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These studies have resulted in substantial advances in the field of osteoporosis and osteoarthritis research. Crucial contributions to pivotal osteoporosis GWAS identified 518 bone mineral density and 13 fracture loci that now account for over 20% of the population variance in bone density. We identified over 300 novel eBMD loci and validated numerous genes, including (i) transferrin receptor-2 as a novel regulator of bone mass acting via BMP/p38MAPK/Wnt signalling, (ii) over 100 genes that determine bone mass, quality and strength comprising enzymes, ion and amino acid transporters, cell cycle regulators, transcription factors and modulators of non-canonical Wnt signalling, and (iii) age-specific and sexually dimorphic genetic effects on bone mineral density. Recent discoveries include (i) identification of a new cell type with a unique transcriptome, termed the “osteomorph”. Bone resorbing multinucleated osteoclasts undergo cycles of cell fission and fusion, recycling via osteomorphs in the bone marrow to regulate osteoclast motility and dynamic bone remodelling in vivo, (ii) elucidation of a transcriptome map of genes expressed in osteocytes, the master regulatory cells in bone. Osteocyte signature genes correlate closely with loci identified in human GWAS and in the nosology of monogenic skeletal disorders, establishing the cellular pathogenesis of various skeletal diseases, and (iii) development of novel imaging methods in osteoarthritis disease models and generation of the first multi ‘omic molecular QTL map of human disease to accelerate causative gene discovery in osteoarthritis. This multidisciplinary and international approach is transformative and has resulted in a comprehensive atlas of human and murine genetic influences on bone and joint disease that offer novel insights into the pathophysiology of osteoporosis and osteoarthritis with exciting opportunities for biomarker discovery and drug development. This body of work has resulted in invitations to contribute seminal chapters in major international textbooks, including (i) Genetics of Bone Biology and Skeletal Disease (2018) and (ii) Osteoporosis (2020), and Plenary Lectures to the (i) 21st World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (IOFESCEO WCO), (ii) ASBMR Bone Turnover Markers Annual Meeting, and (iii) 9th Congress of the Romanian Society of Osteoporosis and Musculoskeletal Diseases (all in 2021). My work was recognised by the European Calcified Tissue Society Steven Boonen Clinical Research Award (2018), and I was elected Fellow of the Academy of Medical Sciences (2019), Member of Academia Europaea (2021) and Fellow of the Association of Physicians of Great Britain & Ireland (2021). Open Access

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Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.

SummaryGenome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project (H2P2): a catalog of cellular GWAS comprised of 79 phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance (p−8) for phenotypes ranging from pathogen replication to cytokine production. Combining H2P2 with clinical association data from the eMERGE Network and experimental validation revealed evidence for mechanisms of action and connections with diseases. We identified a SNP near CXCL10 as a cis-cytokine-QTL and a new risk factor for inflammatory bowel disease. A SNP in ZBTB20 demonstrated pleiotropy, partially mediated through NFκB signaling, and was associated with viral hepatitis. Data are available in an H2P2 web portal to facilitate further interpreting human genome variation through the lens of cell biology.

Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes.

