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Generation of cartilage from induced pluripotent stem cells: gene pathways and small molecules
No full textInduced pluripotent stem cells (iPSCs) are a promising cell source for regenerative medicine including the treatment of articular cartilage defects and osteoarthritis (OA). There is currently an unmet clinical need for cell-based therapies and pharmacological treatments for OA and cartilage repair. Somatic cells are reprogrammed to iPSCs by the delivery of reprogramming transcription factors. Genome integrating transgenes increase the risk of tumorigenicity, therefore integration-free reprogramming approaches are preferred. iPSCs are commonly used for modelling specific diseases, and can be utilised in screening platforms for disease modifying drugs. The potential of iPSCs for clinical therapies is being explored, and their capacity for cartilage repair has been demonstrated in animal models in vivo. The primary focus is to generate iPSC derived articular cartilage for clinical applications. Numerous approaches to derive cartilage from iPSCs have been described with different levels of success. These include directed differentiation methods that recapitulate developmental signalling cues in vitro, indirect approaches such as embryoid body (EB) outgrowth and one-step media changes, or coculturing with articular chondrocytes (ACs). In general, iPSCs are induced to chondroprogenitor (iCP) or mesenchymal stromal cell (iMSC) intermediates that can generate cartilage tissue. A number of challenges associated with iPSC differentiation include cell heterogeneity, loss of chondrogenic potential during passaging, and the presence of hypertrophic and fibrous cartilage tissue. Furthermore iPSCs have variable induction efficiencies and differentiation propensities. iPSCs reprogrammed by episomal vectors were characterised and found to have unstable karyotypes by chromosomal microarray analysis. The differentiation efficiency of iPSCs toward chondrocytic and mesenchymal cells was assessed, following directed differentiation through a paraxial mesoderm or neural crest lineage. Two iPSC lines were found to have good induction efficiencies and chondrogenic propensities. Transcriptomic datasets were explored with Qiagen’s Ingenuity Pathway Analysis (IPA) causal networks analysis tool, to predict potential regulators of chondrogenesis. Molecules of interest were investigated by gene expression analysis in two BM-MSC lines with strong and weak chondrogenic propensities, during the first three days of chondrogenesis. USP18, SEMA4C, RCAN1, TEAD4, and FIBIN may have a role in early chondrogenic differentiation and require further investigation. A small molecule screening assay was developed using an automated liquid handling system, to screen for molecules enhancing the production of glycosaminoglycans (GAGs) in iPSC derived cells and BM-MSCs. Forskolin, sesamin, and baicalin enhanced GAG synthesis in iPSC derived cells, while no small molecules enhanced GAG synthesis in BM-MSCs any further than TGFb3 alone.2026-05-0
Advancing kidney stone management: A technical and commercial review of intraoperative medical device
No full textThe prevalence of kidney stones is increasing due to poor diet, hydration, and potentially rising global temperatures from climate change. Concurrently, the number of urologists is declining, necessitating innovative solutions to meet growing demand and reduce the risk of burnout among urologists.
The intraoperative treatment of kidney stones, particularly ureteroscopy, has seen limited innovation, and existing devices do not ensure complete extraction of kidney stone dust or fragments post-lithotripsy. Incomplete removal of kidney stones heightens the risk of recurrence, requiring additional treatment. Enhancing the "stone free rate" is critical, as higher stone free rates are linked to better patient outcomes. However, the definition of stone free rate remains inconsistent among urologists and researchers.
Recent advancements in the aspiration of kidney stone dust and alternative lithotripsy methods indicate a strong interest in improving procedures, yet these innovations fail to achieve complete dust and fragment removal.
Additionally, longer procedure times are associated with a higher risk of urosepsis, a significant mortality risk for what is typically an elective procedure. Research observations indicate that much of the time in ureteroscopy is spent "fishing" for fragments post-lithotripsy.
A method that fully removes all stone dust and fragments could standardize treatment and reduce inconsistencies. Improving the efficiency and effectiveness of stone removal is expected to enhance patient outcomes and throughput. Further research is necessary to validate the hypothesis that easier and complete removal of stones post-lithotripsy will improve patient outcomes and reduce procedure time, thereby increasing the number of patients treated by a declining number of urologists.
This study comparatively assesses design concepts for such a method to meet the defined criteria of an ideal solution, completes an initial assessment of intellectual property, and outlines a proposal for the pathway to implementation.
