Search

Elif Iliria Emin,1 Ece Emin,2 Alexios Bimpis,3 Michael Pierides,4 Aikaterini Dedeilia,5 Zibad Javed,6 Kathrine-Sofia Rallis,6 Ferha Saeed,6 Georgios Theophilou,7 Apostolos Karkanevatos,8 Dilek Kitapcioglu,9 Mehmet Emin Aksoy,9 Apostolos Papalois,10 Michail Sideris6 1Department of Acute Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 2EGA Institute for Women’s Health, University College London, London, UK; 3Department of Neurosurgery, Tzaneio General Hospital, Piraeus, Greece; 4Department of Acute Medicine, Kettering General Hospital NHS Trust, Northamptonshire, UK; 5School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 6Faculty of Medicine and Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 7Department of Gynaecological Oncology, St James Institute of Oncology, Leeds, UK; 8Department of ENT Surgery, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK; 9Center of Advanced Simulation and Education, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; 10Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, GreeceCorrespondence: Michail Sideris, Faculty of Medicine and Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary university of London, London, UK, Email m.sideris@qmul.ac.ukAbstract: Although considerable efforts have been made to incorporate simulation-based learning (SBL) in undergraduate medical education, to date, most of the medical school curricula still focus on pure knowledge or individual assessment of objective structured clinical examination skills (OSCE). To this end, we designed a case study named “iG4 (integrated generation 4) virtual on-call (iVOC)”. We aimed to simulate an on-call shift in a high-fidelity virtual hospital setting in order to assess delegates’ team-based performance on tas

This article describes some potential uses of Bayesian estimation for time-series and panel data models by incorporating information from prior probabilities (i.e., priors) in addition to observed data. Drawing on econometrics and other literatures we illustrate the use of informative “shrinkage” or “small variance” priors (including so-called “Minnesota priors”) while extending prior work on the general cross-lagged panel model (GCLM). Using a panel dataset of national income and subjective well-being (SWB) we describe three key benefits of these priors. First, they shrink parameter estimates toward zero or toward each other for time-varying parameters, which lends additional support for an income → SWB effect that is not supported with maximum likelihood (ML). This is useful because, second, these priors increase model parsimony and the stability of estimates (keeping them within more reasonable bounds) and thus improve out-of-sample predictions and interpretability, which means estimated effect should also be more trustworthy than under ML. Third, these priors allow estimating otherwise under-identified models under ML, allowing higher-order lagged effects and time-varying parameters that are otherwise impossible to estimate using observed data alone. In conclusion we note some of the responsibilities that come with the use of priors which, departing from typical commentaries on their scientific applications, we describe as involving reflection on how best to apply modeling tools to address matters of worldly concern., Peer Reviewed

This article describes some potential uses of Bayesian estimation for time-series and panel data models by incorporating information from prior probabilities (i.e., priors) in addition to observed data. Drawing on econometrics and other literatures we illustrate the use of informative "shrinkage" or "small variance" priors (including so-called "Minnesota priors") while extending prior work on the general cross-lagged panel model (GCLM). Using a panel dataset of national income and subjective well-being (SWB) we describe three key benefits of these priors. First, they shrink parameter estimates toward zero or toward each other for time-varying parameters, which lends additional support for an income → SWB effect that is not supported with maximum likelihood (ML). This is useful because, second, these priors increase model parsimony and the stability of estimates (keeping them within more reasonable bounds) and thus improve out-of-sample predictions and interpretability, which means estimated effect should also be more trustworthy than under ML. Third, these priors allow estimating otherwise under-identified models under ML, allowing higher-order lagged effects and time-varying parameters that are otherwise impossible to estimate using observed data alone. In conclusion we note some of the responsibilities that come with the use of priors which, departing from typical commentaries on their scientific applications, we describe as involving reflection on how best to apply modeling tools to address matters of worldly concern.

Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol-containing natural products such as cysteine. As such, these enzymes have relevance to the development of Alzheimer's and Parkinson's diseases in the brain. Recent crystal structure coordinates of cysteine and 3-mercaptopropionate dioxygenase (CDO and MDO) showed major differences in the second-coordination spheres of the two enzymes. To understand the difference in activity between these two analogous enzymes, we created large, active-site cluster models. We show that CDO and MDO have different iron(III)-superoxo-bound structures due to differences in ligand coordination. Furthermore, our studies show that the differences in the second-coordination sphere and particularly the position of a positively charged Arg residue results in changes in substrate positioning, mobility and enzymatic turnover. Furthermore, the substrate scope of MDO is explored with cysteinate and 2-mercaptosuccinic acid and their reactivity is predicted.

Paradoxes are historically embedded in institutions and organizations. Latent paradoxes pose danger if they become salient; sociological analyses can identify historically embedded latent paradoxes. The emergency management paradox, in which the state invests vast resources, establishing formidable organizational arrangements that rely on knowledge to respond to unanticipated events in advance of their occurrence, even though such events can only ever be known after they occur, is a paradox of this kind. Deploying methodological ‘dual integrity’ we trace through historical description and sociological conceptualization the institutional and organizational history of the emergency management paradox in Australia, where uncontrollable bushfires are becoming increasingly common, before drawing more general conclusions about how a response to grand challenges, such as climate change, demands an interdisciplinary understanding of the rituals and realities of paradoxes that emerge historically from our collective attempts to handle uncertainty via risk. Our research serves as a warning of the grave consequences that can result from ignoring a paradox’s history, whether intentionally or unwittingly.

Paradoxes are historically embedded in institutions and organizations. Latent paradoxes pose danger if they become salient; sociological analyses can identify historically embedded latent paradoxes. The emergency management paradox, in which the state invests vast resources, establishing formidable organizational arrangements that rely on knowledge to respond to unanticipated events in advance of their occurrence, even though such events can only ever be known after they occur, is a paradox of this kind. Deploying methodological “dual integrity” we trace through historical description and sociological conceptualization the institutional and organizational history of the emergency management paradox in Australia, where uncontrollable bushfires are becoming increasingly common, before drawing more general conclusions about how a response to grand challenges, such as climate change, demands an interdisciplinary understanding of the rituals and realities of paradoxes that emerge historically from our collective attempts to handle uncertainty via risk. Our research serves as a warning of the grave consequences that can result from ignoring a paradox’s history, whether intentionally or unwittingly.

Paradoxes are historically embedded in institutions and organizations. Latent paradoxes pose danger if they become salient; sociological analyses can identify historically embedded latent paradoxes. The emergency management paradox, in which the state invests vast resources, establishing formidable organizational arrangements that rely on knowledge to respond to unanticipated events in advance of their occurrence, even though such events can only ever be known after they occur, is a paradox of this kind. Deploying methodological “dual integrity” we trace through historical description and sociological conceptualization the institutional and organizational history of the emergency management paradox in Australia, where uncontrollable bushfires are becoming increasingly common, before drawing more general conclusions about how a response to grand challenges, such as climate change, demands an interdisciplinary understanding of the rituals and realities of paradoxes that emerge historically from our collective attempts to handle uncertainty via risk. Our research serves as a warning of the grave consequences that can result from ignoring a paradox’s history, whether intentionally or unwittingly.

This article describes some potential uses of Bayesian estimation for time-series and panel data models by incorporating information from prior probabilities (i.e., priors) in addition to observed data. Drawing on econometrics and other literatures we illustrate the use of informative “shrinkage” or “small variance” priors (including so-called “Minnesota priors”) while extending prior work on the general cross-lagged panel model (GCLM). Using a panel dataset of national income and subjective well-being (SWB) we describe three key benefits of these priors. First, they shrink parameter estimates toward zero or toward each other for time-varying parameters, which lends additional support for an income → SWB effect that is not supported with maximum likelihood (ML). This is useful because, second, these priors increase model parsimony and the stability of estimates (keeping them within more reasonable bounds) and thus improve out-of-sample predictions and interpretability, which means estimated effect should also be more trustworthy than under ML. Third, these priors allow estimating otherwise under-identified models under ML, allowing higher-order lagged effects and time-varying parameters that are otherwise impossible to estimate using observed data alone. In conclusion we note some of the responsibilities that come with the use of priors which, departing from typical commentaries on their scientific applications, we describe as involving reflection on how best to apply modeling tools to address matters of worldly concern., Peer Reviewed

