A Comprehensive and Detailed Within-Host Modeling Study involving crucial Bio markers and Optimal Drug regimen for Lepra Type-I Reaction : A Deterministic Approach

Leprosy (Hansen's disease) is an infectious, neglected tropical disease caused by the Mycobacterium Leprae (M. Leprae). Each year there are approximately 2,02,189 new cases are detected globally. In the year 2017 more than half million people were disabled due to leprosy and almost 50000 new cases are added every year world wide. In leprosy, lepra reactions are the major cause for nerve damage leading to disability. Early detection of lepra reactions through study of biomarkers have important role in prevention of subsequent disabilities. To our knowledge there seems to be very limited literature available on within-host modeling at cellular level involving the crucial biomarkers and the possible optimal drug regimen for leprosy disease and lepra reactions. Motivated by these observations, in this study, we have proposed and analyzed a three dimensional mathematical model to capture the dynamics of susceptible schwann cells, infected schwann cells and the bacterial load based on the pathogenesis of leprosy. We estimated the parameters from various clinical papers to make the model more practical. The sensitivity of couple of parameters was evaluated through PRCC method to find out the single most influential parameter and also combination of two most influential parameters was studied using SRCC method. The sensitivity of other remaining parameters was evaluated using Sobol's index. We then have framed and studied an optimal control problem considering the different medication involved in the Multi Drug Therapy (MDT) as control variables. We further studied this optimal control problem along with both MDT and steroid interventions. The finding from this novel and comprehensive study will help the clinicians and public health researchers involved in the process of elimination and eradication of leprosy

Immunogenic Modulations Induced by Prospective Anti-Malarial Herbal Extracts in Murine Model

Keeping in view the ever increasing problem of drug resistance and affordability of the antimalarial drugs by the poor mass, herbal medicines can become an important and alternative sustainable strategy for malaria treatment. Aqueous extracts of three Himalayan herbs― _Equisetum ravense_, _Artemisia vulgaris_ and _Centella asiatica_, with reported antimalarial property were screened for clinical efficacy against a local strain of _Plasmodium vivax_ antigen in murine model. _E. arvense_ extract was consistent in boosting phagocytic activity, nitric oxide generation, acid phosphatase and alkaline phosphatase activities in the peritoneal macrophages. The effectiveness of the rest herbals was discrete. A need for further detailed investigation to evaluate the clinical efficacy of these herbals seems essential