As we write this concluding commentary, Europe is on the edge of a deepening recession as Greece and now Italy are dealing with serious fiscal deficits which threaten the Eurozone monetary system and beyond. The age of the austerity is now a widespread reality fuelling greater levels of impoverishment, social anxiety and protests across Europe as austerity measures start to bite. The hope among many politicians is that these difficult times will be short term and will ultimately lead to greater European integration creating a better fiscal footing for the future. However, swingeing cuts in public services inevitably affect disadvantaged groups and create more poverty among the most vulnerable of families and communities. In every society across Europe ethnic minorities, asylum seekers and refugees are amongst the most vulnerable to the impacts of these austere times. At the same time as the downward pressure from governments increases so resentments build within civil society toward incomers or those perceived as ‘other’ or ‘outsiders’ and manifests itself in various forms of hostility including Islamaphobia, the resurgence of racist nationalism, and the demand for increasingly restrictive policies of immigration control, detainment, expulsion and exclusion of migrants. The link between downturns in the economy, immigration control and prejudicial attitudes towards migrants has long been documented (Zick et al 2008). Lean times bring resentments and divisions in their wake. Across Europe the discourse of difference and diversity is infused with hostility, fear and contradictory imperatives that delimit the rights of minority ethnic populations and fuel moral panics (Castles et al 2006). As a consequence of Europe’s ambivalence towards its minorities, policy responses havelacked coherence and consistency and there remains a big gap between stated aspirations and implementation. Whilst racial and ethnic equality and social integration is firmly on the agenda of the European Commission as embodied in its two Race Equality Directives (200/43/EC and 2000/87/EC) there is little consensus or shared vision among member states in taking policy forward. Degrees of differentiation of legislation and policy between member states necessarily reflect particular historical trajectories, social and political contexts. Yet the actions of government too often fail to address these patterns of historical, structural, systemic, institutional and indirect racial discrimination generated by the particular European experiences of colonialism and (im)migration’ and posit manifestations of racism as the result of random individual aberrations (Grigolo et al 2011:1636). In the absence of an even commitment to race equality and anti-discrimination legislation the rights of minorities are easily undermined or withheld and pan national agreements that serve to exacerbate the exclusion of minorities hold sway. We are mindful, of course that in this discussion we construct a particular sense of Europe which is in reality hugely diverse: diverse in its political cultures, traditions and framework for service delivery and legal conceptions regulating citizenship. Social work itself is also a very diverse body of activity inthese contexts reflecting different disciplinary traditions, status and practice orientations. Hence, Lorenz (2006) uses the term ‘social professions’ to encompass the broad range and diversity of professional practice across Europe. There is no room therefore for the imposition of standardized formulas of response; the search is more for the establishment of principles, value commitments and bedrock rights. The forthcoming decades are clearly going to present critical challenges in terms of raceand ethnic relations, not solely relating to issues of integration and cohesion but crucially in responding to the incontrovertible fact that race and ethnicity determine life chances. Whilst poverty ravages through families casting the long shadow of disadvantage forward from childhood into adult lives and discriminations continue to deny hard fought rights the bedrock interplay between social inequality and particular ethnicities demands critical exploration. The stain of such inequality is increasingly apparent in all European societies and will be difficult to ignore as it impinges on the comforts of majorities. It is worth reiterating Wilkinson and Pickett’s (2010) dictum that more unequal societies are more socially damaged societies characterised as a whole by higher rates of distress and lower levels of life expectancy, educational attainment, social mobility and, of course, trust. Societies across Europe are characterized by growing diversity and large scale migrationsand mobilities. Issues facing settled minorities, new migrants, undocumented migrants (the rightless), asylum seekers, refugees and the seam of migrants who don’t want to settle or become citizens will demand ongoing policy attention and practical responses. This trend will continue and the disruptions such movement brings will continue to challenge and make demands of welfare professionals. This is no longer simply ‘an encounter’ but more an ongoing relationship in which social work occupy a critical role. Social work cannot afford to define its engagement with these issues simply in terms of concentrating on the migrant and their cultural differences but must be cognizant of the wider exclusionary processes that impact on these peoples as service users. Lorenz (1998, 2006) has insightfully pointed to the tensions inherent social work’s positioning – a situation in which social work can be both implicated in a process of ‘ethnification of social relations’ – reifying and essentialising ethnic groups on the one hand through their focus on migrant attributes and ‘a retreat to a project of uncritical support for the nation state on the other, which could mean supporting a unified Europe characterized by a ‘fortress mentality’ (1998:263). In this vein we would argue that this demands a social work characterized by the ability to imbue both personal and political factors into its methodologies and approaches to practice and able to assert a confident critical autonomy. A synthesis of analysis at micro and macro level is required that contributes to the development of a critical social policy stance. Migrants and minorities are not passive in this relationship. Their movements carve outpatterns of self-help, collective action and protest and increasingly the framework of governance in many societies has enabled new forms of participation and representation. Pressures are exerted on the profession as a result of these bottom-up demands as well as top-down. It is notable however that the ability of minority groupings themselves to mobilise for self-support has been severely undermined in the current political context. Civil society is not only being squeezed by lack of funding and overburdened by public service retrenchment but such community groups and collectivities have themselves become a focus for suspicion and fear as the ‘war on terror’ proceeds inexorably, and becomes a self-reinforcing and politically legitimized trajectory. As these vital resources of support for minority individuals and communities are undermined so, in counterproductive ways, the pressure on public service professionals increases. Lorenz has argued that ‘the migrant is the paradigmatic test case for social work’ (1998:259). The positioning of migrants in any society reflects back onthat society its claims to be well ordered, rational, enlightened and modern and raises a question over the role of social work in negotiating rightful and respectful conditions for minorities as part of the ‘civilising’ project.

