School of Medicine

Adjustment Disorders: A diagnosis whose time has come

Sun, 01 Jan 2017 00:00:00 GMT

Adjustment Disorders: A diagnosis whose time has come Bachem, Rahel; Casey, Patricia R. Background: Adjustment disorder is among the most frequently diagnosed mental dis-orders in clinical practice although it has received little academic attention and been the subject of substantial criticism over the past decades. While those suffering with ad-justment disorders are often treated by mental health professionals, research interest in the origin of the disorder or the effectiveness of psychotherapeutic and medical inter-ventions has only recently begun to emerge. This article summarizes the empirical liter-ature published on adjustment disorder and points out current diagnostic develop-ments in DSM-5 and ICD-11. Methods: Literature for this review was identified through established online search tools, including publications in English, German, and Spanish. Results: This paper reviews literature on the evolution of adjustment disorder, and highlights the current state of research with regard to genesis and treatment. Im-portantly, for the first time ICD-11 intends to define adjustment disorder by explicit symptom groups, unlike DSM-5. Limitations: Publications without an English abstract were not included. Conclusions: Key directions for future research include investigating the concordance of the ICD-11 and DSM-5 concepts and the effect that the diverging con-ceptualizations may have. Risk and protective factors specific to AD should be identified and the biological underpinnings of the disorder should be explored. Finally, given the high prevalence of AD in certain clinical settings effective disorder-specific interven-tions should be developed and evaluated.

Attitudes and reported practice of paediatricians and child psychiatrists regarding the assessment and treatment of ADHD in Ireland

Sun, 01 Jan 2017 00:00:00 GMT

Attitudes and reported practice of paediatricians and child psychiatrists regarding the assessment and treatment of ADHD in Ireland Honorio Neto, Fabiola; Tatlow-Golden, Mimi; Mulligan, Aisling; Blanaid, Gavin; McNicholas, Fiona Objectives: This mixed-method national survey has obtained original data on attention deficit hyperactivity disorder (ADHD) attitudes, assessment and treatment regimes reported by paediatricians and child psychiatrists; and has compared their clinics. It has examined the extent of involvement of Irish paediatricians in the management of ADHD. Methods: A questionnaire was designed, based on a review of literature and ADHD guidelines, and piloted by expert clinicians. Universal recruitment was conducted among Child and Adolescent Mental Health Services (CAMHS) consultants (n = 71) and community/general paediatric consultants (n = 72). Quantitative and qualitative data was collected and analysed. Results: There was an overall response rate of 43%. A dedicated ADHD clinic is offered in 79% of CAMHS services, but only in one paediatric service. Participants reported that the assessment of ADHD involves multidisciplinary work and this was only established in CAMHS clinics. Medication is initiated by 82% of child psychiatrists and only 22% of paediatricians. Conclusions: This first national study of ADHD attitudes and practices presents comprehensive data regarding the management of children with ADHD in CAMHS and paediatric settings in Ireland. Paediatricians reported a minor role in managing ADHD. Study limitations are related to subjective reporting rather than case note audit, and a moderate response rate for the paediatricians’ participants.

Clinician-Scientist Training in Addiction Medicine: A Novel Programme in Canadian Setting

Sun, 01 Oct 2017 00:00:00 GMT

Clinician-Scientist Training in Addiction Medicine: A Novel Programme in Canadian Setting Klimas, Jan; McNeil, Ryan; Small, Will; Cullen, Walter Medical education has long been the missing element in the response to the global addiction problem. Instead of treating addiction as a disease, governments have focused on drug prohibition and law enforcement. This approach has failed by many measures, and, as a result, millions of people have suffered. Addiction science has increasingly identified a range of evidence-based approaches to treat substance-use disorders, particularly through early identification and treatment. However, most interventions are underused. Better physician education can improve accurate use of evidence-based treatments.

Core Addiction Medicine Competencies for Doctors, An International Consultation on Training

Sat, 01 Jul 2017 00:00:00 GMT

Core Addiction Medicine Competencies for Doctors, An International Consultation on Training Ayu, Astri Parawita; el-Guebaly, Nady; Schellekens, Arnt; Cullen, Walter; Klimas, Jan; et al. BACKGROUND:Despite the high prevalence of substance use disorders, associated comorbidities and the evidence-base upon which to base clinical practice, most health systems have not invested in standardised training of healthcare providers in addiction medicine. As a result, people with substance use disorders often receive inadequate care, at the cost of quality of life and enormous direct health care costs and indirect societal costs. Therefore, we undertook this study to assess the views of international scholars, representing different countries, on the core set of addiction medicine competencies that need to be covered in medical education.METHODS:We interviewed 13 members of the International Society of Addiction Medicine (ISAM), from 12 different countries (37% response rate), over Skype, email survey or in-person - at the annual conference. We content-analysed the interview transcripts, using constant comparison methodology.RESULTS:We identified recommendations related to the core set of the addiction medicine competencies at three educational levels: (i) undergraduate (ii) postgraduate and (iii) continued medical education (CME). The participants described broad ideas, such as knowledge / skills / attitudes towards addiction to be obtained at undergraduate level, or knowledge of addiction treatment to be acquired at graduate level, as well as specific recommendations, including the need to tailor curriculum to national settings and different specialties.CONCLUSIONS:While it is unclear whether a global curriculum is needed, a consensus on a core set of principles for progression of knowledge, attitude and skills in addiction medicine to be developed at each educational level amongst medical graduates would likely have substantial value.

Prevalence of Heavy Alcohol Use Among People Receiving Methadone Following Change to Methadose

Thu, 01 Jun 2017 00:00:00 GMT

Prevalence of Heavy Alcohol Use Among People Receiving Methadone Following Change to Methadose Klimas, Jan; Wood, Evan; Nosova, Ekaterina; et al. BACKGROUND: A recent switch in methadone formulation from methadone (1 mg/mL) to Methadose (10 mg/mL) in British Columbia (BC), Canada, was associated with increased reports of opioid withdrawal and increases in illicit opioid use. Impacts on other forms of drug use have not been assessed. Since alcohol use is common among people receiving Medication-Assisted Treatment (MAT), we assessed if switch was associated with increased prevalence of heavy alcohol use. METHODS: Drawing on data from two open prospective cohort studies of people who inject drugs in Vancouver, BC, generalized estimating equations (GEE) model examined relationship between methadone formulation change and heavy alcohol use, defined by National Institute for Alcohol Abuse and Alcoholism (NIAAA). A sub-analysis examined relationship with heavier drinking defined as at least eight drinks per day on average in last six months. RESULTS: Between June 2013 and May 2015, a total of 787 participants on methadone were eligible for the present analysis, of which 123 (15.6%) reported heavy drinking at least once in last six months. In an unadjusted GEE model, Methadose use was not significantly associated with an increased likelihood of heavy drinking [Odds Ratio (OR) = 1.03; 95% Confidence interval (CI) = 0.87-1.21]. Methadose use was not significantly associated with an increased likelihood of drinking at least eight drinks daily on average (OR = 1.09, 95% CI = 0.72-1.65). CONCLUSIONS: Despite reported changes in opioid use patterns coinciding with the change, there appeared to be no effect of the methadone formulation change on heavy drinking in this setting.