This article compares a general cross-lagged model (GCLM) to other panel data methods based on their coherence with a causal logic and pragmatic concerns regarding modeled dynamics and hypothesis testing. We examine three “static” models that do not incorporate temporal dynamics: random- and fixed-effects models that estimate contemporaneous relationships; and latent curve models. We then describe “dynamic” models that incorporate temporal dynamics in the form of lagged effects: cross-lagged models estimated in a structural equation model (SEM) or multilevel model (MLM) framework; Arellano-Bond dynamic panel data methods; and autoregressive latent trajectory models. We describe the implications of overlooking temporal dynamics in static models and show how even popular cross-lagged models fail to control for stable factors over time. We also show that Arellano-Bond and autoregressive latent trajectory models have various shortcomings. By contrasting these approaches, we clarify the benefits and drawbacks of common methods for modeling panel data, including the GCLM approach we propose. We conclude with a discussion of issues regarding causal inference, including difficulties in separating different types of time-invariant and time-varying effects over time., Australian Research Council https://doi.org/10.13039/501100000923, Peer Reviewed

This is the first paper in a series of two that synthesizes, compares, and extends methods for causal inference with longitudinal panel data in a structural equation modeling (SEM) framework. Starting with a cross-lagged approach, this paper builds a general cross-lagged panel model (GCLM) with parameters to account for stable factors while increasing the range of dynamic processes that can be modeled. We illustrate the GCLM by examining the relationship between national income and subjective well-being (SWB), showing how to examine hypotheses about short-run (via Granger-Sims tests) versus long-run effects (via impulse responses). When controlling for stable factors, we find no short-run or long-run effects among these variables, showing national SWB to be relatively stable, whereas income is less so. Our second paper addresses the differences between the GCLM and other methods. Online Supplementary Materials offer an Excel file automating GCLM input for Mplus (with an example also for Lavaan in R) and analyses using additional data sets and all program input/output. We also offer an introductory GCLM presentation at https://youtu.be/tHnnaRNPbXs. We conclude with a discussion of issues surrounding causal inference., Australian Research Council https://doi.org/10.13039/501100000923, Peer Reviewed

This is the first paper in a series of two that synthesizes, compares, and extends methods for causal inference with longitudinal panel data in a structural equation modeling (SEM) framework. Starting with a cross-lagged approach, this paper builds a general cross-lagged panel model (GCLM) with parameters to account for stable factors while increasing the range of dynamic processes that can be modeled. We illustrate the GCLM by examining the relationship between national income and subjective well-being (SWB), showing how to examine hypotheses about short-run (via Granger-Sims tests) versus long-run effects (via impulse responses). When controlling for stable factors, we find no short-run or long-run effects among these variables, showing national SWB to be relatively stable, whereas income is less so. Our second paper addresses the differences between the GCLM and other methods. Online Supplementary Materials offer an Excel file automating GCLM input for Mplus (with an example also for Lavaan in R) and analyses using additional data sets and all program input/output. We also offer an introductory GCLM presentation at https://youtu.be/tHnnaRNPbXs. We conclude with a discussion of issues surrounding causal inference.