A venturi receives incoming material through an inlet tube and subjects the material to pulverization. The material, as it undergoes pulverization, is further subject to moisture extraction and drying. An airflow generator, coupled to the venturi, generates a high speed airflow to pull the material through the venturi and into an inlet aperture in the airflow generator. The airflow generator directs the received pulverized material to an outlet where the material may be subsequently separated from the air.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.

Funder: Medical Research Council Centre for Integrated Research into Musculoskeletal Ageing grant (148985), Funder: Versus Arthritis; Tissue Engineering and Regenerative Therapies Centre (21156), Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.

Funder: Medical Research Council Centre for Integrated Research into Musculoskeletal Ageing grant (148985), Funder: Versus Arthritis; Tissue Engineering and Regenerative Therapies Centre (21156), Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis., Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

Osteoporosis is a disease of low bone mineral density (BMD) and altered bone architecture leading to an increased risk of fracture. Worldwide, osteoporosis affects millions of people and causes an enormous and increasing healthcare burden. Reduced BMD is the major risk factor for fracture and is a highly heritable trait. Genome wide association studies (GWAS) have identifed the 9q34.11 locus containing Far Upstream Binding Protein 3 (FUBP3) as associated with BMD, fracture and height. FUBP3 is a DNA and RNA binding protein and transcriptional regulator of c-myc, but has no previously confrmed role in the skeleton. I hypothesised that FUBP3 is the causative gene underlying the association with BMD, fracture and height at the 9q34.11 locus and that FUBP3 is needed for normal bone development and maintenance. To test this hypothesis, I used bioinformatic tools to interrogate the 9q34.11 locus and prioritise FUBP3 for further study and studied the skeletal phenotype of an FUBP3 deficient mouse. Skeletal assessment included analysis of growth, bone mineral content and bone structure, strength, and cellular parameters. Analysis of the 9q34.11 locus confirmed that FUBP3 was the most likely causal gene underlying the association with BMD and was expressed in bone. Compared to wild type mice, FUBP3 defcient mice were short and demonstrated reduced bone mineral content, altered trabecular bone parameters and reduced strength, suggesting an important role of FUBP3 in both development and adult bone maintenance. Finally, I investigated the cellular phenotype underlying the skeletal changes seen with FUBP3 loss. These did not demonstrate a deficit in osteoblastic bone formation or osteoclastic bone resorption with FUBP3 deficiency. Nevertheless, the data presented in this thesis provide the first demonstration of a functional role of FUBP3 in the skeleton and confirm FUBP3 as the most likely causal gene at the 9q34.11 BMD, height and fracture GWAS locus. Open Access

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

In 2015 the United Nations proposed the Sustainable Development Goals (SDGs), a set of universal goals for meeting the urgent environmental, political and economic challenges in the world. Universities play an important role to support and contribute to the SDGs mainly through education and research. To evaluate the contributions through research, universities aim at relating their scientific publications to SDGs, and automatically quantify the connectedness of these publications to the detailed targets and the unique indicators under SDGs. In this paper, we apply deep learning techniques to estimate the unknown indicators (third level) and targets (second level) for each publication, and output all its possible goals (first level). Specifically, we first exploit the dependency of categories at different levels (goals, targets, and indicators) to extract the dependent label features. Then we calculate the degree of matching between categories and publications in a bottom-up way and design a hierarchical structure to transfer such matching information level by level until obtaining the predicted SDGs of the publications. This is the first application of a deep learning method on this SDG prediction task and our experiments clearly demonstrate the good performance of our model on this real-world SDGs matching task, the extraction of key information as well as the prediction of potential sub-categories. As auxiliary analysis, we visualize the extraction of key semantic information and the probability of the hierarchical SDG categories.

The difficulty to validate clustering reliability hinders the adoption of clustering in real-life applications. We propose: (a) a set of symbolic representations to interpret problem spaces and (b) the CluReAL algorithm to refine any clustering result regardless of the used technique. Both approaches are grounded by recently published absolute cluster validity indices. Conducted experiments show how the refinement algorithm improves performances in a wide variety of scenarios and builds more interpretable solutions, whereas symbolic representations are shown to offer explainable summaries of problem contexts. Refinement and interpretability are both crucial to reduce failure and increase performance control and operational awareness in processes that depend on clustering.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease., Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.