There is a substantial market for improved kidney stone treatment, yet little evidence suggests existing intellectual property for a device capable of fully addressing this need. Therefore, there is opportunity for innovation to prevent the dispersal of kidney stones for total extraction during ureteroscopy to improve stone free rate
Using spatial light modulators to investigate the limitations of adaptive optics performance for the European Extremely Large Telescope
No full textThe European Extremely Large Telescope (E-ELT) will be the world’s largest ground based optical / near-infrared telescope ever built. Its primary mirror, M1, will be 39 m in diameter and consist of 798 individual hexagonal segments, each with a diam eter of 1.2 m. The telescope will host various cutting-edge instruments, including a Multi-Conjugate Adaptive Optics (MCAO) instrument, spectrographs, and imagers, all of which are being built alongside the telescope, with some of them planned to be operational for first light. In particular, the Multiconjugate adaptive Optics Relay For ELT Observations (MORFEO) instrument is planned to be one of the first instruments installed, along with the High Angular Resolution Monolithic Optical and Near-infrared Integral field spectrograph (HARMONI), Multi-AO Imaging Camera for Deep Observations (MICADO), and Mid-infrared ELT Imager and Spectrograph (METIS) instruments. This means that MORFEO needs to be calibrated and tested before integration into the ELT infrastructure. For this, the Calibration / Test Unit (CU/TU) is being developed as a method to ensure MORFEO is working as expected before installation. The CU/TU will be required to provide six Laser Guide Star (LGS), three Natural Guide Star (NGS), science sources, emulated turbulence and dynamic aberrations, as well as wavefront correction which emulates the functionality of the M4 mirror, and the segmentation effects of the M1 mirror. This thesis is focused on the Spatial Light Modulator (SLM), a device which consists of an array of Liquid Crystal (LC) pixels which have a controllable index of refraction. This allows for the spatial modification of the phase of any wavefront that passes through the liquid crystals. Here, their ability to emulate atmospheric turbulence and segmented mirrors will be tested, with the intention of using them in a calibration unit for an Adaptive Optics (AO) system. Specifically, this work will use off-the-shelf SLMs for the emulation of atmospheric turbulence with different Fried parameters, and for the emulation of segmented mirrors with different numbers of segments and phase discontinuities. This will test whether they can; i) reproduce the sharp discontinuities one would expect by using small segmented mirrors, and; ii) have these edges detected by a pyramid wavefront sensor and use the measurements to produce a calibration curve which can be used to estimate the phase discontinuity across a misaligned edge. Additionally, the devices will be used to emulate a digital, reconfigurable pyramid wavefront sensor as an alternative method to sensing phase discontinuities. The output of this research will be to determine whether these easily available SLMs could be used to accurately test and calibrate an adaptive optic system, and whether the specific requirements of the MORFEO system could be met by them
Exploring advanced methodologies for the generation of synthetic data
No full textIn the field of computer vision and machine learning the need for high-quality diverse data sets are crucial. However, acquiring such data sets with detailed ground truth can be challenging. This problem led to the increased attention towards synthetic data generation as a cost-effective and scalable solution. This research introduces a novel pipeline to generate synthetic data sets, lever aging both open-source and commercially available software. This approach democ ratizes synthetic data creation which often restricted to large organizations with extensive resources. The pipeline employs an innovative use of OpenPose, a tool for estimating facial landmarks, to fit an animatable mesh to each 3D scan. By refining and filtering OpenPose predictions, the accuracy of mesh fitting is significantly improved, leading to the generation of more diverse synthetic data. Further, we use a custom rendering pipeline built on Blender, an open-source 3D creation suite, to simulate intricate lighting scenarios improving the realism of the synthetic data. The data set is rich with variations in expressions, lighting, eye gaze, and head pose orientations that mirrors the complexities of real-world situations. Alongside synthetic facial images our pipeline generates a wealth of metadata such as bounding boxes, expression/action values as well as eye gaze and head pose values. This accurately labeled metadata serves as a rich source of ground truth data, extending the utility of our data set to various computer vision and image analysis tasks
Assessment of measuring and monitoring safety in healthcare in Ireland and Saudi Arabia
