Doctor of Philosophy

dissertationAn important aspect of medical research is the understanding of anatomy and its relation to function in the human body. For instance, identifying changes in the brain associated with cognitive decline helps in understanding the process of aging and age-related neurological disorders. The field of computational anatomy provides a rich mathematical setting for statistical analysis of complex geometrical structures seen in 3D medical images. At its core, computational anatomy is based on the representation of anatomical shape and its variability as elements of nonflat manifold of diffeomorphisms with an associated Riemannian structure. Although such manifolds effectively represent natural biological variability, intrinsic methods of statistical analysis within these spaces remain deficient at large. This dissertation contributes two critical missing pieces for statistics in diffeomorphisms: (1) multivariate regression models for cross-sectional study of shapes, and (2) generalization of classical Euclidean, mixed-effects models to manifolds for longitudinal studies. These models are based on the principle that statistics on manifold-valued information must respect the intrinsic geometry of that space. The multivariate regression methods provide statistical descriptors of the relationships of anatomy with clinical indicators. The novel theory of hierarchical geodesic models (HGMs) is developed as a natural generalization of hierarchical linear models (HLMs) to describe longitudinal data on curved manifolds. Using a hierarchy of geodesics, the HGMs address the challenge of modeling the shape-data with unbalanced designs typically arising as a result of follow-up medical studies. More generally, this research establishes a mathematical foundation to study dynamics of changes in anatomy and the associated clinical progression with time. This dissertation also provides efficient algorithms that utilize state-of-the-art high performance computing architectures to solve models on large-scale, longitudinal imaging data. These manifold-based methods are applied to predictive modeling of neurological disorders such as Alzheimer's disease. Overall, this dissertation enables clinicians and researchers to better utilize the structural information available in medical images

Enhancement of fault current contribution from inverter-based resources

The reduction in levels of fault current infeed as inverter-based resources (IBR) displace synchronous machines undermines the ability of a conventional protection system to identify and isolate faults in an effective manner and is therefore a concern for system operators (SOs). This observation provided the motivation to investigate the limitations of IBRs when injecting fault current and to explore how these limitations might be overcome. This thesis investigates techniques aimed at significantly increasing Fault Current Contribution (FCC) from an IBR system so that renewable energy resources can continue to be deployed without compromising the protection system. The techniques for enhancing FCC are at three different levels of an IBR system: at semiconductor or device level, circuit level and system level. The first study uses phase change materials (PCM) to provide a short-term overload rating to insulated-gate bipolar transistors (IGBTs) and found them to have very limited potential to provide FCC. A Finite Element Analysis (FEA) of heat-flow concluded that, although the PCM was useful for dealing with short over-load currents, it was unsuitable for facilitating large fault currents of several times normal load current. The view was that if the fault current cannot be created at device level through better thermal management, then a circuit level innovation would be required. The second study investigates series/parallel switching of submodules in modular converters. This takes advantage of the fact that during a fault, the line voltage is reduced, and if it falls below 0.5 pu then half of the sub-modules (SMs) can be put into parallel with the other half to double the FCC (2 pu) at half the voltage (0.5 pu). Similarly, if the voltage drops below 0.25 pu, parallel connection of four groups of SMs would enable 4 pu current capability. A model of a static synchronous compensator (STATCOM) was developed, inspired by the alternate arm converter (AAC), with the director switch of the AAC used as part of the reconfiguration circuit. The conclusion of this study was that the penalty paid in power losses in the additional semiconductor devices used for reconfiguration is reasonable for the 2 pu FCC case but not at the 4 pu FCC case. The third study was based on circuit reconfiguration but beyond the converter itself and in this case the windings of the coupling transformer of a STATCOM. Sections of winding were switched using thyristors to tap-change the transformer by a large factor. Using the proposed thyristor-based electronic tap-changer (eTC), the number of turns of the grid-side winding was reduced during a voltage dip, so that larger current can be delivered to the network for the same converter current. The STATCOM was controlled in the natural frame (abc frame) and this control is used to actively drive the currents in the tap-changer thyristors to zero when needed so that they can be commuted rapidly. The transformer was configured to give a normal ratio of 1:4 and be able to tap-down to 1:2 and 1:1 to increase FCC to 2 pu or 4 pu. Theoretical analysis of, and operating principles for, the proposed eTC, together with their associated control schemes, are verified by time-domain simulation at full-scale. The case-study circuit demonstrates delivery of substantial fault current contribution (FCC) of up to 4 pu at the point of common coupling (PCC) in less than half a cycle (10 ms) after detection of three- and single-phase faults. The results demonstrate that the proposed eTC is a good candidate for the enhancement of fault current from IBR systems that employ coupling transformers, allowing them thereby to make a contribution to future electricity networks dominated by IBR.Open Acces