Osteoarthritis (OA) is a debilitating joint disease characterised by articular cartilage damage, chondrocyte hypertrophy and subchondral bone changes. Thyroid hormone (TH) regulates chondrocyte differentiation, endochondral ossification and bone maintenance, acting mainly through thyroid hormone receptor alpha (TRα). Genetic, pathological and experimental data have implicated a role for TH availability in OA pathogenesis. I hypothesised that inhibition of TH signalling will decrease susceptibility to OA and delay disease progression. Osteoarthritis was assessed in mice treated with dronedarone (a TRα antagonist), TRα knockouts (TRα0/0) or wild type controls 4, 8 and 16 weeks after joint destabilisation surgery (DMM). Overall, articular cartilage damage was not reduced in either mutant or dronedarone treated mice but the studies were underpowered. Subchondral bone mineral content (BMC) in sham operated knees was increased in mutants but reduced with dronedarone treatment. Destabilising surgery increased subchondral BMC and mass but changes were attenuated in mutant and dronedarone treated mice. Mutant mice lacking iodothyronine deiodinase type 2 (D2KO) that are unable to activate thyroid hormone locally were investigated for OA development with ageing. Mutants had no change in cartilage damage but had increased subchondral BMC. TRα was further investigated as an osteoporosis drug target. Significantly, dronedarone increased femoral cortical thickness and BMC but did not affect bone strength. These results suggest a regulatory role for TH in subchondral bone remodelling. The absence of chondroprotection suggest that any potential role of TH in osteoarthritis pathogenesis may be mediated via subchondral bone. Further adequately powered studies with dronedarone are needed to confirm cartilage and bone observations and should include mechanistic studies to explain subchondral bone changes. Further experiments using established models of osteoporosis and more sensitive measures of bone strength should be used to confirm TRα as a novel drug target for osteoporosis. Open Access

Osteoporosis is characterised by low bone mass, reduced bone mineral density and a deterioration of bone microarchitecture, resulting in increased susceptibility to fragility fractures. Oestrogen deficiency and thyrotoxicosis are established risk factors for osteoporosis. Oestrogen and thyroid hormone have opposing actions on adult bone and I hypothesise that accelerated bone loss at the menopause is due to unopposed actions of thyroid hormone on the skeleton. To test this hypothesis, I investigated the effect of altered thyroid status on the skeleton in adult sham-operated and ovariectomised wild type and thyroid hormone receptor (TR) α and β knockout mice (TRα0/0 and TRβ-/-). Skeletal phenotype analysis included determination of structural, densitometric, histomorphometric and biomechanical parameters. Skeletal phenotypes of euthyroid wild type mice were compared to hypothyroid and thyrotoxic wild type as well as TRα0/0and TRβ-/- mice. Bone mass was elevated in TRα0/0and reduced in TRβ-/- mice despite similar bone formation rates. These data suggest that the differences in bone mass are due to differing osteoclast activity. The skeletal phenotypes of TRα0/0 and TRβ-/- mice following manipulation of thyroid status were then described in detail. TRβ-/- and wild type mice rendered hypothyroid, had significantly lower bone formation than hypothyroid TRα0/0 mice suggesting that, in the absence of thyroid hormone, TRα may inhibit bone formation. Finally, the effect of oestrogen withdrawal in each of these groups of mice was also investigated. These studies demonstrate oestrogen deficiency bone loss was greater in hypothyroid compared to hyperthyroid mice, indicating that accelerated bone loss following oestrogen withdrawal cannot result from unopposed actions of thyroid hormones. Nevertheless, the studies contained in this thesis provide new insight regarding the roles of TRα and TRβ in bone maintenance and the effects of interactions between oestrogen and thyroid hormones on the regulation of bone mass. Open Access

In various real-world applications, it is very useful mining unanticipated episodes where certain event patterns unexpectedly lead to outcomes, e.g., taking two medicines together sometimes causing an adverse reaction. These unanticipated episodes are usually unexpected and infrequent, which makes existing data mining techniques, mainly designed to find frequent patterns, ineffective. In this paper, we propose unexpected temporal association rules (UTARs) to describe them. To handle the unexpectedness, we introduce a new interestingness measure, residual-leverage, and develop a novel case-based exclusion technique for its calculation. Combining it with an event-oriented data preparation technique to handle the infrequency, we develop a new algorithm MUTARC to find pairwise UTARs. The MUTARC is applied to generate adverse drug reaction (ADR) signals from real-world healthcare administrative databases. It reliably shortlists not only six known ADRs, but also another ADR, flucloxacillin possibly causing hepatitis, which our algorithm designers and experiment runners have not known before the experiments. The MUTARC performs much more effectively than existing techniques. This paper clearly illustrates the great potential along the new direction of ADR signal generation from healthcare administrative databases.