Pycnodysostosis- A Rare Diagnosis Not to Miss

Key Words: Pycnodysostosis, fracture, autosomal recessive Background Pycnodysostosis derived from the Greek words pycnos-density, dys-defect, ostosis-bone is a rare inherited disorder of the bone with an incidence of 1.7 per million births 1. It is one of the lysosomal storage disorders with a deficiency of enzyme cathepsin K. Along with a history of repeated fractures of the bones, patients with Pycnodysostosis have a short stature, dolichocephalic skull, obtuse mandibular angle, short terminal phalanx. They also have dental abnormalities such as the delayed eruption of permanent teeth, and double rows of teeth. Mild psychomotor problems were noted in a few individuals 1, 2. Pycnodysostosis is diagnosed by clinical and radiological features as there is no diagnostic criterion. Skulls show open fontanels, generalized osteosclerosis, loss of the normal angle of the jaw, and hypoplasia of facial bones 3. Social and occupational support needed to prevent recurrent fractures. Orthopaedic and orthodontic cares are needed 4-7. The Case A non-diabetic normotensive male of 63 years presented to the medicine outpatients department (OPD) with complaints of burning type, non-radiating moderate intensity pain in the epigastric region for three months following taking of NSAIDs.  He gave a history of fractures of different bones following minimal trauma since his childhood and used to take NSAIDs every now and then. He did take orthopaedic consultation for those fractures but the underlying pathophysiology was not explored. Malunion of long bones resulted in a deformed limb. The rest of his past medical history and family history was unremarkable. On clinical examination, we found the patient had short stature with proportionately short limbs. He had dysmorphic features with a large head, small facial structures, frontal and bilateral parietal bossing. Examination of the oral cavity revealed a narrow high arched palate and hypoplastic, overcrowded teeth. His digits were short and stubby. The lower limbs of the patient have angular deformities that resulted from malunion of bones from previous fracture. Haematological and biochemical investigations were normal. Chest X-ray showed multiple ribs fracture on the right side. The patient's clavicle was normal in X-ray. Both tibia and fibula showed a malunited fracture in diaphysis. Computed tomography (CT) of the skull, as well as 3D reconstruction of CT, found open fontanelles and widening of sutures (Figure 1). Frontal and parietal bossing was noted. There was hypoplasia of the air sinuses. CT scans showed dysplasia of the bones of the face and hands. Hypoplasia was noted in the terminal phalanx of fingers. An endoscopy of the upper gastrointestinal tract found multiple erosion around the antrum of the stomach. Considering the clinical and radiological feature diagnosis of Pycnodysostosis with NSAIDs-induced antral erosion was made. The patient and his caregivers were briefed about the diagnosis.  Consultation from a multidisciplinary team was done concerning his treatment. Conclusion It is important to diagnose Pycnodysostosis early as it allows proper planning to prevent future fractures. While assessing a patient with short stature with a history of repeated bone fracture Pycnodysostosis should be considered along with other differentials

Optimal Drug Regimen and Combined Drug Therapy and its Efficacy in the Treatment of COVID-19 : An Within-Host Modeling Study

The COVID-19 pandemic has resulted in more than 30.35 million infections and 9, 50, 625 deaths in 212 countries over the last few months. Different drug intervention acting at multiple stages of pathogenesis of COVID-19 can substantially reduce the infection induced mortality. The current within-host mathematical modeling studies deals with the optimal drug regimen and the efficacy of combined therapy in treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Inteferon (INF) and Lopinavir/Ritonavir. It is concluded that these drug interventions when administered individually or in combination reduce the infected cells and viral load. Four scenarios involving administration of single drug intervention, two drug interventions, three drug interventions and all the four have been discussed. In all these scenarios the optimal drug regimen is proposed based on two methods. In the first method these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem is formulated. In this setting the optimal drug regimen is proposed. Later using the the comparative effectiveness method the optimal drug regimen is proposed based on basic reproduction number and viral load. The average infected cell count and viral load decreased the most when all the four interventions were applied together. On the other hand the average susceptible cell count decreased the best when Arbidol alone was administered. The basic reproduction number and viral count decreased the best when all the four interventions were applied together reinstating the fact obtained earlier in the optimal control setting. These findings may help physicians with decision making in treatment of life-threatening COVID-19 pneumonia.Comment: 16 pages, 13 figure

A comprehensive and detailed within-host modeling study involving crucial biomarkers and optimal drug regimen for type I Lepra reaction: A deterministic approach

Leprosy (Hansen’s disease) is an infectious, neglected tropical disease caused by the Mycobacterium Leprae (M. Leprae). About 2,02,189 new cases are diagnosed worldwide each year. Lepra reactions are an off shoot of leprosy infection causing major nerve damage leading to disability. Early detection of lepra reactions through the study of biomarkers can prevent subsequent disabilities. Motivated by these observations, in this study, we have proposed and analyzed a three-dimensional mathematical model to capture the dynamics of susceptible schwann cells, infected schwann cells, and the bacterial load based on the pathogenesis of leprosy. We did the stability analysis, numerical simulations, and also performed the sensitivity analysis using Spearman’s rank correlation coefficient, partial rank correlation coefficient, and Sobol’s index methods. We later performed the optimal control studies with both multi-drug therapy and steroid interventions as control variables. Finally, we did the comparative and effectiveness study of these different control interventions