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81.
Chrysovalantis Voutouri Mohammad Reza Nikmaneshi C. Corey Hardin Ankit B. Patel Ashish Verma Melin J. Khandekar Sayon Dutta Triantafyllos Stylianopoulos Lance L. Munn Rakesh K. Jain 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(3)
Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, incorporating the renin−angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines, and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of comorbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age; comorbidities such as obesity, diabetes, and hypertension; and dysregulated immune response. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8+ T cells and sufficient control of the innate immune response. Furthermore, the best treatment—or combination of treatments—depends on the preinfection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.COVID-19 has created unprecedented challenges for the health care system, and, until an effective vaccine is developed and made widely available, treatment options are limited. A challenge to the development of optimal treatment strategies is the extreme heterogeneity of presentation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a syndrome that ranges in severity from asymptomatic to multiorgan failure and death. In addition to local complications in the lung, the virus can cause systemic inflammation and disseminated microthrombosis, which can cause stroke, myocardial infarction, or pulmonary emboli (1–4). Risk factors for poor COVID-19 outcome include advanced age, obesity, diabetes, and hypertension (5–13).Computational analyses can provide insights into the transmission, control, progression, and underlying mechanisms of infectious diseases. Indeed, epidemiological and statistical modeling has been used for COVID-19, providing powerful insights into comorbidities, transmission dynamics, and control of the disease (14–17). However, to date, these analyses have been population dynamics models of SARS-CoV-2 infection and transmission or correlative analyses of COVID-19 comorbidities and treatment response. Simple viral dynamics models have been also developed and used to predict the SARS-CoV-2 response to antiviral drugs (18, 19). These models, however, do not explicitly consider the biological or physiological mechanisms underlying disease progression or the time course of response to various therapeutic interventions, and only a few more-sophisticated models have been developed toward this direction (20, 21).Several therapies targeting various aspects of COVID-19 pathogenesis have been proposed and have either completed—or are currently being tested in—clinical trials (22). Despite strong biologic rationale, these treatments have generally produced conflicting results in the clinic. For example, trials of antiviral therapies (e.g., remdesivir) have been mixed: The original trial from China failed (23), a subsequent trial in the United States led to approval of remdesivir in the United States and other countries (24), and the recent results of the World Health Organization Solidarity trial again show no benefit (25). Other antiviral drugs alone or in combination are also showing promise (26).Other potential treatments include antiinflammatory drugs and antithrombotic agents. Because of the systemic inflammation seen in many patients, antiinflammatory drugs have been tested, including anti-IL6/IL6R therapy (e.g., tocilizumab, siltuximab) and anti-JAK1/2 drugs (e.g., barcitinib). It is not clear whether these drugs will be effective as stand-alone treatments, particularly after the recent failure of tocilizumab in a phase III trial (1, 27–29). In addition, given that a common complication of COVID-19 is the development of coagulopathies with microvascular thrombi potentially leading to the dysfunction of multiple organ systems (2, 3), antithrombotic drugs (e.g., low molecular weight heparin) are being tested. Recognizing the interactions of COVID-19 with the immune system (30), the corticosteroid dexamethasone has been tested, showing some promising results. Given the large range of patient comorbidities, disease severities, and variety of complications such as thrombosis, it is likely that patients will have heterogeneous responses to any given therapy, and such heterogeneity will continue to be a challenge for clinical trials of unselected COVID-19 patients (31).Here, we developed a systems biology-based mathematical model to address this urgent need. Our model incorporates the known mechanisms of SARS-CoV-2 pathogenesis and the potential mechanisms of action of various therapeutic interventions that have been tested in COVID-19 patients. In previous work, we have exploited angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEis) for the improvement of cancer therapies and developed mathematical models of the renin−angiotensin system in the context of cancer desmoplasia (32–35). Using a similar approach, we developed a detailed model that includes lung infection by the SARS-CoV-2 virus and a pharmacokinetic/pharmacodynamic (PK/PD) model of infection and thrombosis to simulate events that take place throughout the body during COVID-19 progression (Fig. 1 and SI Appendix, Fig. S1). The model is first validated against clinical data of healthy people and COVID-19 patients and then used to simulate disease progression in patients with specific comorbidities. Subsequently, we present model predictions for various therapies currently employed for treatment of COVID-19 alone or in combination, and we identify protocols for optimal clinical management for each of the clinically observed COVID-19 phenotypes.Open in a separate windowFig. 1.Schematic of the detailed lung model. The model incorporates the virus infection of epithelial and endothelial cells, the RAS, T cells activation and immune checkpoints, the known IL6 pathways, neutrophils, and macrophages, as well as the formation of NETs, and the coagulation cascade. The lung model is coupled with a PK/PD model for the virus and thrombi dissemination through the body. 相似文献
82.