Quantitative researchers often discuss research ethics as if specific ethical problems can be reduced to abstract normative logics (e.g., virtue ethics, utilitarianism, deontology). Such approaches overlook how values are embedded in every aspect of quantitative methods, including ‘observations,’ ‘facts,’ and notions of ‘objectivity.’ We describe how quantitative research practices, concepts, discourses, and their objects/subjects of study have always been value-laden, from the invention of statistics and probability in the 1600s to their subsequent adoption as a logic made to appear as if it exists prior to, and separate from, ethics and values. This logic, which was embraced in the Academy of Management from the 1960s, casts management researchers as ethical agents who ought to know about a reality conceptualized as naturally existing in the image of statistics and probability (replete with ‘constructs’), while overlooking that S&P logic and practices, which researchers made for themselves, have an appreciable role in making the world appear this way. We introduce a different way to conceptualize reality and ethics, wherein the process of scientific inquiry itself requires an examination of its own practices and commitments. Instead of resorting to decontextualized notions of ‘rigor’ and its ‘best practices,’ quantitative researchers can adopt more purposeful ways to reason about the ethics and relevance of their methods and their science. We end by considering implications for addressing ‘post truth’ and ‘alternative facts’ problems as collective concerns, wherein it is actually the pluralistic nature of description that makes defending a collectively valuable version of reality so important and urgent.

This article compares a general cross-lagged model (GCLM) to other panel data methods based on their coherence with a causal logic and pragmatic concerns regarding modeled dynamics and hypothesis testing. We examine three “static” models that do not incorporate temporal dynamics: random- and fixed-effects models that estimate contemporaneous relationships; and latent curve models. We then describe “dynamic” models that incorporate temporal dynamics in the form of lagged effects: cross-lagged models estimated in a structural equation model (SEM) or multilevel model (MLM) framework; Arellano-Bond dynamic panel data methods; and autoregressive latent trajectory models. We describe the implications of overlooking temporal dynamics in static models and show how even popular cross-lagged models fail to control for stable factors over time. We also show that Arellano-Bond and autoregressive latent trajectory models have various shortcomings. By contrasting these approaches, we clarify the benefits and drawbacks of common methods for modeling panel data, including the GCLM approach we propose. We conclude with a discussion of issues regarding causal inference, including difficulties in separating different types of time-invariant and time-varying effects over time.

Researchers misunderstand their role in creating ethical problems when they allow dogmas to purportedly divorce scientists and scientific practices from the values that they embody. Cortina (J Bus Ethics. https://doi.org/10.1007/s10551-019-04195-8, 2019), Edwards (J Bus Ethics. https://doi.org/10.1007/s10551-019-04197-6, 2019), and Powell (J Bus Ethics. https://doi.org/10.1007/s10551-019-04196-7, 2019) help us clarify and further develop our position by responding to our critique of, and alternatives to, this misleading separation. In this rebuttal, we explore how the desire to achieve the separation of facts and values is unscientific on the very terms endorsed by its advocates—this separation is refuted by empirical observation. We show that positivists like Cortina and Edwards offer no rigorous theoretical or empirical justifications to substantiate their claims, let alone critique ours. Following Powell, we point to how classical pragmatism understands ‘purpose’ in scientific pursuits while also providing an alternative to the dogmas of positivism and related philosophical positions. In place of dogmatic, unscientific cries about an abstract and therefore always-unobservable ‘reality,’ we invite all organizational scholars to join us in shifting the discussion about quantitative research towards empirically grounded scientific inquiry. This makes the ethics of actual people and their practices central to quantitative research, including the thoughts, discourses, and behaviors of researchers who are always in particular places doing particular things. We propose that quantitative researchers can thus start to think about their research practices as a kind of work, rather than having the status of a kind of dogma. We conclude with some implications that this has for future research and education, including the relevance of research and research methods.

Drawing on a wide range of social science and humanities literature on the centrality of time and temporality in the social world, over the past few months we have come together to develop a research agenda that makes use of time as a crucial lens through which to understand and study the pandemic as it unfolds. This has led to a new collaboration between scholars at the Universities of Kent, Edinburgh, Goldsmiths, Stirling and the Mass Observation Archive to investigate the structure and experience of time in the pandemic.