Comparative study of functional outcome of distal one-third shaft tibia fractures treated with tip locking tibia nailing versus precontoured anatomical locking plate

Background: The distal 1/3rd shaft tibia extra-articular fractures are treated with both tip locking intra-medullary nailing (TLIMN) and precontoured anatomical locking plates (PCALP). The aim of this study was to compare the results of TLIMN and PCALP in distal tibia fractures and to determine dominant strategies. The complications and functional outcome in both groups were compared. Methods: Forty patients with distal 1/3rd shaft tibia were randomly assigned to TLIMN (group 1) and PCALP group (group 2). The functional outcomes were evaluated using American Orthopaedic Foot and Ankle Society (AOFAS) score. Complications like infection, delayed union, non-union, malunion, hardware prominence and secondary interventions were compared. Results: The average union time was 15.05±3.33 weeks in group 1 and 13.4±2.46 weeks in group 2 (p=0.045). The mean AOFAS score at 1 year follow up was 89.8±6.13 in group 1 and 89.1±6.15 in group 2 (p=0.262). Five patients in group 1 and one in group 2 had mal-alignment. Deep infection was present in one and superficial infection was present in two cases in group 2. Four patients in group 1 developed anterior knee pain and five patients in group 2 had hardware prominence. Conclusions: We conclude that tip locking intra-medullary nail is a reliable and satisfactory method for treatment of fractures of distal 1/3rd shaft tibia AO type 42A, 42B and 42C fractures with good functional outcomes and high union rates with comparatively low complications. Prevalence of malunion was higher in TLIMN group and hardware prominence was more prevalent in PCALP group. Implant removal are more in PCALP group mostly due to implant irritation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Biliary peritonitis due to gall bladder perforation after percutaneous nephrolithotomy

A 19-year-old male patient underwent right percutaneous nephrolithotomy (PNL) for right renal 1.5 × 1.5 cm lower pole stone. The procedure was completed uneventfully with complete stone clearance. The patient developed peritonitis and shock 48 h after the procedure. Exploratory laparotomy revealed a large amount of bile in the abdomen along with three small perforations in the gall bladder (GB) and one perforation in the caudate lobe of the liver. Retrograde cholecystectomy was performed but the patient did not recover and expired post-operatively. This case exemplifies the high mortality of GB perforation after PNL and the lack of early clinical signs

Introduction to Advanced Combustion Techniques and Engine Technologies for Automotive Sector

To resolve the transportation sector issues such as rapidly increasing petroleum consumption and stringent emission norms for vehicles, researchers have proposed three solution strategies namely advanced combustion techniques, after-treatment systems and alternative fuels. This book covers all three aspects for automotive sector. A dedicated section of this book is based on methanol, which discusses about the methanol utilization strategies in vehicles, especially in two wheelers. Second section of this book is based on advanced combustion techniques, which includes gasoline compression ignition (GCI), gasoline direct injection (GDI), and spark assisted compression ignition (SACI). Fourth section is based on emissions and after treatments systems. Last section of this book includes two different aspects. First is the vehicle lightweighting and second is the development of UAVs for defence applications. Overall this book emphasizes on different techniques, which can improve engine efficiency and reduce harmful emissions for a sustainable transport system

Epigallocatechin Gallate-Gold Nanoparticles Exhibit Superior Antitumor Activity Compared to Conventional Gold Nanoparticles: Potential Synergistic Interactions

Epigallocatechin gallate (EGCG) possesses significant antitumor activity and binds to laminin receptors, overexpressed on cancer cells, with high affinity. Gold nanoparticles (GNPs) serve as excellent drug carriers and protect the conjugated drug from enzymatic metabolization. Citrate-gold nanoparticles (C-GNPs) and EGCG-gold nanoparticles (E-GNPs) were synthesized by reduction methods and characterized with UV-visible spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Cytotoxicity of citrate, EGCG, C-GNPs, and E-GNPs was evaluated by the water-soluble tetrazolium salt (WST-1) assay. Nanoparticle cellular uptake studies were performed by TEM and atomic absorption spectroscopy (AAS). Dialysis method was employed to assess drug release. Cell viability studies showed greater growth inhibition by E-GNPs compared to EGCG or C-GNPs. Cellular uptake studies revealed that, unlike C-GNPs, E-GNPs were taken up more efficiently by cancerous cells than noncancerous cells. We found that E-GNP nanoformulation releases EGCG in a sustained fashion. Furthermore, data showed that E-GNPs induced more apoptosis in cancer cells compared to EGCG and C-GNPs. From the mechanistic standpoint, we observed that E-GNPs inhibited the nuclear translocation and transcriptional activity of nuclear factor-kappaB (NF-κB) with greater potency than EGCG, whereas C-GNPs were only minimally effective. Altogether, our data suggest that E-GNPs can serve as potent tumor-selective chemotoxic agents