V.K. Malhotra Navreet Singh R.S. Bishnoi D.S. Chadha P. Bhardwaj H. Madan R. Dutta A.K. Ghosh S. Sengupta P. Perumal 《Medical Journal Armed Forces India》2015,71(4):324-329
Background
Competitive sports training causes structural and conductive system changes manifesting by various electrocardiographic alterations. We undertook this study to assess the prevalence of abnormal ECG in trained Indian athletes and correlate it with the nature of sports training, that is endurance or strength training.Methods
We evaluated a standard resting, lying 12 lead Electrocardiogram (ECG) in 66 actively training Indian athletes. Standard diagnostic criteria were used to define various morphological ECG abnormalities.Results
33/66 (50%) of the athletes were undertaking endurance training while the other 33 (50%) were involved in a strength-training regimen. Overall 54/66 (81%) sportsmen had significant ECG changes. 68% of these changes were considered as normal training related features, while the remaining 32% were considered abnormal. There were seven common training related ECG changes–Sinus Bradycardia (21%), Sinus Arrhythmia (16%), 1st degree Atrioventricular Heart Block (6%), Type 1 2nd-degree Atrioventicular Heart Block (3%), Incomplete Right bundle branch block (RBBB) (24%), Early Repolarization (42%), Left Ventricular Hypertrophy (LVH) (14%); while three abnormal ECG changes--T-wave inversion (13%), RBBB(4%), Right ventricular hypertrophy (RVH) with strain (29%) were noted. Early repolarization (commonest change), sinus bradycardia, and incomplete RBBB were the commoner features noticed, with a significantly higher presence in the endurance trained athletes.Conclusion
A high proportion of athletes undergoing competitive level sports training are likely to have abnormal ECG recordings. Majority of these are benign, and related to the physiological adaptation to the extreme levels of exertion. These changes are commoner during endurance training (running) than strength training (weightlifting). 相似文献83.
Pulkit Rastogi Prashant Sharma Neelam Varma Dmitry Sukhachev Naveen Kaushal Ishwar Bihana Man Updesh Singh Sachdeva Shano Naseem Pankaj Malhotra 《Indian journal of hematology & blood transfusion》2018,34(4):623-631
Automated blood counts revealing lymphocytosis necessitate smear reviews. Even expert morphological evaluation may however, fail to differentiate a benign-versus-malignant etiology without further testing. Automated analyser-derived quantitative data on leukocyte cell populations remain undertested for distinguishing such etiologies. Instrument manufacturers claim that if successful, they may be used to generate software flags that help under-resourced laboratories better triage hemogram specimens requiring further testing. We tested the diagnostic accuracy of volume-conductivity-scatter (VCS) indices together with complete blood count (CBC) parameters in such scenarios. We compared LH780-derived (Beckman Coulter, FL, USA) CBC + VCS parameters from patients with clonal lymphoproliferations (n = 42, including 30 chronic lymphocytic leukemia cases) versus 83 controls with absolute or relative lymphocytosis (derivation cohort). Diagnostic performances of 11 logistic regression equations derived were subsequently evaluated on two specific validation cohorts (n = 130 and n = 1465). Clonal lymphocytoses showed significantly lower hemoglobin and higher leukocyte counts but similar lymphocyte percentages (LY %) vis-à-vis controls. The most significant, albeit overlapping predictor of clonality was the absolute lymphocyte count, LY# (47.8 ± 48.4 × 109/L vs. 2.9 ± 1.4 × 109/L in clonal vs. benign cases). In eleven logistic regression equations constructed using four combinatorial approaches, only the models with LY# (highest sensitivity/specificity of 99.3%/100%) and the lymphocytic VCS parameters alone (highest sensitivity/specificity of 76.2%/90.2%) performed consistently in both validation cohorts. Lymphocytic VCS parameters were moderately successful in distinguishing benign-versus-malignant lymphocytes. Other approaches of CBC-plus-VCS parameters did not sustain their initial excellent performances in the validation cohorts, highlighting a need for careful appraisal and better standardization of automated cellular analysis technologies. 相似文献
84.