The use of digital media by women using the maternity services in a developed country

Mon, 01 Dec 2014 00:00:00 GMT

The use of digital media by women using the maternity services in a developed country O'Higgins, Amy; Murphy, Olivia C.; Egan, Aileen; Mullaney, Laura; Sheehan, S.; Turner, Michael The provision of high quality healthcare information about pregnancy is important to women and to healthcare professionals and it is driven, in part, by a desire to improve clinical outcomes. The objective of this study was to examine the use of digital media by women to access pregnancy information. A questionnaire was distributed to women attending a large maternity hospital. Of the 522 respondents, the mean age was 31.8 years, 45% (235/522) were nulliparous, 62% (324/522) lived in the capital city and 29% (150/522) attended the hospital as private patients. Overall 95% (498/522) used the internet for pregnancy information, 76% (399/522) had a smartphone and 59% (235/399) of smartphone owners had used a pregnancy smartapp. The nature of internet usage for pregnancy information included discussion forums (70%), social networks (67%), video media (48%), e-books (15%), blogs (13%), microblogs (9%) and podcasts (4%). Even women who were socially disadvantaged reported high levels of digital media usage. In contemporary maternity care women use digital media extensively for pregnancy information. All maternity services should have a digital media strategy.

Impact of a brief addiction medicine training experience on knowledge self-assessment among medical learners

Tue, 21 Feb 2017 00:00:00 GMT

Impact of a brief addiction medicine training experience on knowledge self-assessment among medical learners Klimas, Jan; Ahamad, Keith; Fairgrieve, Kit; McLean, Mark; et al. Background: Implementation of evidence-based approaches to the treatment of various substance use disorders is needed to tackle the existing epidemic of substance use and related harms. Most clinicians, however, lack knowledge and practical experience with these approaches. Given this deficit, the authors examined the impact of an inpatient elective in addiction medicine amongst medical trainees on addiction-related knowledge and medical management. Methods: Trainees who completed an elective with a hospital-based Addiction Medicine Consult Team (AMCT) in Vancouver, Canada, from May 2015 to May 2016, completed a 9-item self-evaluation scale before and immediately after the elective. Results: A total of 48 participants completed both pre and post AMCT elective surveys. On average, participants were 28 years old (interquartile range [IQR] = 27–29) and contributed 20 days (IQR = 13–27) of clinical service. Knowledge of addiction medicine increased significantly post elective (mean difference [MD] = 8.63, standard deviation [SD] = 18.44; P = .002). The most and the least improved areas of knowledge were relapse prevention and substance use screening, respectively. Conclusions: Completion of a clinical elective with a hospital-based AMCT appears to improve medical trainees' addiction-related knowledge. Further evaluation and expansion of addiction medicine education is warranted to develop the next generation of skilled addiction care providers.

Neuron Sub-Populations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Thu, 01 Jan 2015 00:00:00 GMT

Neuron Sub-Populations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment Blasiak, Agata; Lee, Gil U.; Kilinc, Devrim Correct wiring of the nervous system requires guidance cues, diffusible or substrate-bound proteins that steer elongating axons to their target tissues. Netrin-1, the best characterized member of the Netrins family of guidance molecules, is known to induce axon turning and modulate axon elongation rate; however, the factors regulating the axonal response to Netrin-1 are not fully understood. Using microfluidics, we treated fluidically isolated axons of mouse primary cortical neurons with Netrin-1 and characterized axon elongation rates, as well as the membrane localization of deleted in colorectal cancer (DCC), a well-established receptor of Netrin-1. The capacity to stimulate and observe a large number of individual axons allowed us to conduct distribution analyses, through which we identified two distinct neuron subpopulations based on different elongation behavior and different DCC membrane dynamics. Netrin-1 reduced the elongation rates in both subpopulations, where the effect was more pronounced in the slow growing subpopulation. Both the source of Ca2+ influx and the basal cytosolic Ca2+ levels regulated the effect of Netrin-1, for example, Ca2+ efflux from the endoplasmic reticulum due to the activation of Ryanodine channels blocked Netrin-1-induced axon slowdown. Netrin-1 treatment resulted in a rapid membrane insertion of DCC, followed by a gradual internalization. DCC membrane dynamics were different in the central regions of the growth cones compared to filopodia and axon shafts, highlighting the temporal and spatial heterogeneity in the signaling events downstream of Netrin-1. Cumulatively, these results demonstrate the power of microfluidic compartmentalization and distribution analysis in describing the complex axonal Netrin-1 response.

Bio-Nano-Magnetic Materials for Localized Mechanochemical Stimulation of Cell Growth and Death

Wed, 20 Jul 2016 00:00:00 GMT

Bio-Nano-Magnetic Materials for Localized Mechanochemical Stimulation of Cell Growth and Death Kilinc, Devrim; Dennis, Cindi L.; Lee, Gil U. Magnetic nanoparticles are promising new tools for therapeutic applications, such as magnetic nanoparticle hyperthermia therapy and targeted drug delivery. Recent in vitro studies have demonstrated that a force application with magnetic tweezers can also affect cell fate, suggesting a therapeutic potential for magnetically modulated mechanical stimulation. The magnetic properties of nanoparticles that induce physical responses and the subtle responses that result from mechanically induced membrane damage and/or intracellular signaling are evaluated. Magnetic particles with various physical, geometric, and magnetic properties and specific functionalization can now be used to apply mechanical force to specific regions of cells, which permit the modulation of cellular behavior through the use of spatially and time controlled magnetic fields. On one hand, mechanochemical stimulation has been used to direct the outgrowth on neuronal growth cones, indicating a therapeutic potential for neural repair. On the other hand, it has been used to kill cancer cells that preferentially express specific receptors. Advances made in the synthesis and characterization of magnetic nanomaterials and a better understanding of cellular mechanotransduction mechanisms may support the translation of mechanochemical stimulation into the clinic as an emerging therapeutic approach.

Advances in magnetic tweezers for single molecule and cell biophysics

Sat, 01 Nov 2014 00:00:00 GMT

Advances in magnetic tweezers for single molecule and cell biophysics Kilinc, Devrim; Lee, Gil U. Magnetic tweezers (MTW) enable highly accurate forces to be transduced to molecules to study mechanotransduction at the molecular or cellular level. We review recent MTW studies in single molecule and cell biophysics that demonstrate the flexibility of this technique. We also discuss technical advances in the method on several fronts, i.e., from novel approaches for the measurement of torque to multiplexed biophysical assays. Finally, we describe multi-component nanorods with enhanced optical and magnetic properties and discuss their potential as future MTW probes.

Magnetic Tweezers-Based Force Clamp Reveals Mechanically Distinct apCAM Domain Interactions

Wed, 19 Sep 2012 00:00:00 GMT

Magnetic Tweezers-Based Force Clamp Reveals Mechanically Distinct apCAM Domain Interactions Kinlic, Devrim; Blasiak, Agata; O'Mahony, James; Suter, Daniel M.; Lee, Gil U. Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) play a crucial role in cell-cell interactions during nervous system development and function. The Aplysia CAM (apCAM), an invertebrate IgCAM, shares structural and functional similarities with vertebrate NCAM and therefore has been considered as the Aplysia homolog of NCAM. Despite these similarities, the binding properties of apCAM have not been investigated thus far. Using magnetic tweezers, we applied physiologically relevant, constant forces to apCAM-coated magnetic particles interacting with apCAM-coated model surfaces and characterized the kinetics of bond rupture. The average bond lifetime decreased with increasing external force, as predicted by theoretical considerations. Mathematical simulations suggest that the apCAM homophilic interaction is mediated by two distinct bonds, one involving all five immunoglobulin (Ig)-like domains in an antiparallel alignment and the other involving only two Ig domains. In summary, this study provides biophysical evidence that apCAM undergoes homophilic interactions, and that magnetic tweezers-based, force-clamp measurements provide a rapid and reliable method for characterizing relatively weak CAM interactions.

