Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

Technological change in agriculture : the development experience of Tamil Nadu

Summary available 2nd pag

IgM-Associated Cryoglobulinaemia

Cryoglobulinaemia is characterised by serum immunoglobulins that precipitate at temperatures below 37 ◦C and redissolve on warming. Monoclonal IgM immunoglobulin can be associated with type I and II cryoglobulinaemia with underlying Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance, or another non-Hodgkin lymphoma. In this research, we review the clinical characteristics of monoclonal IgM-associated cryoglobulinaemia and suggest a management approach for addressing them. Laboratory testing is critical as even a minimal amount of measurable cryoglobulin may result in symptoms. Accurate detection of cryoglobulins may be challenging, care must be taken with preanalytical variables, and repeated testing of monoclonal protein and cryoglobulins is indicated if clinical suspicion is high. Presentations range from asymptomatic to showing multisystem involvement, meaning that careful evaluation of the features and a thorough interrogation of organ systems and the underlying clone are critical. Immediate management is required for clinical red-flag features. Due to their rarity, data to inform treatment decisions are scant and collaborative research is imperative must be conducted to aid researchers in efforts to define optimal treatment strategies

Immune reconstitution of B cell and T cell compartments following reduced intensity allogeneic stem cell transplantation for myeloma.

Immune reconstitution following conventional allogeneic transplantation is a major determinant of survival. A detailed investigation of T and B cell immune reconstitution and clinical outcome in 19 patients with myeloma undergoing reduced intensity stem cell transplantation using in vivo T cell-depletion with alemtuzumab was undertaken. The rate of recovery of lymphocyte numbers and function following transplant was studied using immunophenotyping with 3-colour flow cytometry and intracellular cytokine staining. In addition, T and B cell spectratyping were used to study the repertoire of immune recovery. The patients in this study experienced delayed T cell recovery and T cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly following the administration of DLI and subsequent conversion to full donor T cell chimerism. Post transplant recovery of B cells was also significantly delayed. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalisation in spectratype complexity by 6- 12 months post transplant. There was a high incidence of viral infection, particularly CMV reactivation but the regimen related mortality was low, perhaps due to the very low incidence of severe acute graft-versus-host disease (GVHD). A total of 10 patients experienced GVHD. Of these patients, 8 eventually demonstrated a disease response alongside clinical evidence of GVHD, demonstrating that the graft-versus-myeloma effect is frequently obtained at the expense of GVHD. Over 80% of all patients have relapsed at a median of 9 months following transplant, suggesting that the initially low rate of GVHD has been achieved at the expense of the desired graft-versus-myeloma effect

Exploration of how children and young people self-construe following a traumatic experience

Trauma experience influences an individual’s emotional wellbeing, self-concept and relationships (e.g., Beck, Grant, Clapp, & Paylo, 2009) as well as increasing their risk of experiencing trauma in the future (Copeland, Keeler, Angold, & Costello, 2007). Accordingly clinical guidance for trauma presentations recommends treatment to alleviate distress and improve emotional wellbeing (van der Hart et al., 2006). Correspondingly, a literature review, using a meta-synthesis design, explored how adults experience talking therapies for complex trauma. From this, two themes were identified which noted that, in contrast to remaining detached from the trauma and associated difficulties as a means of surviving, adults were able to access therapy and instead reconnect with their trauma experience, others, and importantly self. This finding highlighted that exploring the impact of trauma on self is important and underrepresented in literature. Given research exploring self and trauma remains limited to adults, the research paper explored how children and young people self construe following a traumatic event(s). Seven young people completed a Trauma Symptoms Checklist Children – Alternative (TSCC-A) measure. Following this a pictorial self characterisation (Kelly, 1955; Ravenette, 1996), based on personal construct psychology, was used to encourage a creative and developmentally appropriate exploration of how they construed. These included four overarching themes which were developed using thematic analysis (Braun & Clarke, 2006): The Inferior Self, The Misfortunate Self, The Protective Self and The Enhanced Self. The clinical implications of this suggest that working therapeutically with the metaphor “self as community” (Mair, 1977) offers powerful opportunities to explore and understand different selves, reduce vast differences between selves, and to develop healthier core constructs. Future specialist trauma interventions should emphasise the importance of exploring self from the perspective of the individual (e.g., Ronen, 1996). Finally the critical appraisal provides reflections on the limitations and strengths of this research