James M. Walter Chitaru Kurihara Thomas C. Corbridge Ankit Bharat 《Heart & lung : the journal of critical care》2018,47(4):398-400
Background
Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is increasingly utilized in the management of severe acute respiratory distress syndrome (ARDS). Providers who care for patients on VV-ECMO should be familiar with common circuit complications.Objectives
To provide an example of a common complication, circuit “chugging,” and suggest a management algorithm which aims to avoid excessive fluid administration to patients with ARDS.Methods
We use a clinical case to illustrate chugging and discuss potential management strategies.Results
Our patient received frequent boluses of albumin for intermittent circuit chugging contributing to a net positive fluid balance of roughly 6 liters 4 days after cannulation.Conclusions
Chugging is a common complication for patients on VV ECMO. A thoughtful approach to management may help limit potentially harmful fluid administration for patients with ARDS. 相似文献85.
86.
Vijay Subramanian Ankit Bharat Neeta Vachharajani Jeffrey Crippin Surendra Shenoy Thalachallour Mohanakumar William C Chapman 《HPB : the official journal of the International Hepato Pancreato Biliary Association》2014,16(3):282-294
Objectives:Perioperative factors can affect outcomes of liver transplantation (LT) in recipients with hepatitis C virus (HCV) infection. This study was conducted to investigate whether the immunomodulatory effects of packed red blood cells (PRBC) and platelets administered in the perioperative period might affect immune responses to HCV and thus outcomes in LT recipients.Methods:Data for a total of 257 HCV LT recipients were analysed. Data on clinical demographics including perioperative transfusion (during and within the first 24 h), serum cytokine concentration, HCV-specific interferon-γ (IFN-γ) and interleukin-17 (IL-17) producing cells, and outcomes including graft and patient survival were analysed.Results:Patient survival was higher in HCV LT recipients who did not receive transfusions (Group 1, n = 65) than in those who did (Group 2, n = 192). One-year patient survival was 95% in Group 1 and 88% in Group 2 (P = 0.02); 5-year survival was 77% in Group 1 and 66% in Group 2 (P = 0.05). Group 2 had an increased post-transplant viral load (P = 0.032) and increased incidence of advanced fibrosis at 1 year (P = 0.04). After LT, Group 2 showed increased IL-10, IL-17, IL-1β and IL-6, and decreased IFN-γ, and a significantly increased rate of IL-17 production against HCV antigen. Increasing donor age (P = 0.02), PRBC transfusion (P < 0.01) and platelets administration were associated with worse survival.Conclusions:Transfusion had a negative impact on LT recipients with HCV. The associated early increase in pro-HCV IL-17 and IL-6, with decreased IFN-γ, suggests that transfusion may be associated with the modulation of HCV-specific responses, increased fibrosis and poor transplant outcomes. 相似文献
87.
Eric J. Kezirian George S. Goding Jr Atul Malhotra Fergal J. O'Donoghue Gary Zammit John R. Wheatley Peter G. Catcheside Philip L. Smith Alan R. Schwartz Jennifer H. Walsh Kathleen J. Maddison David M. Claman Tod Huntley Steven Y. Park Matthew C. Campbell Carsten E. Palme Conrad Iber Peter R. Eastwood David R. Hillman Maree Barnes 《Journal of sleep research》2014,23(1):77-83
Reduced upper airway muscle activity during sleep is a key contributor to obstructive sleep apnea pathogenesis. Hypoglossal nerve stimulation activates upper airway dilator muscles, including the genioglossus, and has the potential to reduce obstructive sleep apnea severity. The objective of this study was to examine the safety, feasibility and efficacy of a novel hypoglossal nerve stimulation system (HGNS®; Apnex Medical, St Paul, MN, USA) in treating obstructive sleep apnea at 12 months following implantation. Thirty‐one subjects (35% female, age 52.4 ± 9.4 years) with moderate to severe obstructive sleep apnea and unable to tolerate positive airway pressure underwent surgical implantation and activation of the hypoglossal nerve stimulation system in a prospective single‐arm interventional trial. Primary outcomes were changes in obstructive sleep apnea severity (apnea–hypopnea index, from in‐laboratory polysomnogram) and sleep‐related quality of life [Functional Outcomes of Sleep Questionnaire (FOSQ)]. Hypoglossal nerve stimulation was used on 86 ± 16% of nights for 5.4 ± 1.4 h per night. There was a significant improvement (P < 0.001) from baseline to 12 months in apnea–hypopnea index (45.4 ± 17.5 to 25.3 ± 20.6 events h?1) and Functional Outcomes of Sleep Questionnaire score (14.2 ± 2.0 to 17.0 ± 2.4), as well as other polysomnogram and symptom measures. Outcomes were stable compared with 6 months following implantation. Three serious device‐related adverse events occurred: an infection requiring device removal; and two stimulation lead cuff dislodgements requiring replacement. There were no significant adverse events with onset later than 6 months following implantation. Hypoglossal nerve stimulation demonstrated favourable safety, feasibility and efficacy. 相似文献
88.