Preliminary Results and Publication Impact of a Dedicated Addiction Clinician Scientist Research Fellowship

Wed, 01 Feb 2017 00:00:00 GMT

Preliminary Results and Publication Impact of a Dedicated Addiction Clinician Scientist Research Fellowship Klimas, Jan; Fernandes, Elaine; deBeck, Kora; Cullen, Walter; et al. Clinician-scientists serve to bridge the gap between addiction research and clinical practice but cultivating clinician-scientists, who are able to develop and publish clinical research, remains a challenge. Therefore, we describe the design and first-year data from a controlled, non-randomized comparison trial that prospectively evaluates how a dedicated research-training program for addiction medicine physicians contributed to subsequent research involvement and research productivity.

In vitro study of the interaction of heregulin-functionalized magnetic-optical nanorods with MCF7 and MDA-MB- 231 cells

Mon, 01 Sep 2014 00:00:00 GMT

In vitro study of the interaction of heregulin-functionalized magnetic-optical nanorods with MCF7 and MDA-MB- 231 cells Lesniak, Anna; Kilinc, Devrim; Rashdan, Suad Ahmed; Kriegsheim, Alexander von; Ashall, B.; Zerulla, Dominic; Kolch, Walter; Lee, Gil U. Multifunctional nanoparticles that actively target specific cells are promising tools for cancer diagnosis and therapy. In this article we review the synthesis and surface chemistry of Fe–Au nanorods and their characterization using microscopy. The diameter of the rods used in this study was selected to be 150–200 nm so that they did not enter the cells. The 80 nm-long Au tips of the nanorods were functionalized with heregulin (HRG), and the micron-long Fe portion was coated with a poly(ethylene glycol) monolayer to minimize non-specific interactions. Nanorods functionalized with HRG were found to preferentially bind to MCF7 cells that express high levels of the receptor tyrosine-protein kinase ErbB2/3. Magnetic tweezers measurements were used to characterize the kinetic properties of the bond between the HRG on the rods and ErbB2/3 on the surface of the cells. The strong magnetization of Fe–Au nanorods makes them excellent candidates for in-vitro and in-vivo imaging, and magnetic therapeutic applications targeting cancer cells in circulation.

Resistive Pulse Sensing of Analyte-Induced Multicomponent Rod Aggregation Using Tunable Pores

Fri, 06 Jul 2012 00:00:00 GMT

Resistive Pulse Sensing of Analyte-Induced Multicomponent Rod Aggregation Using Tunable Pores Platt, Mark; Willmott, Geoff; Lee, Gil U. Resistive pulse sensing is used to monitor individual and aggregated rod-shaped nanoparticles as they move through tunable pores in elastomeric membranes. By comparing particles of similar dimensions, it is demonstrated that the resistive pulse signal of a rod is fundamentally different from that of a sphere. Rods can be distinguished using two measurements: the blockade event magnitude (Δip), which reveals the particle's size, and the full width at half maximum (FWHM) duration, which relates to the particle's speed and length. While the observed Δip values agree well with simulations, the measured FWHM times are much larger than expected. This increase in dwell time, caused by rods moving through the pore in various orientations, is not observed for spherical particles. These differences are exploited in a new agglutination assay using rod-shaped particles. By controlling the surface chemistry and location of the capture ligand, rods are made to form either long “end-on-end” or wide 'side-on' aggregates upon the addition of an analyte. This observation will facilitate multiplexed detection in agglutination assays, as particles with a particular aspect ratio can be distinguished by two measurements. This is first demonstrated with a biotinylated target and avidin capture probe, followed by the detection of platelet-derived growth factor (PDGF-BB) using an aptamer capture probe, with limits of detection down to femtomolar levels.

Affinity Separation: M13 Bacteriophage-Activated Superparamagnetic Beads for Affinity Separation

Mon, 06 Aug 2012 00:00:00 GMT

Affinity Separation: M13 Bacteriophage-Activated Superparamagnetic Beads for Affinity Separation Muzard, Julien; Platt, Mark; Lee, Gil U. The growth of the biopharmaceutical industry has created a demand for new technologies for the purification of genetically engineered proteins.The efficiency of large-scale, high-gradient magnetic fishing could be improved if magnetic particles offering higher binding capacity and magnetization were available. This article describes several strategies for synthesizing microbeads that are composed of a M13 bacteriophage layer assembled on a superparamagnetic core. Chemically cross-linking the pVIII proteins to a carboxyl functionalized bead produced highly responsive superparamagnetic particles (SPM) with a side-on oriented, adherent virus monolayer. Also, the genetic manipulation of the pIII proteins with a His6 peptide sequence allowed reversible assembly of the bacteriophage on a nitrilotriacetic acid functionalized core in an end-on configuration. These phage-magnetic particles were successfully used to separate antibodies from high-protein concentration solutions in a single step with a > 90 % purity. The dense magnetic core of these particles makes themfive times more responsive to magnetic fields than commercial materialscomposed of polymer-iron oxide compositesand a monolayer of phage could produced a 1000 fold higher antibody binding capacity. These new bionanomaterials appear to be well-suited to large-scale high-gradient magnetic fishing separation and promise to be cost effective as a result of the self-assembling and self-replicating properties of genetically engineered M13 bacteriophage

Isolation of Bowman-Birk-Inhibitor from soybean extracts using novel peptide probes and high gradient magnetic separation

Mon, 15 Oct 2012 00:00:00 GMT

Isolation of Bowman-Birk-Inhibitor from soybean extracts using novel peptide probes and high gradient magnetic separation Fields, Conor; Mallee, Paul; Lee, Gil U. Soybean proteins offer exceptional promise in the area of cancer prevention and treatment. Specifically, Bowman-Birk Inhibitor (BBI) has the ability to suppress carcinogenesis in vivo, which has been attributed to BBI’s inhibition of serine protease (trypsin and chymotrypsin) activity. The lack of molecular probes for the isolation of this protein has made it difficult to work with, limiting its progress as a significant candidate in the treatment of cancer. This study has successfully identified a set of novel synthetic peptides targeting the BBI, and has demonstrated the ability to bind BBI in vitro. One of those probes has been covalently immobilised on superparamagnetic microbeads to allow the isolation of BBI from soy whey mixtures in a single step. Our ultimate goal is the use of the described synthetic probe to facilitate the isolation of this potentially therapeutic protein for low cost, scalable analysis and production of BBI.

Resistive pulse sensing of magnetic beads and supraparticle structures using tunable pores

Sun, 01 Jan 2012 00:00:00 GMT

Resistive pulse sensing of magnetic beads and supraparticle structures using tunable pores Willmott, Geoff; Platt, Mark; Lee, Gil U. Tunable pores (TPs) have been used for resistive pulse sensing of 1 μm superparamagnetic beads, both dispersed and within a magnetic field. Upon application of this field, magnetic supraparticle structures (SPSs) were observed. Onset of aggregation was most effectively indicated by an increase in the mean event magnitude, with data collected using an automated thresholding method. Simulations enabled discrimination between resistive pulses caused by dimers and individual particles. Distinct but time-correlated peaks were often observed, suggesting that SPSs became separated in pressure-driven flow focused at the pore constriction. The distinct properties of magnetophoretic and pressure-driven transport mechanisms can explain variations in the event rate when particles move through an asymmetric pore in either direction, with or without a magnetic field applied. Use of TPs for resistive pulse sensing holds potential for efficient, versatile analysis and measurement of nano- and microparticles, while magnetic beads and particle aggregation play important roles in many prospective biosensing applications.

