Polymorphs solvates and co-crystals of molecular materials

The scope of my research project is to produce and characterize new crystalline forms of organic compounds, focusing the attention on co-crystals and then transferring these notions on APIs to produce co-crystals of potential interest in the pharmaceutical field. In the first part of this work co-crystallization experiments were performed using as building blocks the family of aliphatic dicarboxylic acids HOOC-(CH2)n-COOH, with n= 2-8. This class of compounds has always been an object of study because it is characterized by an interesting phenomenon of alternation of melting points: the acids with an even number of carbon atoms show a melting point higher than those with an odd one. The acids were co-crystallized with four dipyridyl molecules (formed by two pyridine rings with a different number of bridging carbon atoms) through the formation of intermolecular interactions N•••(H)O. The bases used were: 4,4’-bipyridine (BPY), 1,2-bis(4-pyridyl)ethane (BPA), 1,2-(di-4-pyridyl)ethylene (BPE) and 1,2-bis(4-pyridyl)propane (BPP). The co-crystals obtained by solution synthesis were characterized by different solid-state techniques to determine the structure and to see how the melting points in co-crystals change. In the second part of this study we tried to obtain new crystal forms of compounds of pharmaceutical interest. The APIs studied are: O-desmethylvenlafaxine, Lidocaine, Nalidixic Acid and Sulfadiazine. Each API was subjected to Polymorph Screening and Salt/Co-crystal Screening experiments to identify new crystal forms characterized by different properties. In a typical Salt/Co-crystal Screening the sample was made to react with a co-former (solid or liquid) through different methods: crystallization by solution, grinding, kneading and solid-gas reactions. The new crystal forms obtained were characterized by different solid state techniques (X-ray single crystal diffraction, X-ray powder diffraction, Differential Scanning Calorimetry, Thermogravimetric Analysis, Evolved gas analysis, FT-IR – ATR, Solid State N.M.R).

Shear behaviour of reinforced cconcrete slab under concentrated load: an investigation through non-linear and sequentially linear analysis

English: The assessment of safety in existing bridges and viaducts led the Ministry of Public Works of the Netherlands to finance a specific campaing aimed at the study of the response of the elements of these infrastructures. Therefore, this activity is focused on the investigation of the behaviour of reinforced concrete slabs under concentrated loads, adopting finite element modeling and comparison with experimental results. These elements are characterized by shear behaviour and crisi, whose modeling is, from a computational point of view, a hard challeng, due to the brittle behavior combined with three-dimensional effects. The numerical modeling of the failure is studied through Sequentially Linear Analysis (SLA), an alternative Finite Element method, with respect to traditional incremental and iterative approaches. The comparison between the two different numerical techniques represents one of the first works and comparisons in a three-dimensional environment. It's carried out adopting one of the experimental test executed on reinforced concrete slabs as well. The advantage of the SLA is to avoid the well known problems of convergence of typical non-linear analysis, by directly specifying a damage increment, in terms of reduction of stiffness and resistance in particular finite element, instead of load or displacement increasing on the whole structure . For the first time, particular attention has been paid to specific aspects of the slabs, like an accurate constraints modeling and sensitivity of the solution with respect to the mesh density. This detailed analysis with respect to the main parameters proofed a strong influence of the tensile fracture energy, mesh density and chosen model on the solution in terms of force-displacement diagram, distribution of the crack patterns and shear failure mode. The SLA showed a great potential, but it requires a further developments for what regards two aspects of modeling: load conditions (constant and proportional loads) and softening behaviour of brittle materials (like concrete) in the three-dimensional field, in order to widen its horizons in these new contexts of study.