This publication is with permission of the rights owner freely accessible due to an alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively., This is the first paper in a series of two that synthesizes, compares, and extends methods for causal inference with longitudinal panel data in a structural equation modeling (SEM) framework. Starting with a cross-lagged approach, this paper builds a general cross-lagged panel model (GCLM) with parameters to account for stable factors while increasing the range of dynamic processes that can be modeled. We illustrate the GCLM by examining the relationship between national income and subjective well-being (SWB), showing how to examine hypotheses about short-run (via Granger-Sims tests) versus long-run effects (via impulse responses). When controlling for stable factors, we find no short-run or long-run effects among these variables, showing national SWB to be relatively stable, whereas income is less so. Our second paper addresses the differences between the GCLM and other methods. Online Supplementary Materials offer an Excel file automating GCLM input for Mplus (with an example also for Lavaan in R) and analyses using additional data sets and all program input/output. We also offer an introductory GCLM presentation at https://youtu.be/tHnnaRNPbXs. We conclude with a discussion of issues surrounding causal inference., Australian Research Council https://doi.org/10.13039/501100000923, Peer Reviewed

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich., This article compares a general cross-lagged model (GCLM) to other panel data methods based on their coherence with a causal logic and pragmatic concerns regarding modeled dynamics and hypothesis testing. We examine three “static” models that do not incorporate temporal dynamics: random- and fixed-effects models that estimate contemporaneous relationships; and latent curve models. We then describe “dynamic” models that incorporate temporal dynamics in the form of lagged effects: cross-lagged models estimated in a structural equation model (SEM) or multilevel model (MLM) framework; Arellano-Bond dynamic panel data methods; and autoregressive latent trajectory models. We describe the implications of overlooking temporal dynamics in static models and show how even popular cross-lagged models fail to control for stable factors over time. We also show that Arellano-Bond and autoregressive latent trajectory models have various shortcomings. By contrasting these approaches, we clarify the benefits and drawbacks of common methods for modeling panel data, including the GCLM approach we propose. We conclude with a discussion of issues regarding causal inference, including difficulties in separating different types of time-invariant and time-varying effects over time., Australian Research Council https://doi.org/10.13039/501100000923, Peer Reviewed

Drawing on a wide range of social science and humanities literature on the centrality of time and temporality in the social world, over the past few months we have come together to develop a research agenda that makes use of time as a crucial lens through which to understand and study the pandemic as it unfolds. This has led to a new collaboration between scholars at the Universities of Kent, Edinburgh, Goldsmiths, Stirling and the Mass Observation Archive to investigate the structure and experience of time in the pandemic.

Drawing on a wide range of social science and humanities literature on the centrality of time and temporality in the social world, over the past few months we have come together to develop a research agenda that makes use of time as a crucial lens through which to understand and study the pandemic as it unfolds. This has led to a new collaboration between scholars at the Universities of Kent, Edinburgh, Goldsmiths, Stirling and the Mass Observation Archive to investigate the structure and experience of time in the pandemic.

In this essay, we draw the attention of scholars contributing to the broad field of organisation studies, especially that part of it that constitutes the sociology of organisations, to a problem regarding the maintenance of social order in practical intellectual life as a university employee. We direct our readers’ attention to the performance-related practices governing Business and Management scholars that are currently contributing to the most acute expression of this problem because they elaborate powerful individuating forces that undermine the existing social order, without putting forward any normative or positive commitment to what a different social order might be that would or should replace what was previously there. Our core concern is that this destructive tendency undermines the sociology of organisation as a legitimate form of social inquiry and ultimately undermines the capacity of organisational scholars to understand and improve social affairs.