Advances in Affinity Ligand-Functionalized Nanomaterials for Biomagnetic Separation

Fri, 01 Jan 2016 00:00:00 GMT

Advances in Affinity Ligand-Functionalized Nanomaterials for Biomagnetic Separation Fields, Conor; Li, Peng; O'Mahony, James J.; Lee, Gil U. The downstream processing of proteins remains the most significant cost in protein production, and is largely attributed to rigorous chromatographic purification protocols, where the stringency of purity for biopharmaceutical products sometimes exceeds 99%. With an ever burgeoning biotechnology market, there is a constant demand for alternative purification methodologies, to ameliorate the dependence on chromatography, while still adhering to regulatory concerns over product purity and safety. In this article, we present an up-to-date view of bioseparation, with emphasis on magnetic separation and its potential application in the field. Additionally, we discuss the economic and performance benefits of synthetic ligands, in the form of peptides and miniaturized antibody fragments, compared to full-length antibodies. We propose that adoption of synthetic affinity ligands coupled with magnetic adsorbents, will play an important role in enabling sustainable bioprocessing in the future.

Flow enhanced non-linear magnetophoretic separation of beads based on magnetic susceptibility

Tue, 20 Aug 2013 00:00:00 GMT

Flow enhanced non-linear magnetophoretic separation of beads based on magnetic susceptibility Li, Peng; Kilinc, Devrim; Ying, Fen Ran; Lee, Gil U. Magnetic separation provides a rapid and efficient means of isolating biomaterials from complex mixtures based on their adsorption on superparamagnetic (SPM) beads. Flow enhanced non-linear magnetophoresis (FNLM) is a high-resolution mode of separation in which hydrodynamic and magnetic fields are controlled with micron resolution to isolate SPM beads with specific physical properties. In this article we demonstrate that a change in the critical frequency of FNLM can be used to identify beads with magnetic susceptibilities between 0.01 and 1.0 with a sensitivity of 0.01 Hz(-1). We derived an analytical expression for the critical frequency that explicitly incorporates the magnetic and non-magnetic composition of a complex to be separated. This expression was then applied to two cases involving the detection and separation of biological targets. This study defines the operating principles of FNLM and highlights the potential for using this technique for multiplexing diagnostic assays and isolating rare cell types.

Flow-Enhanced Nonlinear Magnetophoresis for High-Resolution Bioseparation

Wed, 20 Apr 2011 00:00:00 GMT

Flow-Enhanced Nonlinear Magnetophoresis for High-Resolution Bioseparation Li, Peng; Mahmood, Aamer; Lee, Gil U. A new mode of transport is described that was capable of high-resolution separation of superparamagnetic materials from complex mixtures based on their size. Laminar flow and a rotating external magnetic field were applied to superparamagnetic beads assembled on a semiperiodic micromagnet array. Beads at the edge of the micromagnet array oscillated in-phase with the external magnetic field with an amplitude that decreased with increasing frequency, omega, until they reached an immobilization frequency, omega(nu) where the beads stopped moving. Laminar flow along the edge of the array could be tuned to sweep the beads for which omega omega(i) undisturbed. Flow-enhanced nonlinear magnetophoresis (F-NLM) promises to enable multiple superparamagnetc bead types to be used in the fractionation of cells and implementation of diagnostic assays.

Paediatric imaging radiation dose awareness and use of referral guidelines amongst radiology practitioners and radiographers

Mon, 01 Feb 2016 00:00:00 GMT

Paediatric imaging radiation dose awareness and use of referral guidelines amongst radiology practitioners and radiographers Portelli, Jonathan L.; McNulty, Jonathan P.; Bezzina, Paul; Rainford, Louise A. Objectives: The objectives are to investigate radiology practitioners' and radiographers' radiation dose awareness and use of referral guidelines for paediatric imaging examinations. Methods: A prospective cross-sectional survey was conducted amongst radiology practitioners and radiographers working at a primary paediatric referral centre in Malta. Part of the survey asked participants to indicate the typical effective dose (ED) for several commonly performed paediatric imaging examinations, answer five true-false statements about radiation protection principles, and specify their use of referral guidelines for paediatric imaging. Results: The return of 112 questionnaires provided a response rate of 66.7 %. Overall, imaging practitioners demonstrated poor awareness of radiation doses associated with several paediatric imaging examinations, with only 20 % providing the correct ED estimate for radiation-based examinations. Nearly all participants had undertaken radiation protection training, but the type and duration of training undertaken varied. When asked about the use of referral guidelines for paediatric imaging, 77.3 % claimed that they 'did not' or 'were not sure' if they made use of them. Conclusions: Poor awareness of radiation doses associated with paediatric imaging examinations and the non-use of referral guidelines may impede imaging practitioners' role in the justification and optimisation of paediatric imaging examinations. Education and training activities to address such shortcomings are recommended.

Obesity and lung disease: a toxic mix

Wed, 01 Apr 2015 00:00:00 GMT

Obesity and lung disease: a toxic mix McLoughlin, Paul Obesity is associated with an increased incidence of lung diseases including such common conditions as asthma, COPD, ARDS, sleep apnoea syndrome and pulmonary hypertension. The adverse effects of obesity on the respiratory system are mediated by a number of mechanisms including the production of pro-inflammatory cytokines by adipose tissue, mechanical restriction of thoracic volumes and obesity-induced hypoventilation

On the personalised modelling of cancer signalling

Wed, 12 Oct 2016 00:00:00 GMT

On the personalised modelling of cancer signalling Fey, Dirk; Kuehn, Axel; Kholodenko, Boris N. Dynamic modelling has long been used to understand fundamental principles of cell signalling and its dysregulation in cancer. More recently these models have also been used to understand the individual risks of cancer patients, and predict their survival probabilities. However, the current methodologies for integrating tumour data and generating patient-specific simulations suffer from the lack of general applicability; they only work for cell signalling models in which only posttranslational protein modifications are considered, so that the total protein concentrations are conserved. Here, we present novel, generally applicable method. The method is based on a simple theoretical framework for modelling gene-regulation, and the indirect estimation of patient-specific parameters from tumour data. Because our method does not require time-invariance of the total-protein concentrations, it can be applied to models of any nature, including the many cancer signalling models involving gene-regulation. 6th IFAC Conference on Foundations of Systems Biology in Engineering (FOSBE 2016), Magdeburg, Germany, 9-12 October 2016

Alcohol use in opioid agonist treatment

Thu, 08 Dec 2016 00:00:00 GMT

Alcohol use in opioid agonist treatment Nolan, Seonaid; Klimas, Jan; Wood, Evan Alcohol misuse among individuals receiving agonist treatment for an opioid use disorder is common and is associated with significant morbidity and mortality. At present, though substantial research highlights effective strategies for the screening, diagnosis and management of an alcohol or opioid use disorder individually, less is known about how best to care for those with a dual diagnosis especially since common treatments for opioid addiction may be contraindicated in a setting of alcohol use. This review summarizes existing research and characterizes the prevalence, clinical implications and management of alcohol misuse among individuals with opioid addiction. Furthermore, it highlights clinically relevant management strategies in need of future research to advance care for this unique, but important, patient population.

Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence

Sun, 01 Dec 2013 00:00:00 GMT

Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence Ash, Simon A.; Buggy, Donal J. Cancer continues to be a key cause of morbidity and mortality worldwide and its overall incidence continues to increase. Anaesthetists are increasingly faced with the challenge of managing cancer patients, for surgical resection to debulk or excise the primary tumour, or for surgical emergencies in patients on chemotherapy or for the analgesic management of disease- or treatment-related chronic pain. Metastatic recurrence is a concern. Surgery and a number of perioperative factors are suspected to accelerate tumour growth and potentially increase the risk of metastatic recurrence. Retrospective analyses have suggested an association between anaesthetic technique and cancer outcomes, and anaesthetists have sought to ameliorate the consequences of surgical trauma and minimise the impact of anaesthetic interventions. Just how anaesthesia and analgesia impact cancer recurrence and consequent survival is very topical, as understanding the potential mechanisms and interactions has an impact on the anaesthetist's ability to contribute to the successful outcome of oncological interventions. The outcome of ongoing, prospective, randomized trials are awaited with interest.