Treatment of knee articular cartilage defects: surgical strategies, results and analysis of factors determining the clinical outcome

Articular cartilage lesions, with their inherent limited healing potential, are hard to treat and remain a challenging problem for orthopedic surgeons. Despite the development of several treatment strategies, the real potential of each procedure in terms of clinical benefit and effects on the joint degeneration processes is not clear. Aim of this PhD project was to evaluate the results, both in terms of clinical and imaging improvement, of new promising procedures developed to address the challenging cartilage pathology. Several studies have been followed in parallel and completed over the 3-year PhD, and are reported in detail in the following pages. In particular, the studies have been focused on the evaluation of the treatment indications of a scaffold based autologous chondrocyte implantation procedure, documenting its results for the classic indication of focal traumatic lesions, as well as its use for the treatment of more challenging patients, older, with degenerative lesions, or even as salvage procedure for more advanced stages of articular degeneration. The second field of study involved the analysis of the results obtained treating lesions of the articular surface with a new biomimetic osteochondral scaffold, which showed promise for the treatment of defects where the entire osteochondral unit is involved. Finally, a new minimally invasive procedure based on the use of growth factors derived from autologous platelets has been explored, showing results and underlining indicatios for the treatment of cartilage lesions and different stages of joint degeneration. These studies shed some light on the potential of the evaluated procedures, underlining good results as well as limits, they give some indications on the most appropriate candidates for their application, and document the current knowledge on cartilage treatment procedures suggesting the limitations that need to be addressed by future studies to improve the management of cartilage lesions.

The application of a new psychotherapeutic strategy for enhancing eudaimonic well-being in children with mood and anxiety disorders

The aim of the dissertation was to test the feasibility of a new psychotherapeutic protocol for treating children and adolescents with mood and anxiety disorders: Child-Well-Being Therapy (CWBT). It originates from adult Well-Being Therapy protocol (WBT) and represents a conceptual innovation for treating affective disorders. WBT is based on the multidimensional model of well-being postulated by Ryff (eudaimonic perspective), in sequential combination with cognitive-behavioral therapy (CBT). Results showed that eudaimonic well-being was impaired in children with affective disorders in comparison with matched healthy students. A first open investigation aimed at exploring the feasibility of a 8-session CWBT protocol in a group of children with emotional and behavioural disorders has been implemented. Data showed how CWBT resulted associated to symptoms reduction, together with the decrease of externalizing problems, maintained at 1-year follow-up. CWBT triggered also an improvement in psychological well-being as well as an increasing flourishing trajectory over time. Subsequently, a modified and extended version of CWBT (12-sessions) has been developed and then tested in a controlled study with 34 patients (8 to 16 years) affected by mood and anxiety disorders. They were consecutively randomized into 3 different groups: CWBT, CBT, 6-month waiting list (WL). Both treatments resulted effective in decreasing distress and in improving well-being. Moreover, CWBT was associated with higher improvement in anxiety and showed a greater recovery rate (83%) than CBT (54%). Both groups maintained beneficial effects and CWBT group displayed a lower level of distress as well as a higher positive trend in well-being scores over time. Findings need to be interpret with caution, because of study limitations, however important clinical implications emerged. Further investigations should determine whether the sequential integration of well-being and symptom-oriented strategies could play an important role in children and adolescents’ psychotherapeutic options, fostering a successful adaptation to adversities during the growth process.

Determining the effect of regulation on Microfinance Institutions Financial Self-Sustainability. A Cross-Country Comparison

Microfinance is an initiative which seeks to address financial inclusion, micro-entrepreneurship, and poverty reduction without over burdening governments. However, the current sector of microfinance is still heavily dependent on the good will of donors. The over-reliance on donations is a feature which threatens the long term sustainability of microfinance. Much has been written about this reliance, but research to date hasn’t empirically examined the effect of regulation as a mediator. This is a critical area of study because regulation directly affects Microfinance Institutions’ (MFI) innovation, and innovation is what shapes the future of microfinance. This thesis considers the role that regulation plays in affecting MFI’s and their ability to innovate in products, services and long-term sustainability via access to capital. Interviews were undertaken with stakeholders in MFI’s, NGO’s, Self-Regulating Bodies, and Regulators in India, Pakistan, and Bangladesh. This thesis discusses findings from interviews in relation to regulatory measures regarding financial self-sustainability of MFI’s. The conclusions of this thesis have implications for policy and inform the microfinance literature.

