of the M PRO protein using a geometric deep learning model. Second, I conducted virtual screening (at one of the sites identified) on FDA-approved drugs and selected 91 drugs with the highest binding affinities (below -8.0 kcal/mol). Then, I conducted 10 ns of molecular dynamics (MD) simulations using classical force fields and classified 37 drugs to be binding (including Lopinavir, Saquinavir, and Indinavir) based on the RMSD between MD-binding trajectories. To drastically improve the dynamics profile of the 37 selected drugs, I used the highly accurate neural network force field (ANI) method trained on coupled-cluster method (CCSD(T)/CBS) data points and performed 1 ns of binding dynamics for each drug with the protein. Using this approach, 19 drugs were qualified based on their RMSD cutoffs, and based on free energy (ANI/MM/PBSA) computations, 7 of the drugs were rejected. The final selection of 12 drugs was validated based on an MD trajectory clustering approach where 11 of the 12 drugs (Targretin, Eltrombopag, Rifaximin, Deflazacort, Ergotamine, Doxazosin, Lastacaft, Rifampicin, Victrelis, Trajenta, Toposar, and Indinavir) were confirmed to exhibit binding. Further investigations were performed to study their interactions with the protein and an accurate 2D-interaction map was generated. These findings and mappings of drug-protein interactions are highly accurate and may be potentially used to guide rational drug discovery against COVID-19.