Commentary on Zeremski et al. (2016): Improvements in HCV-related Knowledge Among Substance Users on Opioid Agonist Therapy After an Educational Intervention

Sat, 01 Oct 2016 00:00:00 GMT

Commentary on Zeremski et al. (2016): Improvements in HCV-related Knowledge Among Substance Users on Opioid Agonist Therapy After an Educational Intervention McCombe, Geoff; Henihan, Anne Marie; Leahy, Dorothy; Klimas, Jan; Lambert, John J.; Cullen, Walter Zeremski et al highlight how improving patients’ knowledge about Hepatitis C virus (HCV) care can enhance adherence to treatment plans and improved treatment outcomes (Zeremski et al. 2016). In this regard we believe that patients’ knowledge of HCV care can best be optimised through community based approaches to HCV treatment as supported by recent findings from Wade et al and Grebely et al (Wade et al. 2015, Grebely et al. 2016).

Alcohol Use among Persons on Methadone Treatment

Fri, 01 Jan 2016 00:00:00 GMT

Alcohol Use among Persons on Methadone Treatment Klimas, Jan; Dong, Huiru; Dobrer, Sabina; et al. We read with interest Dr Varshney et al.'s article on brief interventions for alcohol use among persons on maintenance treatment published ahead-of-print on August 11, 2015. While alcohol is found in the majority of drug-related deaths that involve illicit drugs, around the globe, maintenance therapy with methadone (MMT), or buprenorphine, reduces morbidity and mortality among people who use opiates. Although one common clinical challenge is comorbid alcohol use and opioid use disorder, with guidelines often recommending withholding methadone in this context given the potential for fatal overdose due to drug interactions, alcohol's impact on the health outcomes of MMT patients has been 'overlooked and underestimated'. Therefore, we examined the impact of heavy alcohol use on mortality among MMT patients.

Primary care: a key route for distribution of naloxone in the community

Thu, 01 Dec 2016 00:00:00 GMT

Primary care: a key route for distribution of naloxone in the community Klimas, Jan; Tobin, Helen; Egan, Mairead; Tomas, Barry; Bury, Gerard Heroin use continues to drive opioid-related overdoses and mortality globally (Degenhardt & Hall, 2012). Not-as-prescribed use of prescription opioids increases the number of victims of this epidemic (Logan, Liu, Paulozzi, Zhang, & Jones, 2013). Naloxone has been shown to reduce mortality in overdose among people who use heroin and other opioids; however, its administration in a number of countries, including Ireland, is limited to paramedics and health professionals (Bury, 2015), despite proven effectiveness of overdose education and naloxone distribution (OEND) programmes by trained lay-people worldwide (McAuley, Aucott, & Matheson, 2015). The effectiveness of these programmes has been demonstrated around outcomes such as knowledge, skills, attitudes and reduced overdose deaths (Coffin & Sullivan, 2013), and involved groups including social workers and needle-exchange staff as well as family and friends of people who use opioids (Walley et al., 2013). While recent systematic reviews have demonstrated the efficacy and feasibility of training diverse groups in OEND (Behar, Santos, Wheeler, Rowe, & Coffin, 2015), the potential and capacity of general practice (GP), to contribute in this area have not been fully characterised (Nielsen & Van Hout, 2016). A naloxone demonstration project is underway in Ireland at the moment and aims to reduce Ireland’s high number of opioid-related deaths (Department of Health, 2015).

Optimizing writing schemes for addiction researchers

Fri, 02 Dec 2016 00:00:00 GMT

Optimizing writing schemes for addiction researchers Klimas, Jan Writing constitutes a significant challenge for junior addiction researchers. Writing support programmes appear to improve writing skills and enhance productivity. However, addiction researchers have not benefited from writing support groups to the same extent as other professions, mainly due to the lack of support for and considerable variation among these programmes. Given a lack of research about the contribution of writing support programmes to publication productivity among early-stage addiction researchers, this article offers critical insights into the process and outcomes of such programmes, based on the substantial experience accumulated from taking part in several writing support programmes, including the scheme of the International Society of Addiction Journal Editors (ISAJE). A better understanding of what makes writing groups effective may help build evidence for writing programs and universities to equip addiction investigators with the skills they need to improve the health of people with substance use disorders via better writing.

How Can We Investigate the Role of Topiramate in the Treatment of Cocaine Use Disorder More Thoroughly?

Sun, 01 Jan 2017 00:00:00 GMT

How Can We Investigate the Role of Topiramate in the Treatment of Cocaine Use Disorder More Thoroughly? Klimas, Jan; Wood, Evan; Werb, Dan We read with interest Drs Darke and Farrell’s commentary on our meta-analysis of Topiramate published in the eight issue of 2016. To elaborate on some of the ideas raised by the commentary, we focus our response on the question of why some studies implied a benefit and others did not. Overall, although the current evidence is not strong enough to support the routine clinical use of Topiramate for the treatment of cocaine use disorder, it may be useful for researching in certain circumstances in terms of helping people with cocaine use disorders stay abstinent from cocaine use.

Feasibility of alcohol screening among people receiving Opioid treatment in primary care

Sat, 05 Nov 2016 00:00:00 GMT

Feasibility of alcohol screening among people receiving Opioid treatment in primary care Henihan, Anne Marie; McCombe, Geoff; Klimas, Jan; Lambert, John; Cullen, Walter; et al. Background: Identifying and treating problem alcohol use among people who also use illicit drugs is a challenge. Primary care is well placed to address this challenge but there are several barriers which may prevent this occurring. The objective of this study was to determine if a complex intervention designed to support screening and brief intervention for problem alcohol use among people receiving opioid agonist treatment is feasible and acceptable to healthcare providers and their patients in a primary care setting. Methods: A randomised, controlled, pre-and-post design measured feasibility and acceptability of alcohol screening based on recruitment and retention rates among patients and practices. Efficacy was measured by screening and brief intervention rates and the proportion of patients with problem alcohol use. Results: Of 149 practices that were invited, 19 (12.8 %) agreed to participate. At follow up, 13 (81.3 %) practices with 81 (62.8 %) patients were retained. Alcohol screening rates in the intervention group were higher at follow up than in the control group (53 % versus 26 %) as were brief intervention rates (47 % versus 19 %). Four (18 %) people reduced their problem drinking (measured by AUDIT-C), compared to two (7 %) in the control group. Conclusions: Alcohol screening among people receiving opioid agonist treatment in primary care seems feasible. A definitive trial is needed. Such a trial would require over sampling and greater support for participating practices to allow for challenges in recruitment of patients and practices.

Evaluation of prediction models for the staging of prostate cancer

Fri, 15 Nov 2013 00:00:00 GMT

Evaluation of prediction models for the staging of prostate cancer Boyce, Susie; Fan, Yue; Watson, R. William; Murphy, Thomas Brendan Background: There are dilemmas associated with the diagnosis and prognosis of prostate cancer which has lead to over diagnosis and over treatment. Prediction tools have been developed to assist the treatment of the disease. Methods: A retrospective review was performed of the Irish Prostate Cancer Research Consortium database and 603 patients were used in the study. Statistical models based on routinely used clinical variables were built using logistic regression, random forests and k nearest neighbours to predict prostate cancer stage. The predictive ability of the models was examined using discrimination metrics, calibration curves and clinical relevance, explored using decision curve analysis. The N=603 patients were then applied to the 2007 Partin table to compare the predictions from the current gold standard in staging prediction to the models developed in this study. Results: 30% of the study cohort had non organ-confined disease. The model built using logistic regression illustrated the highest discrimination metrics (AUC=0.622, Sens=0.647, Spec=0.601), best calibration and the most clinical relevance based on decision curve analysis. This model also achieved higher discrimination than the 2007 Partin table (ECE AUC=0.572 & 0.509 for T1c and T2a respectively). However, even the best statistical model does not accurately predict prostate cancer stage. Conclusions: This study has illustrated the inability of the current clinical variables and the 2007 Partin table to accurately predict prostate cancer stage. New biomarker features are urgently required to address the problem clinicians face in identifying the most appropriate treatment for their patients. This paper also demonstrated a concise methodological approach to evaluate novel features or prediction models.