Partab Rai Rivka Lederman Shabirul Haque Shabina Rehman Viki Kumar Kavithalakshmi Sataranatrajan Ashwani Malhotra Balakuntalam S. Kasinath Pravin C. Singhal 《Experimental and molecular pathology》2014
Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R. 相似文献
89.
Hema Mittal Sunita Rai Dheeraj Shah S. V. Madhu Gopesh Mehrotra Rajeev Kumar Malhotra Piyush Gupta 《Indian pediatrics》2014,51(4):265-272
Objective
To evaluate the non-inferiority of a lower therapeutic dose (300,000 IU) in comparison to standard dose (600,000) IU of Vitamin D for increasing serum 25(OH) D levels and achieving radiological recovery in nutritional rickets.Design
Randomized, open-labeled, controlled trial.Setting
Tertiary care hospital.Participants
76 children (median age 12 mo) with clinical and radiologically confirmed rickets.Intervention
Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day.Outcome variables
Primary: Serum 25(OH)D, 12 weeks after administration of vitamin D3; Secondary: Radiological healing and serum parathormone at 12 weeks; and clinical and biochemical adverse effects.Results
Serum 25(OH)D levels [geometric mean (95% CI)] increased significantly from baseline to 12 weeks after therapy in both the groups [Group 1: 7.58 (5.50–10.44) to 16.06 (12.71–20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66–9.25) to 17.60 (13.71–22.60, P<0.001]. The adjusted ratio of geometric mean serum 25(OH)D levels at 12 weeks between the groups (taking baseline value as co-variate) was 0.91 (95% CI: 0.65–1.29). Radiological healing occurred in all children by 12 weeks. Both groups demonstrated significant (P<0.05) and comparable fall in the serum parathormone and alkaline phosphatase levels at 12 weeks. Relative change [ratio of geometric mean (95% CI)] in serum PTH and alkaline phosphatase, 12 weeks after therapy, were 0.98 (0.7–1.47) and 0.92 (0.72–1.19), respectively. The serum 25(OH)D levels were deficient (<20 ng/mL) in 63% (38/60) children after 12 weeks of intervention [Group 1: 20/32 (62.5%); Group 2: 18/28 (64.3%)]. No major clinical adverse effects were noticed in any of the children. Hypercalcemia was documented in 2 children at 4 weeks (1 in each Group) and 3 children at 12 weeks (1 in Group 1 and 2 in Group 2). None of the participants had hypercalciuria or hypervitaminosis D.Conclusion
A dose of 300,000 IU of vitamin D3 is comparable to 600,000 IU, administered orally, over a single day, for treating rickets in under-five children although there is an unacceptably high risk of hypercalcemia in both groups. None of the regime is effective in normalization of vitamin D status in majority of patients, 3 months after administering the therapeutic dose. 相似文献90.
Adam S. DuVall Jessica K. Fairley Laura Sutherland Amaya L. Bustinduy Peter L. Mungai Eric M. Muchiri Indu Malhotra Uriel Kitron Charles H. King 《The American journal of tropical medicine and hygiene》2014,90(4):638-645
To better delineate the impact of parasitic coinfection in coastal Kenya, we developed a novel specimen-sparing bead assay using multiplex flow immunoassay (MFI) technology to simultaneously measure serum or plasma immunoglobulin G4 (IgG4) against Brugia malayi antigen (BMA) and Schistosoma haematobium soluble worm antigen (SWAP). Properties of the bead assay were estimated by latent class analysis using data from S. haematobium egg counts/filarial rapid diagnostic cards (RDTs), parasite-specific enzyme-linked immunosorbent assays (ELISAs), and the multichannel IgG4 assay. For schistosomiasis, the bead assay had an estimated sensitivity of 81% and a specificity of 45%, and it was more sensitive than ELISA or urine egg counts for diagnosing infection. For filariasis, it had a sensitivity of 86% and a specificity of 39%, and it was more sensitive than ELISA or RDT. Measuring antibody by MFI is feasible and may provide more accurate epidemiological information than current parasitological tests, especially in the setting of low-intensity infections. 相似文献