Atomistic simulations of liquid crystals in the bulk and at their interfaces

In this thesis, we have dealt with several problems concerning liquid crystals (LC) phases, either in the bulk or at their interfaces, by the use of atomistic molecular dynamics (MD) simulations. We first focused our attention on simulating and characterizing the bulk smectic phase of 4-n-octyl-4'-cyanobiphenyl (8CB), allowing us to investigate the antiparallel molecular arrangement typical of SmAd smectic phases. A second topic of study was the characterization of the 8CB interface with vacuum by simulating freely suspended thin films, which allowed us to determine the influence of the interface on the orientational and positional order. Then we investigated the LC-water and LC-electrolyte water solution interface. This interface has recently found application in the development of sensors for several compounds, including biological molecules, and here we tried to understand the re-orientation mechanism of LC molecules at the interface which is behind the functioning of these sensors. The characterization of this peculiar interface has incidentally led us to develop a polarizable force field for the pentyl-cyanobiphenyl mesogen, whose process of parametrization and validation is reported here in detail. We have shown that this force field is a significant improvement over its previous, static charge non polarizable version in terms of density, orientational order parameter and translational diffusion.

Dynamics of coastal aquifers: data-driven forecasting and risk analysis

This work is focused on the study of saltwater intrusion in coastal aquifers, and in particular on the realization of conceptual schemes to evaluate the risk associated with it. Saltwater intrusion depends on different natural and anthropic factors, both presenting a strong aleatory behaviour, that should be considered for an optimal management of the territory and water resources. Given the uncertainty of problem parameters, the risk associated with salinization needs to be cast in a probabilistic framework. On the basis of a widely adopted sharp interface formulation, key hydrogeological problem parameters are modeled as random variables, and global sensitivity analysis is used to determine their influence on the position of saltwater interface. The analyses presented in this work rely on an efficient model reduction technique, based on Polynomial Chaos Expansion, able to combine the best description of the model without great computational burden. When the assumptions of classical analytical models are not respected, and this occurs several times in the applications to real cases of study, as in the area analyzed in the present work, one can adopt data-driven techniques, based on the analysis of the data characterizing the system under study. It follows that a model can be defined on the basis of connections between the system state variables, with only a limited number of assumptions about the "physical" behaviour of the system.

The use of satellite remote sensing for flood risk management

Over the last decades the impact of natural disasters to the global environment is becoming more and more severe. The number of disasters has dramatically increased, as well as the cost to the global economy and the number of people affected. Among the natural disaster, flood catastrophes are considered to be the most costly, devastating, broad extent and frequent, because of the tremendous fatalities, injuries, property damage, economic and social disruption they cause to the humankind. In the last thirty years, the World has suffered from severe flooding and the huge impact of floods has caused hundreds of thousands of deaths, destruction of infrastructures, disruption of economic activity and the loss of property for worth billions of dollars. In this context, satellite remote sensing, along with Geographic Information Systems (GIS), has become a key tool in flood risk management analysis. Remote sensing for supporting various aspects of flood risk management was investigated in the present thesis. In particular, the research focused on the use of satellite images for flood mapping and monitoring, damage assessment and risk assessment. The contribution of satellite remote sensing for the delineation of flood prone zones, the identification of damaged areas and the development of hazard maps was explored referring to selected cases of study.

Analytical model for the prediction of wrinkling of rear pressure bulkheads

In Airbus GmbH (Hamburg) has been developed a new design of Rear Pressure Bulkhead (RPB) for the A320-family. The new model has been formed with vacuum forming technology. During this process the wrinkling phenomenon occurs. In this thesis is described an analytical model for prediction of wrinkling based on the energetic method of Timoshenko. Large deflection theory has been used for analyze two cases of study: a simply supported circular thin plate stamped by a spherical punch and a simply supported circular thin plate formed with vacuum forming technique. If the edges are free to displace radially, thin plates will develop radial wrinkles near the edge at a central deflection approximately equal to four plate thicknesses w0/ℎ≈4 if they’re stamped by a spherical punch and w0/ℎ≈3 if they’re formed with vacuum forming technique. Initially, there are four symmetrical wrinkles, but the number increases if the central deflection is increased. By using experimental results, the “Snaptrhough” phenomenon is described.