Hypoxic pulmonary hypertension: the paradigm is changing

Sun, 01 Jun 2014 00:00:00 GMT

Hypoxic pulmonary hypertension: the paradigm is changing Rowan, Simon C.; McLoughlin, Paul We began in the early 2000s to explore the hypothesis that vasoconstrictor mechanisms, selectively altered in the lung, were significant contributors to the increase in pulmonary vascular resistance in pulmonary hypertension. We found that in the normal rat pulmonary circulation the RhoA-ROCK pathway is a greater contributor to vasoconstriction than it is in systemic vessels, demonstrating an important phenotypic difference in the regulation of vascular tone in the two circulations.

Off the record: Substance-related disorders in the undergraduate medical curricula in Ireland

Wed, 06 Apr 2016 00:00:00 GMT

Off the record: Substance-related disorders in the undergraduate medical curricula in Ireland Wilson, Mitch; Cullen, Walter; Goodair, Christine; Klimas, Jan Background: Substance use disorders (SUDs) are a worldwide problem, and have become a major health concern in Ireland particularly. We aimed to determine the extent to which addiction medicine is embedded in the undergraduate medical curriculum in Ireland. Methods: To further investigate the degree to which drug addiction is taught in the Irish medical curriculum an online literature search was performed using Google Scholar, PubMed (from 2009 to present), EMBASE, PsycINFO, CINAHL, and Medline using the keywords 'substancerelated disorders,' 'undergraduate,' 'curriculum' and 'Ireland.' Additionally, all Irish medical school websites were examined (n = 6), and a Google search and manual searches of conference programs were performed. We used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines to systematically review and discuss findings. Results: A total of zero published studies met the criteria for inclusion in an updated systematic literature search of addiction medicine education in the undergraduate medical curriculum in Ireland. Conclusion: There is currently no documentation of drug addiction teaching sessions in Irish medical schools. Investigations that offer direct contact with medical schools, such as a telephone survey, may provide a more accurate representation of how addiction medicine education is incorporated into the medical school curricula.

General practitioners tackle complex addictions: how complex interventions can assist in dealing with addiction

Tue, 30 Aug 2016 00:00:00 GMT

General practitioners tackle complex addictions: how complex interventions can assist in dealing with addiction Klimas, Jan Substance use disorder treatment is a complex problem. Complex problems require complex interventions, ideally tested via randomised controlled trials. Complex interventions are best developed in stages, using established implementation frameworks. Starting with a historical patient case study, we explore how treatment of this challenging population group has been approached, how an evidence-based framework has informed formulation of a complex health intervention and how this has been progressed via the U.K.'s Medical Research Council (MRC) approach.

Elevated plasma CXCL12a is associated with a poorer prognosis in pulmonary arterial hypertension

Thu, 09 Apr 2015 00:00:00 GMT

Elevated plasma CXCL12a is associated with a poorer prognosis in pulmonary arterial hypertension McCullagh, Brian N.; Costello, Christine M.; Li, Lili; O'Connell, Caroline; Codd, Mary; McLoughlin, Paul; et al. Recent work in preclinical models suggests that signalling via the pro-angiogenic and pro-inflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12a were elevated in patients with PAH and related to mortality. Plasma samples were collected from patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with connective tissue diseases (CTD-PAH) attending two pulmonary hypertension referral centres (n = 95) and from age and gender matched healthy controls (n = 44). Patients were subsequently monitored throughout a period of five years. CXCL12a concentrations were elevated in PAH groups compared to controls (P<0.05) and receiver-operating-characteristic analysis showed that plasma CXCL12a concentrations discriminated patients from healthy controls (AUC 0.80, 95% confidence interval 0.73-0.88). Kaplan Meier analysis indicated that elevated plasma CXCL12a concentration was associated with reduced survival (P<0.01). Multivariate Cox proportional hazards model showed that elevated CXCL12a independently predicted (P<0.05) earlier death in PAH with a hazard ratio (95% confidence interval) of 2.25 (1.01-5.00). In the largest subset by WHO functional class (Class 3, 65% of patients) elevated CXCL12a independently predicted (P<0.05) earlier death, hazard ratio 2.27 (1.05-4.89). Our data show that elevated concentrations of circulating CXCL12a in PAH predicted poorer survival. Furthermore, elevated circulating CXCL12a was an independent risk factor for death that could potentially be included in a prognostic model and guide therapy.

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

Fri, 01 Jan 2016 00:00:00 GMT

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study Gold, Ralf; Arnold, Douglas L.; Bar-Or, Amit; Hutchinson, Michael; et al. Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

Bayesian methods for proteomic biomarker development

Tue, 01 Dec 2015 00:00:00 GMT

Bayesian methods for proteomic biomarker development Hernández, Belinda; Pennington, S. R. (Stephen R.); Parnell, Andrew C. The advent of liquid chromatography mass spectrometry has seen a dramatic increase in the amount of data derived from proteomic biomarker discovery. These experiments have seemingly identified many potential candidate biomarkers. Frustratingly, very few of these candidates have been evaluated and validated sufficiently such that that they have progressed to the stage of routine clinical use. It is becoming apparent that the statistical methods used to evaluate the performance of new candidate biomarkers are a major limitation in their development. Bayesian methods offer some advantages over traditional statistical and machine learning methods. In particular they can incorporate external information into current experiments so as to guide biomarker selection. Further, they can be more robustto over-fitting than other approaches, especially when the number of samples used for discovery is relatively small. In this review we provide an introduction to Bayesian inference and demonstrate some of the advantages of using a Bayesian framework. We summarize how Bayesian methods have been used previously in proteomics and other areas of bioinformatics. Finally, we describe some popular and emerging Bayesian models from the statistical literature and provide a worked tutorial including code snippets to show how these methods may be applied for the evaluation of proteomic biomarkers.

Interpregnancy changes in maternal weight and body mass index

Thu, 01 Jan 2015 00:00:00 GMT

Interpregnancy changes in maternal weight and body mass index Crosby, David A.; Collins, Martha; O'Higgins, Amy; Mullaney, Laura; Farah, Nadine; Turner, Michael Objective: This longitudinal study compared changes in maternal weight and body mass index (BMI) in early pregnancy in the time interval between when a woman first attended for antenatal care with her first child and when she next attended for antenatal care. Study Design: We studied women with a singleton pregnancy who delivered their first baby weighing ≥ 500 g in 2009 and who attended again for antenatal care with an ongoing pregnancy before January 1, 2012. Maternal weight and height were measured before 18 weeks' gestation in both pregnancies and BMI was calculated. Results: Of the 3,284 primigravidas, the mean weight at the first visit in 2009 was 66.4 kg (standard deviation [SD] 12.7). The mean BMI was 24.5 kg/m2 (SD 4.6), and 11.3% (n = 370) were obese. Of the 3,284 women, 1,220 (37.1%) re-attended for antenatal care before 2012 after sonographic confirmation of an ongoing pregnancy. Of the 1,220 women who re-attended, 788 (64.6%) had gained weight (mean 4.6 kg [SD 3.9]), 402 (33%) had lost weight (mean 3 kg [SD 2.9]), and 30 (2.4%) had maintained their weight. Conclusion: The birth of a first baby was associated with an increase in maternal weight in two-thirds of women when they next attended for antenatal care.

