Graceful transitions between periodic motions for nonlinear and hybrid systems

The objective of this dissertation is to provide a set of methods by which a graceful transition is synthesised for a large class of nonlinear and hybrid systems. A special focus of this thesis is on transitioning between periodic orbits. The primary motivation for this is in the application to legged locomotion. The Gluskabi Raccordation provides a general framework to accomplish this. In this thesis, we utilize the Gluskabi raccordation as a general framework for encapsulating the abstract notion of gracefulness. We extend the kernel method to a certain class of hybrid systems. We show how to construct a carefully formulated optimization problem, the solution of which yields graceful transitions. This is illustrated on hopping systems on elastic and granular terrain. The image method, which is dual to the kernel method, is also used as an alternative method to realize graceful transitions. This involves the careful formulation of a parameterized optimal control problem, the solution of which yields parameterized periodic orbits. A dynamically feasible trajectory is then constructed staying close to this orbit family, which yields a different notion of gracefulness. The method is illustrated on fully actuated and underactuated planar bipedal robots. Finally, energy efficient locomotion is also considered in the context of bipedal robots. The partial hybrid zero dynamics framework is employed to generate stable energy efficient periodic walking gaits. An optimal control problem is solved which generates energy efficient transitions between these stable periodic walking gaits.Ph.D

Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression

Convalescent Plasma Immunotherapy - A Possible Mitigation Strategy for SARS-CoV-2 Pandemic

Recently, a newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic coronavirus disease (COVID-19). More than 10 million confirmed cases and 503,867 associated deaths of SARS-CoV-2 have been reported worldwide to WHO in the end of July 2020. According to WHO guidelines, there is no effective therapy available for treating devastating SARS-CoV-2. Consequently, lack of evidence for appropriate treatment and vaccines has led to the re-emergence of convalescent plasma (CP) immunotherapy. Herein, we discuss the historical perspectives of CP against SARS-CoV, MERS-CoV, H1N1 pandemic and mainly the clinical outcomes of COVID-19 patients with respect to neutralizing antibodies (nAbs). A brief possible clinical protocol for CP transfusion with its adverse effects and limitation were also highlighted. It is concluded that, CP transfusion with high neutralizing antibody titer administered in early course of disease significantly improved clinical outcomes in COVID-19 patients by reducing morbidity and mortality. Thus, CP immunotherapy is considered as noteworthy candidate to be further re-evaluated as a most suitable therapeutic option against SARS-CoV-2 pandemic

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Reporting trends, practices, and resource utilization in neuroendocrine tumors of the prostate gland: a survey among thirty-nine genitourinary pathologists

Background: Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods: Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results: A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion: There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Inventory and Modelling of Different Objective Functions and their Impact on Optimal Design of an Offshore Wind Farm

The design of an offshore wind farm (OWF) is multidisciplinary in nature as it involves the design of many disciplines such as the wake effects, support structure, electrical cables etc. For the optimal design of an OWF, an optimization procedure is required where all the disciplines are optimized simultaneously. The objective function plays a significant role in optimization as it expresses the main aim of the model which is to be either minimized or maximized. So far, cost of energy (COE) and annual energy production (AEP) are one of the commonly used objective functions for OWF optimization as far as the author is aware. However, there might be other objective functions that may influence the optimal design of an OWF as well. This may include maximizing the profit, minimizing the environmental impact, reducing their carbon emissions etc. Hence, this thesis investigates the overview of different objective functions and understand its impact on the optimal design of an OWF.An inventory of different objective functions is prepared, and relevant ones are selected for further study. It is observed that even though some objectives are dissimilar, they still depend on the same wind farm parameters and are therefore expected to give similar design results. From the list of objective functions, net present value (NPV) and risk management objectives are chosen for further research.The selected objective functions are then formulated in a metric for optimization. The price of electricity plays a significant role in determining the NPV. It is learnt that electricity price varies with the power supply depending on the site conditions. The electricity price is low if the supply of power is high in a region where there are many OWF’s and vice versa. Moreover, OWF investors value constant power output without any fluctuations. Hence, taking all these aspects into consideration, the electricity price in the NPV function is modelled for a constant value, wind variability and wind power predictability.The risk management function, on the other hand, aims at minimizing the uncertainty associated with an OWF project. The risk here refers to the uncertainty associated with the profit obtained from the OWF. A set of annual average wind speeds is computed using monte carlo simulations and the AEP and NPV are estimated. The mean( NPV_mean) and standard deviation ( NPV_std ) of NPV are then calculated. NPV_std represents the uncertainty in this scenario and is minimized to reduce the risk.A suitable method is then identified to deal with multiple objectives. The NPV function is maximized for maximum profit and this objective is evaluated using a single objective optimization technique. The risk management objective involves the calculation of NPV_mean and NPV_std. Both objectives are contrasting in nature as a significant reduction in NPV_std corresponds to an undesirable reduction in NPV_mean. A tradeoff between both these objectives is the best possible solution. Therefore, a multi- objective optimization technique is used, and a list of solutions is obtained by generating a pareto front.The new approach is then evaluated by implementing different case studies. It is observed that optimum rotor diameter and number of turbines for the single objective optimization technique are influenced by economic indicators such as the real interest rate and lifetime. However, they are not influenced by variation in the electricity price. Nevertheless, the NPV function is sensitive to the economic indicators and variation in the electricity price. For the multi - objective optimization technique, multi criteria analysis was used to determine the weight to the objective functions while moving along the pareto curve. It was observed that the improvement of one objective led to the deterioration of the other objective. Hence, the pareto front provides opportunities to investors to negotiate and decide on the weight they want to specify for their objectives.Electrical Engineering | Sustainable Energy Technolog

B Cell Tolerance in Health and Disease

B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids and have been shown to play crucial roles in the development of autoimmunity in several animal models. In the periphery availability of BAFF, a B cell survival factor plays a critical role in the survival of self-reactive B cells. Antibodies against BAFF have been found to be effective therapeutic agents in lupus like autoimmune diseases. Recent developments are targeting anergy to control the growth of chronic lymphocytic leukemia cells

Optimal Walking Speed Transitions for Fully Actuated Bipedal Robots

In this paper, we utilize the Partial Hybrid Zero Dynamics (PHZD) framework to find a continuous family of stable periodic orbits on the PHZD surface. We find optimal controllers to transition between these types of orbits subject to PHZD constraints, along with finding optimal periodic orbits associated to different PHZD surfaces for different walking speeds. Additionally, optimal controllers that form a connecting surface between these distinct PHZD surfaces, along with transitions between them are synthesized. The two methods are compared with performance metrics associated with the cost of transport. The results are illustrated on a 5 degree of freedom planar bipedal robot

Optimal Walking Speed Transitions for Fully Actuated Bipedal Robots

In this paper, we utilize the Partial Hybrid Zero Dynamics (PHZD) framework to find a continuous family of stable periodic orbits on the PHZD surface. We find optimal controllers to transition between these types of orbits subject to PHZD constraints, along with finding optimal periodic orbits associated to different PHZD surfaces for different walking speeds. Additionally, optimal controllers that form a connecting surface between these distinct PHZD surfaces, along with transitions between them are synthesized. The two methods are compared with performance metrics associated with the cost of transport. The results are illustrated on a 5 degree of freedom planar bipedal robot