No full textIn the past two decades, governments worldwide have prioritised the improvement of health care quality and safety as a primary policy goal. However, progress towards achieving this goal has been limited. The provision of poor care and the prevalence of high levels of harm persist in hospitals. Measurement is considered a crucial and essential initial step in the process of improving patient safety. However, while measuring and monitoring patient safety is widely recognised, there is a lack of agreement on how to achieve it. In this thesis, a multi-method approach was taken to address the dimensions in the Measuring and Monitoring Safety (MMS) framework developed by Vincent et al. to provide a structure for understanding how safety is measured and monitored in hospitals in Ireland and Saudi Arabia. Study 1 is a scoping review of patient safety research carried out in the Republic of Ireland (RoI). It examines the extent, range, and nature of patient safety research activities carried out in the RoI; makes recommendations for future research; and considers how these recommendations align with the Health Service Executive’s (HSE) patient safety strategy. Study 2 considers how safety is measured and monitored in Irish hospitals and offers recommendations for how it can be improved. Study 3 is a scoping review that maps the quantity and nature of current patient safety research in Saudi Arabian hospitals, as well as identifies gaps in the existing literature. Finally, study 4 assesses the Saudi Arabian healthcare safety surveillance system in hospitals using the MMS framework. The findings from the four studies conducted in this thesis demonstrate the availability of an adequate amount of safety data, the availability of diverse methods for collecting safety data, and the expertise necessary to improve safety. The challenge is to identify the most efficient methods for generating key and high-quality data that can help multidisciplinary teams in developing effective interventions tailored to specific health contexts
Essays on estimating effects of star arrival in small open economies: An event-study analysis
No full textAs the economy’s growth becomes more dependent on innovation, science policy is increasing in importance as an instrument for shaping the direction and impact of science on economic development, especially in small open economies. Policymakers in small open economies have shown increased interest in various science policies to stimulate the development of national innovation systems. A potentially attractive strategy in the science-policy mix is the targeted recruitment of star scientists designed to catalyse the development of research clusters in targeted research areas. However, there is little evidence on how stars impact the productivity of their peers in small open economies. In this context, the objective of the thesis is to provide an evidence-based evaluation of the impact of star scientists on their peers. It addresses five specific goals aligned with the objective in five separate empirical and methodological papers. A better understanding of the knowledge spillovers from the star can support the development of star recruitment policies intended to recruit stars and integrate them into local networks to catalyse productivity. Thus, the first paper of this thesis focuses on the co-authorship channel, examining how forming a co-authorship relationship with a co-located star affects the productivity of the co-author, both including and excluding star co-authored output. The latter effect provides a measure of the extent to which star collaborations crowd out/in other output. The analysis is conducted on a matched sample for treated and control authors obtained using coarsened exact matching. An event-study model is employed on the matched sample to estimate the dynamic effect of the star co-authorship on quality-adjusted productivity. In addition, I explore the heterogeneity by period, field, and whether the authors have multiple star co-authorships. While the first study offers valuable insights into the co-authorship relationship with the star, the second paper investigates the dynamic effects of star arrival on the arriving department. It is hoped that the arriving star can positively impact department productivity through channels such as access to better training and knowledge, changing norms relating to research, and even creating collaboration opportunities. An event-study model estimates the dynamic effects of a star arrival on quality-adjusted research output at both the department and matched individual incumbent levels. The matched individual-level sample allows us to make more credible causal inferences about the star arrival effect. To help further understand star impacts on peers, the third paper examines how relatedness to the arriving star modifies the size of the productivity effect on co-located peers. The paper assumes a non-linear relationship between the level of relatedness and the productivity effect, given that higher relatedness, on the one hand, can increase absorptive capacity and, on the other hand, aggravate potential knowledge redundancy. A difference-in-difference model is utilised to estimate the treatment effects for different intensities of treatment, where the intensity is proxied by the relatedness measure. In addition, an event-study model is employed to provide evidence of a causal effect on incumbent productivity from star arrivals, where I use coarsened exact matching to identify a control for each treated incumbent. The previous three papers provide an evidence-based evaluation of star impact using difference-in-difference and event-study research designs. In addition, difference-in differences and event-study research designs are one of the most common methods to estimate treatment effects in the economics of science literature. However, recent developments in the literature on difference-in-differences and event-study models have raised important concerns that when effects are heterogeneous and treatment is staggered, the two-way fixed effects (TWFE) difference-in-differences/event-studies regression can