A dynamic model of the MYCN regulated DNA damage response in Neuroblastoma

Wed, 05 Nov 2014 00:00:00 GMT

A dynamic model of the MYCN regulated DNA damage response in Neuroblastoma Kuehn, Axel; Kholodenko, Boris N.; Fey, Dirk Neuroblastoma is the most common the most common cancer in infancy with an extremely heterogeneous phenotype that is mainly driven by the MYCN oncogene. The MYCN transcription factor and its amplification is commonly associated with poor prognosis in patients, although it has also been shown that elevated MYCN levels correlates with apoptosis sensitization in cells. HMGA1 is one of MYCN target genes and is involved in triggering apoptosis through a DNA Damage Response (DDR) by inducing ataxia-telangiectasia-mutated (ATM) gene expression. But HMGA1 is also involved in preventing apoptosis by directly binding HIPK2 and decreasing its presence in the nucleus, therefore decreasing phosphorylation of p53 at serine 46 which is required for the activation of p53 apoptotic targets. In this article, we propose a model in which MYCN protein regulates the HMGA1-ATM-p53 and HMGA1-HIPK2-p53 subsystems. Because the molecular details concerning the HMGA1-HMGA1 interaction are uncertain several possibilities were explored in simulations. Our model points towards an important role of MYCN-dependent regulation of HMGA1 expression levels and the subsequent HIPK2 nuclear/cytoplasmic re-localization and led to experimentally testable predictions that can discern between alternative model structures. IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2014): Workshop on Empowering Systems Medicine Through Optimal Design of Experimentation and Computational Modeling, Belfast, Northern Ireland, 2-5 November 2014

Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses

Wed, 25 Jun 2014 00:00:00 GMT

Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses Dobrzyński, Maciej; Nguyen, Lan K.; Birtwistle, Marc R.; Kriegsheim, Alexander von; Fernández, Alfonso Blanco; Cheong, Alex; Kolch, Walter; Kholodenko, Boris N. We show theoretically and experimentally a mechanism behind the emergence of wide or bimodal protein distributions in biochemical networks with nonlinear input–output characteristics (the dose–response curve) and variability in protein abundance. Large cell-to-cell variation in the nonlinear dose–response characteristics can be beneficial to facilitate two distinct groups of response levels as opposed to a graded response. Under the circumstances that we quantify mathematically, the two distinct responses can coexist within a cellular population, leading to the emergence of a bimodal protein distribution. Using flow cytometry, we demonstrate the appearance of wide distributions in the hypoxia-inducible factor-mediated response network in HCT116 cells. With help of our theoretical framework, we perform a novel calculation of the magnitude of cell-to-cell heterogeneity in the dose–response obtained experimentally.

3D Power Doppler ultrasound and computerised placental assessment in normal pregnancy

Thu, 01 May 2014 00:00:00 GMT

3D Power Doppler ultrasound and computerised placental assessment in normal pregnancy Moran, Mary; Zombori, Gergely; Ryan, John; McAuliffe, Fionnuala M. Background: In recent years there have been significant developments in the use of 3D Power Doppler (3DPD) imaging and quantitative 3DPD histogram analysis to estimate both placental volume and intra-placental vasculature. This study aims to determine if placental volume, vascularisation and blood flow are correlated with gestational age in normal pregnancy. It also examines whether or not a new software method for analysis of percentage calcification (the ‘placentometer’) correlates well with gestation. Material and method: This was a prospective cohort study of 250 women with normal pregnancies (12 + 6 to 39 + 5 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental volume (calculated at 35–40 weeks gestation), was correlated with birth weight. Following each scan the percentage of calcification was also calculated using the placentometer. Results: Placental volume correlated significantly with gestational age: 66.676 + 0.623 × GA (P < 0.001). No significant change with gestation was noted in VI, FI and VFI (VI: P = 0.199, FI: P = 0.299, VFI: P = 0.557). Software analysis of the percentage of calcification, demonstrated the expected increase in calcification as gestation increased: −4.605 + 0.032 × GA (P < 0.001). From 35 to 40 weeks gestation volume was related to birth weight (P < 0.01). Conclusion: This study shows that in normal low-risk pregnancy placental volume increases with gestational age, whereas vascularisation and blood flow are independent of gestation. Placental volume in late pregnancy is related to birth weight. Software analysis of the percentage of calcification demonstrates an increase with advancing gestation.

Inhibition of the Pim1 Oncogene Results in Diminished Visual Function

Wed, 26 Dec 2012 00:00:00 GMT

Inhibition of the Pim1 Oncogene Results in Diminished Visual Function Yin, Jun; Shine, Lisa; Raycroft, Francis; Deeti, Sudhakar; Reynolds, Alison; Glaviano, Antonino; O'Farrell, Sean; O'Leary, Olivia; Kilty, Claire; Kennedy, Ciarán; McLoughlin, Sarah; Rice, Megan; Russell, Eileen; Higgins, D. (Des); Kennedy, Breandán; et al. Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors results in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.

Preanalytic Laboratory Standards (Letters to the Editor)

Wed, 01 Jun 2016 00:00:00 GMT

Preanalytic Laboratory Standards (Letters to the Editor) Daly, Niamh; Turner, Michael We thank our Canadian colleagues for their interest in our recent article and, in particular, their observations on the need for the 2-h sample with a 75-g OGTT. We note that 25% of their large cohort of 10 773 women had an abnormal 2-h sample using the IADPSG diagnostic criteria and therefore their understandable caution about missing the diagnosis of gestational diabetes mellitus.

Impact of Implementing Preanalytical Laboratory Standards on the Diagnosis of Gestational Diabetes Mellitus: A Prospective Observational Study

Mon, 01 Feb 2016 00:00:00 GMT

Impact of Implementing Preanalytical Laboratory Standards on the Diagnosis of Gestational Diabetes Mellitus: A Prospective Observational Study Daly, Niamh; Flynn, Iseult; Carrol, Ciara; Farren, Maria; McKeating, Aoife; Turner, Michael Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes, but risk is reduced with identification and early treatment. Glucose measurements are affected by preanalytical sample handling, such as temperature of storage, phlebotomy–analysis interval, and use of a glycolysis inhibitor. We evaluated glucose concentrations and the incidence of GDM after strict implementation of the American Diabetes Association (ADA) preanalytical guidelines, compared with usual hospital conditions. Methods: Women screened selectively for GDM at 24 –32 weeks’ gestation were recruited at their convenience before a 75-g oral glucose tolerance test. Paired samples were taken: the first sample followed ADA recommendations and was transferred to the laboratory on an iced slurry for immediate separation and analysis (research conditions), and the second sample was not placed on ice and was transferred according to hospital practice (usual conditions). Results: Of samples from 155 women, the mean fasting, 1-h, and 2-h results were 90.0 (12.6) mg/dL [5.0 (0.7) mmol/L], 142.2 (43.2) mg/dL [7.9 (2.4) mmol/L], and 102.6 (32.4) mg/dL [5.7 (1.8) mmol/L], respectively, under research conditions, and 81 (12.6) mg/dL [4.5 (0.7) mmol/L], 133.2 (41.4) mg/dL [7.4 (2.3) mmol/L], and 99 (32.4) mg/dL [5.5 (1.8) mmol/L] under usual conditions (all P 0.0001). GDM was diagnosed in 38.1% (n 59) under research conditions and 14.2% (n 22) under usual conditions (P 0.0001). The phlebotomy–analysis interval for the fasting, 1-h, and 2-h samples was 20 (9), 17 (10), and 17 (9) min under research conditions and 162 (19), 95 (23), and 32 (19) min under usual conditions (all P 0.0001). All cases of GDM were diagnosed on fasting or 1-h samples; the 2-h test diagnosed no additional cases. Conclusions: Implementation of ADA preanalytical glucose sample handling recommendations resulted in higher mean glucose concentrations and 2.7-fold increased detection of GDM compared with usual hospital practices.