Boundary condition identification of a bridge pier using experimental data and FEM modal updating

Over the past twenty years, new technologies have required an increasing use of mathematical models in order to understand better the structural behavior: finite element method is the one mostly used. However, the reliability of this method applied to different situations has to be tried each time. Since it is not possible to completely model the reality, different hypothesis must be done: these are the main problems of FE modeling. The following work deals with this problem and tries to figure out a way to identify some of the unknown main parameters of a structure. This main research focuses on a particular path of study and development, but the same concepts can be applied to other objects of research. The main purpose of this work is the identification of unknown boundary conditions of a bridge pier using the data acquired experimentally with field tests and a FEM modal updating process. This work doesn’t want to be new, neither innovative. A lot of work has been done during the past years on this main problem and many solutions have been shown and published. This thesis just want to rework some of the main aspects of the structural optimization process, using a real structure as fitting model.

How to assess the external validity of therapeutic trials: a conceptual approach

Background External validity of study results is an important issue from a clinical point of view. From a methodological point of view, however, the concept of external validity is more complex than it seems to be at first glance. Methods Methodological review to address the concept of external validity. Results External validity refers to the question whether results are generalizable to persons other than the population in the original study. The only formal way to establish the external validity would be to repeat the study for that specific target population. We propose a three-way approach for assessing the external validity for specified target populations. (i) The study population might not be representative for the eligibility criteria that were intended. It should be addressed whether the study population differs from the intended source population with respect to characteristics that influence outcome. (ii) The target population will, by definition, differ from the study population with respect to geographical, temporal and ethnical conditions. Pondering external validity means asking the question whether these differences may influence study results. (iii) It should be assessed whether the study's conclusions can be generalized to target populations that do not meet all the eligibility criteria. Conclusion Judging the external validity of study results cannot be done by applying given eligibility criteria to a single target population. Rather, it is a complex reflection in which prior knowledge, statistical considerations, biological plausibility and eligibility criteria all have place.

Does the Presence of a Learning Disability Elicit a Stigmatization?

Aims: To determine whether or not a Learning Disability(LD) label leads to stigmatization. Study Design: This research used a 2(sex of participant) x 2(LD label)x 2 (Sex of stimulus person) factorial design. Place and Duration of Study: Bucknell University, between October 2010 and April 2011. Methodology: Sample: We included 200 participants (137 women and 63 men, ranging in age from 18 – 75 years, M = 26.41. Participants rated the stimulus individual on 27 personality traits, 8 Life success measures, and the Big-5 personality dimensions. Also, participants completed a Social Desirability measure. Results: A MANOVA revealed a main effect for the Learning Disability description, F(6, 185) = 6.41 p< .0001, eta2 = .17,for the Big-5 personality dimensions, Emotional Stability, F(1, 185) = 13.39, p < .001, eta2 = .066, and Openness to Experiences F(1,185) = 7.12, p< .008, eta2 = .036.Stimulus individuals described as having a learning disability were perceived as being less emotionally stable and more open to experiences than those described as not having a learning disability. Another MANOVA revealed a main effect for having a disability or not, F(8, 183) = 4.29, p< .0001, eta2 = .158, for the Life Success items, Attractiveness, F(1, 198) = 16.63, p< .0001, eta2 = .080, and Future Success,F(1, 198) = 4.57, p< .034, eta2 = .023. Stimulus individuals described as having a learning disability were perceived as being less attractive and with less potential for success than those described as not having a learning disability. Conclusion: The results of this research provide evidence that a bias exists toward those who have learning disabilities. The mere presence of an LD label had the ability to cause a differential perception of those with LDs and those without LDs.

STrengthening the reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement

Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

STrengthening the Reporting of OBservational studies in Epidemiology--Molecular Epidemiology STROBE-ME: an extension of the STROBE statement

Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement

Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrenghtening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.