provide biased estimates. Thus, policy formed based on studies using these biased approaches may not be effective. To this end, the fourth paper (a methodological paper) addresses this concern by exploring the relative performance of five alternative estimators with the TWFE estimator for estimating treatment effects on binary and count outcomes within a simulation exercise. Following this, the fifth paper (a replication paper) implements the alternative estimators on a prior published study and compares the results with the original study, highlighting the need for policymakers to pay particular attention to research design before drawing strong policy-related conclusions. The fourth and fifth paper indirectly affects evidence-based policymaking and addresses the broad objective of the thesis. The thesis is a novel contribution to the Irish and international economics of science empirical and policy literature, given the paucity of information currently available on the impact of star scientists in small open economies. This thesis has significant implications for policymakers and institutions designing recruitment strategies and post-arrival support. I hope the results of the five studies undertaken for the thesis will be particularly useful for policymakers and funding agencies in Ireland and other small open economies to form evidence-based star recruitment policies
An stócach nach raibh eagla ar bith air
No full textBhí athair ann tráth a raibh beirt mhac aige. Boc cliste, éirimiúil ba ea an mac ba shine agus bhí guaim aige air féin. Ach amadán dallintinneach a bhí sa mhac ab óige agus cha raibh sé in ann aon rud a fhoghlaim ná a thuiscint. Bhí sé chomh bómánta sin gur ghnách le daoine a rá go mbeadh sé ina ualach ar a athair! Am ar bith a bhíodh rud inteacht le déanamh, an mac ba shine a dhéanadh é; ach dá mbíodh rud inteacht le déanamh nuair a bhíodh sé dorcha amuigh, agus dá mbíodh ar an duine dul fríd an reilig nó fríd áit éigin scanrúil, taibhsiúil dá leithéid leis an rud sin a dhéanamh, an freagra a bhíodh ag an mhac ba shine i dtólamh ná: “Dar fia a Athair, cha dtabharfaidh rud ar bith orm dul ansin, cuireann sé cradhscal orm!” Bhí eagla a chroí ar an mhac ba shine. In amantaí nuair a shuíodh siad uilig cois tine san oíche ag insint scéalta uafáis dá chéile, deireadh na daoine a bhí ag éisteacht a leithéidí, “Arú, cuireann na scéalta sin eagla orm!” Chuala an mac ab óige seo agus é suite sa choirnéal ach char thuig sé a raibh i gceist acu. “Bíonn siad ag rá i dtólamh, ‘Cuireann sé eagla orm! Cuireann sé eagla orm!’ Ach cha gcuireann rud ar bith eagla ormsa. Is dócha go bhfuil sé thar m’acmhainne.”peer-reviewe
An integrated connectivity risk ranking for phosphorus and nitrogen along agricultural open ditches to inform targeted and specific mitigation management
No full textOn dairy farms with poorly drained soils and high rainfall, open ditches receive nutrients from different sources along different pathways which are delivered to surface water. Recently, open ditches were ranked in terms of their hydrologic connectivity phosphorus (P) along the open ditch network. However, the connectivity risk for nitrogen (N) was not considered in that analysis, and remains a knowledge gap. In addition, the P connectivity classification system assumes all source-pathway interactions within open ditches are active, but this may not be the case for N. The objective of the current study, conducted across seven dairy farms, was to create an integrated connectivity risk ranking for P and N simultaneously, to better inform where and which potential mitigation management strategies could be considered. First, a conceptual figure of known N open ditch source-pathway connections, developed using both the literature and observations in the field, was used to identify water grab sampling locations on the farms. During field work, all open ditch networks were digitally mapped, divided into ditch sections, and classified in terms of the existing P connectivity classification system. Sampling was conducted during the hydrologically-active period to ensure maximum connectivity of source-pathways and open ditches. The results from these water samples enabled a qualitative validation of N source-pathway presence or absence for each ditch category. The results showed that not all source-pathways were present across ditch categories for all species of N. This information was used to develop an improved open ditch connectivity classification system. Results showed that farmyard connection ditches were the riskiest for potential point source losses and outlet ditches had the highest connectivity risk among the other ditches associated with diffuse sources. Tailored mitigation options for P and N speciation were identified for these locations to intercept nutrients before reaching receiving waters. Furthermore, in ditches associated with diffuse sources, nitrate was introduced by subsurface sources (i.e., in-field drains and groundwater interactions from springs seepage and upwelling) and ammonium was introduced through surface connectivity pathways (i.e., runoff from internal roadways). In-field drains dominated connectivity pathways in open ditches. On dairy farms where open ditches are prevalent, the integrated classification system and mapping procedure presented herein will enable a targeted and nutrient-specific mitigation plan to be developed.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The authors are grateful to Teagasc for the award of a Walsh Scholarship to the first author (grant number: RMIS-1381) to conduct this research.peer-reviewe