National Variation in Caesarean Section Rates: A Cross Sectional Study in Ireland

Thu, 09 Jun 2016 00:00:00 GMT

National Variation in Caesarean Section Rates: A Cross Sectional Study in Ireland Sinnott, Sarah-Jo; Brick, Aoife; Layte, Richard; Cunningham, Nathan; Turner, Michael Objective: Internationally, caesarean section (CS) rates are rising. However, mean rates of CS across providers obscure extremes of CS provision. We aimed to quantify variation between all maternity units in Ireland. Methods: Two national databases, the National Perinatal Reporting System and the Hospital Inpatient Enquiry Scheme, were used to analyse data for all women delivering singleton births weighing ≥500g. We used multilevel models to examine variation between hospitals in Ireland for elective and emergency CS, adjusted for individual level sociodemographic, clinical and organisational variables. Analyses were subsequently stratified for nullipara and multipara with and without prior CS. Results: The national CS rate was 25.6% (range 18.2% ─ 35.1%). This was highest in multipara with prior CS at 86.1% (range 6.9% ─ 100%). The proportion of variation in CS that was attributable to the hospital of birth was 11.1% (95% CI, 6.0 ─ 19.4) for elective CS and 2.9% (95% CI, 1.4 ─ 5.6) for emergency CS, after adjustment. Stratifying across parity group, variation between hospitals was greatest for multipara with prior CS. Both types of CS were predicted by increasing age, prior history of miscarriage or stillbirth, prior CS, antenatal complications and private model of care. Conclusion: The proportion of variation attributable to the hospital was higher for elective CS than emergency CS suggesting that variation is more likely influenced by antenatal decision making than intrapartum decision making. Multipara with prior CS were particularly subject to variability, highlighting a need for consensus on appropriate care in this group.

A needs assessment of the number of comprehensive addiction care physicians required in a Canadian setting

Fri, 01 Jan 2016 00:00:00 GMT

A needs assessment of the number of comprehensive addiction care physicians required in a Canadian setting McEachern, Jasmine; Ahamad, Keith; Nolan, Seonaid; Mead, Annabel; Wood, Evan; Klimas, Jan Objective: Medical professionals adequately trained to prevent and treat substance use disorders are in short supply in most areas of the world. Whereas physician training in addiction medicine can improve patient and public health outcomes, the coverage estimates have not been established. We estimated the extent of the need for medical professionals skilled in addiction medicine in a Canadian setting. Methods: We used Monte-Carlo simulations to generate medians and 95% credibility intervals for the burden of alcohol and drug use harms, including morbidity and mortality, in British Columbia, by geographic health region. We obtained prevalence estimates for the models from the Medical Services Plan billing, the Discharge Abstract Database data, and the government surveillance data. We calculated a provider availability index (PAI), a ratio of the size of the labor force per 1000 affected individuals, for each geographic health region, using the number of American Board of Addiction Medicine certified physicians in each area. Results: Depending on the data source used for population estimates, the availability of specialized addiction care providers varied across geographic health regions. For drug-related harms, we found the highest PAI of 23.72 certified physicians per 1000 affected individuals, when using the Medical Services Plan and Discharge Abstract Database data. Drawing on the surveillance data, the drug-related PAI dropped to 0.46. The alcohol-related PAI ranged between 0.10 and 86.96 providers, depending on data source used for population estimates. Conclusions: Our conservative estimates highlight the need to invest in healthcare provider training and to develop innovative approaches for more rural health regions.

Poor agreement between operators on grading of the placenta

Sat, 01 Jan 2011 00:00:00 GMT

Poor agreement between operators on grading of the placenta Moran, Mary; Ryan, John; Higgins, Mary; Brennan, Patrick; McAuliffe, Fionnuala M. Abnormal placental grading is associated with poor pregnancy outcome. The aim of this study was to measure intra- and interobserver variability in placental grading. Five expert sonographers independently graded 90 images on two occasions, each viewing separated by 1 week. A number of measures were employed to standardise assessment and minimise potential for variation: prior agreement was established between observers on the classifications for placental grading; a controlled viewing laboratory was used for all viewings; ambient lighting was optimal and monitors were calibrated to the GSDF standard. Kappa (κ) analysis was used to measure observer agreement. Substantial variations between individuals' scores were observed. A mean κ-value of 0.34 (range from 0.19 to 0.50) indicated fair interobserver agreement over the two occasions and only nine of the 90 images were graded the same by all five observers. Intraobserver agreement had a moderate mean κ-value of 0.52, with individual comparisons ranging from 0.45 to 0.66. This study demonstrates that, despite standardised viewing conditions, Grannum grading of the placenta is not a reliable technique even among expert observers. The need for new methods to assess placental health is required and work is ongoing to develop 2D and 3D software-based methods.

Imaging and assessment of placental function

Thu, 01 Sep 2011 00:00:00 GMT

Imaging and assessment of placental function Moran, Mary; McAuliffe, Fionnuala M. The placenta is the vital support organ for the developing fetus. This article reviews current ultrasound (US) methods of assessing placental function. The ability of ultrasound to detect placental pathology is discussed. Doppler technology to investigate the fetal, placental, and maternal circulations in both high-risk and uncomplicated pregnancies is discussed and the current literature on the value of three-dimensional power Doppler studies to assess placental volume and vascularization is also evaluated. The article highlights the need for further research into three-dimensional ultrasound and alternative methods of placental evaluation if progress is to be made in optimizing placental function assessment.

Novel placental ultrasound assessment: Potential role in pre-gestational diabetic pregnancy

Fri, 01 Aug 2014 00:00:00 GMT

Novel placental ultrasound assessment: Potential role in pre-gestational diabetic pregnancy Moran, Mary; Mulcahy, C.; Daly, Leslie E.; Zombori, Gergely; Downey, P.; McAuliffe, Fionnuala M. Objectives: Management of women with pre-gestational diabetes continues to be challenging for clinicians. This study aims to determine if 3D power Doppler (3DPD) analysis of placental volume and flow, and calculation of placental calcification using a novel software method, differ between pregnancies with type 1 or type 2 diabetes and normal controls, and if there is a relationship between these ultrasound placental parameters and clinical measures in diabetics. Methods: This was a prospective cohort study of 50 women with diabetes and 250 controls (12–40 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental calcification was calculated by computer analysis. Results in diabetics were compared with control values, and correlated with early pregnancy HbA1c, Doppler results and placental histology. Results: Placental calcification and volume increased with advancing gestation in pre-gestational diabetic placentae. Volume was also found to be significantly higher than in normal placentae. VI and VFI were significantly lower in diabetic pregnancies between 35 and 40 weeks gestation. A strong relationship was seen between a larger placental volume and both increasing umbilical artery pulsatility index and decreasing middle cerebral artery pulsatility index. FI was significantly lower in cases which had a booking HbA1c level ≥6.5%. Ultrasound assessed placental calcification was reduced with a histology finding of delayed villous maturation. No other correlation with placental histology was found. Conclusions: This study shows a potential role for 3D placental evaluation, and computer analysis of calcification, in monitoring pre-gestational diabetic pregnancies.