In this essay, we draw the attention of scholars contributing to the broad field of organisation studies, especially that part of it that constitutes the sociology of organisations, to a problem regarding the maintenance of social order in practical intellectual life as a university employee. We direct our readers’ attention to the performance-related practices governing Business and Management scholars that are currently contributing to the most acute expression of this problem because they elaborate powerful individuating forces that undermine the existing social order, without putting forward any normative or positive commitment to what a different social order might be that would or should replace what was previously there. Our core concern is that this destructive tendency undermines the sociology of organisation as a legitimate form of social inquiry and ultimately undermines the capacity of organisational scholars to understand and improve social affairs.

Subjectivity and objectivity in statistical modelling is discussed., This is a discussion on the paper "Beyond subjective and objective in statistics" by Gelman and Henning. The full paper and the discussion can be found at https://doi.org/10.1111/rssa.12276.

Background Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on longterm follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. Methods We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as Severe or Mild, based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. Results and conclusions Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10(-3), OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10(-3) adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10(-3)). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts

This editorial offers new ways to ethically practice, evaluate, and use quantitative research (QR). Our central claim is that ready-made formulas for QR, including ‘best practices’ and common notions of ‘validity’ or ‘objectivity,’ are often divorced from the ethical and practical implications of doing, evaluating, and using QR for specific purposes. To focus on these implications, we critique common theoretical foundations for QR and then recommend approaches to QR that are ‘built for purpose,’ by which we mean designed to ethically address specific problems or situations on terms that are contextually relevant. For this, we propose a new tool for evaluating the quality of QR, which we call ‘relational validity.’ Studies, including their methods and results, are relationally valid when they ethically connect researchers’ purposes with the way that QR is oriented and the ways that it is done—including the concepts and units of analysis invoked, as well as what its ‘methods’ imply more generally. This new way of doing QR can provide the liberty required to address serious worldly problems on terms that are both practical and ethically informed in relation to the problems themselves rather than the confines of existing QR logics and practices.

BACKGROUND: Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on long-term follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. METHODS: We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as "Severe" or "Mild", based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. RESULTS AND CONCLUSIONS: Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10-3, OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10-3 adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10-3). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohor

Background Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on longterm follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. Methods We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as Severe or Mild, based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. Results and conclusions Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10(-3), OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10(-3) adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10(-3)). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts

How organisations deal with uncertainty is a core concern in organisation theory. This thesis examines the institutional sources of this problem by investigating emergency management organisations, focusing on the Australian State of Victoria. It shows how contradictions between different logics generate paradoxes that can be made evident in organisations when unpredictable events occur. It argues that developing a better understanding of ‘surprises’ is crucial for improving organisational decision-making in emergency management in particular, and for all organisations in general.