Energy for a sustainable road/rail transport system in India

The main motivation for this study is that the strong transport-energy nexus has not received the attention it deserves, though energy is a crucial constraint on transport, and transport is a major determinant of energy demand. Also, many detailed treatments of the transport sector have not scrutinised the sustainability of the present pattern of development of this sector. Further, the prevailing paradigm guiding the development of the sector is made explicit and critiqued because it is often the root cause of its unsustainability. And, because treatments of transport policy issues tend to proceed without a clear statement of underlying goals and strategies, the entire hierarchy of interventions - from goals to strategies to policies - has been discussed. Finally, an attempt has been made to deal with both the supply and demand aspects of the transport sector. The study is restricted to road and rail transport since air and water (inland waters, and coastal and international seas) transport handle very small fractions of domestic traffic demand. The detailed discussions are preceded by overviews of the main features of the Indian transport system as well as of the energy sector as pertaining to transport. It is suggested that the goal of the Indian transport sector should be an efficient, capital-saving, non-import-intensive, affordable, service-oriented and environmentally sound transport system, i.e., a sustainable transport system. A strategy or broad plan to achieve this goal of a sustainable transport system should consist of several components: (1) minimisation of dependence on petroleum fuels, (2) maximisation of the level of safe, comfortable and time-saving transport services, (3) maximisation of the environmental soundness of the transport system, and in particular, reduction of local and global environmental pollution, (4) minimisation of the capital requirements for the transport modal mix that should also include non-motorised transport (NMT), and (5) minimisation of the energy used by the transport system without a reduction of the services provided. The detailed policies (plans or courses of action) to implement the above strategies for achieving a sustainable transport system fall into the following categories: (1) transport-energy database generation and use, (2) demand management, (3) technological improvements in road transport, (4) improvement of the capacity and quality of road infrastructure, (5) traffic management, (6) improvement of the railways, (7) improvement of urban transport, (8) providing a niche for non-motorised modes of transport, (9) pollution control and abatement, (10) costing and pricing, (11) modal shifts to achieve a least-cost freight modal mix, (12) modal shifts to achieve a least-cost passenger modal mix, (13) solutions to the transport sector's problems through measures in other sectors, (14) alternative fuels. Appropriate policy instruments or mechanisms for initiating and maintaining the policies as well as suitable policy agents to wield the policy instruments have also been identified. The market has the power of being an excellent allocator of money, materials and manpower, but unfortunately also has definite limits - it is not very good at looking after the poor, the environment, the long-term and the infrastructure and national strategic concerns such as self-reliance and external debt, all of which are of crucial relevance to the transport system. Hence, the visible hand of government and the people must complement the invisible hand of the market. In conclusion, both short-term low-cost measures to attract political decision-makers with short time-horizons and long-term measures have been mentioned. The short-term measures consist mainly of better maintenance, better driving practices, optimal routing of buses, dedicated routes for buses with traffic restrictions on these dedicated routes, special lanes for slow traffic, supply constraint on personal vehicles, export orientation to the production of personal vehicles, removal of kerosene and diesel subsidies, no long-haul truck permits, increase of truck taxes and shift of passengers travelling less than 300 km from rail to bus. The long-term measures consist mainly of increases in fuel efficiency, introduction of lower-power bus engines, increases in number of buses and/or suburban trains, investments on mass transportation infrastructure, home electrification, improvement of rail freight operations, truck-rail freight linkage, introduction of CNG for urban fleets, switches to biomass-derived fuels for transportation, biomass-derived fuels as petrol and diesel extenders, silviculture for biomass-derived fuels, and alternative cooking fuels and/or devices to replace kerosene