Repair of Inguinal hernia ranks among the most common surgical procedures worldwide. Large patient numbers necessitate efficacy and sophistication in the procedure. A novel self-attaching composite mesh (Parietene ProGrip , Covidien, Dublin, Ireland) and a sutured light-weight mesh (Parietene Light , Covidien) were compared double-blinded in 394 randomized patients. Outcomes were collected with a symptom diary and telephone contact during immediate convalescence and by clinical assessment one year after the operation. Outcomes up to 5 years after application of either a sutureless bilayer mesh (Prolene® Hernia System, Ethicon Endo-Surgery, Somerville, MA, USA) or standard tension-free repair (Surgipro , AutoSuture, Norwalk, CT, USA) were collected with a postal questionnaire, telephone contact, and clinical assessment in 300 patients. Health-related quality of life before and after open inguinal hernia repair was measured by RAND 36-Item Health Survey 1.0 (RAND Corporation, Santa Monica, CA, USA) in altogether 159 patients aged at least 65 years and 373 patients aged under 65 years. The results were compared within and between age groups as well as with the values from the general population. A database of 932 open mesh-based hernia repairs was subjected to regression analyses for factors predicting the presence of chronic posthernioplasty pain or more intensive postoperative inguinal pain. Outcomes between the self-attaching mesh and sutured light-weight mesh were equivalent. Applying the self-fixating mesh was faster (34 min vs. 42 min, p less than 0.001). Median sick leave was 2 weeks. At one year, 4.7% of patients perceived pain while resting, 2.0% had pain interfering with every-day life, 25.4% experienced discomfort, and 9.5% had losses in sensation in the operated groin. One recurrence (0.3%) was encountered. Sensory dysfunction of groin skin was rarer 5 years after the operation with the bilayer device than after tension-free repair (5.0% vs. 13.9%, p = 0.02, Nivustyrä on yleisimpiä kirurgisia diagnooseja maailmanlaajuisesti. Suomessa nivustyrän korjaus kuuluu kymmenen tavallisimman sairaalassa tehtävän toimenpiteen joukkoon. Väitöskirjassa vertailtiin avokirurgiassa käytettyjä verkkoja, tutkittiin muutoksia potilaiden elämänlaadussa ja etsittiin ennustekijöitä korjauksen jälkeen esiintyvälle nivuskivulle. Verkkojen vertailu suoritettiin vapaaehtoisten potilaiden joukossa kaksoissokkoutetusti. Ensimmäisessä vertailussa puolet potilaista satunnaistettiin saamaan uudenlainen itsestään kiinnittyvä ja osaksi sulava kevytverkko. Puolet potilaista leikattiin perinteiseen tapaan: yksinkertainen kevytverkko kiinnitettiin paikoilleen pysyvin ompelein. Lyhyen aikavälin tulokset kerättiin oirepäiväkirjan ja puhelinsoiton avulla. Vuoden kohdalla lopputuloksen arvioi vastaanotolla lääkäri. Toisessa vertailussa perinteisen korjauksen verrokkina oli ompeleeton kaksoisverkko. Potilaiden tilanne arvioitiin viisi vuotta leikkauksesta kyselylomakkein, puhelinhaastatteluin ja vastaanottokäynnein. Väitöskirjan kolmannessa osiossa vanhusten ja nuorempien potilaiden elämänlaatua mitattiin ennen toimenpidettä ja sen jälkeen kyselymittarilla. Tuloksia verrattiin keskenään ja väestön keskimääräisiin arvoihin. Neljännessä osiossa hyödynnettiin lähes tuhannen nivustyräleikkauksen rekisteriä. Potilaskohtaisten ja leikkauksen yksityiskohtien joukosta etsittiin tilastomenetelmin tekijöitä, jotka ennustivat kroonisen leikkauksenjälkeisen nivuskivun esiintymistä vuoden kohdalla tai voimakkaampaa nivuskipua. Itsestään kiinnittyvän verkon käyttö johti samanlaisiin tuloksiin kuin perinteinen leikkaustapa. Eroja ei esiintynyt toipumisajan, sairauslomantarpeen, leikkauksen jälkeisen kivun, kroonisen kivun tai tyrän uusiutumisen suhteen. Leikkaus itsestään kiinnittyvällä verkolla oli nopeampi. Kaksoisverkko ja perinteinen leikkaustapa johtivat myös samanlaisiin lopputulemiin pitkäaikaisseurannassa. Kaksoisverkolla leikatuilla potilailla oli kuitenkin harvemmi

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.

Background Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure. Methods We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease. Findings Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy. Interpretation CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent

Databases of mutations causing Mendelian disease play a crucial role in research, diagnostic and genetic health care and can play a role in life and death decisions. These databases are thus heavily used, but only gene or locus specific databases have been previously reviewed for completeness, accuracy, currency and utility. We have performed a review of the various general mutation databases that derive their data from the published literature and locus specific databases. Only two—the Human Gene Mutation Database (HGMD) and Online Mendelian Inheritance in Man (OMIM)—had useful numbers of mutations. Comparison of a number of characteristics of these databases indicated substantial inconsistencies between the two databases that included absent genes and missing mutations. This situation strengthens the case for gene specific curation of mutations and the need for an overall plan for collection, curation, storage and release of mutation data.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Sloan School of Management, 1994., Includes bibliographical references (leaf 266)., Ioannis A. Pierides., Ph.D.