Recent Submissions

  • ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly.

    Ubags, Niki D; Baker, Jonathan; Boots, Agnes; Costa, Rita; El-Merhie, Natalia; Fabre, Aurélie; Faiz, Alen; Heijink, Irene H; Hiemstra, Pieter S; Lehmann, Mareike; et al. (2020-03-02)
    In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.
  • Lysosomal Acid Lipase Deficiency: Therapeutic Options.

    Pastores, Gregory M; Hughes, Derralynn A (2020-02-11)
    Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in disease-relevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.
  • Investigation of the long-term yield of auditing for conformity with the ISO 15189:2012 quality standard in a hospital pathology laboratory.

    Green, Alastair David; Kavanagh-Wright, Lucille; Lee, Graham Robert (2020-03-04)
    Introduction: Pathology laboratories are increasingly seeking accreditation to quality standards to assure Quality of Service (QoS). However, there is little data available regarding the value of this in laboratories with well-established Quality Management Systems (QMS). Moreover, critics of accreditation claim it redirects resources toward trivial issues. Our objective was to investigate the value of auditing for conformity with the ISO 15189:2012 standard in such laboratories. Design: and Methods: In total, 483 Audit-Identified Non-Conformities (AINCs) were documented within our department since transitioning to an ISO 15189:2012 compliant QMS. The potential consequences of these were assessed by three clinical laboratorians who assigned them into categories based on their likely impact. These were: Unlikely (no clear consequences); Possible (potential for poor QoS/harm); and Probable (Likely to cause poor QoS/harm). Additionally, total numbers/severity of Real-Time Non-Conformities (RTNCs) detected outside of auditing were examined to provide additional insight into the effects of accreditation on QoS. Results: According to majority decision: 395 (81.8%) of AINCs were classified Unlikely, 88 (18.2%) were Possible, and none were Probable. The relative proportion of Unlikely AINCs also rose over time. Total numbers and severity of RTNCs dropped in the short-term following transition to an ISO 15189:2012 QMS, but steadily rose thereafter. Conclusions: Our data suggest auditing for conformity with ISO 15189:2012 standards may be effective in attaining accreditation, but may have diminishing returns in the long-term once the QMS is established, unless there is continual improvement in the audit process to promote better use of resources.
  • Towards European harmonisation of healthcare for patients with rare immune disorders: outcome from the ERN RITA registries survey.

    Papa, Riccardo; Cant, Andrew; Klein, Christoph; Little, Mark A; Wulffraat, Nico M; Gattorno, Marco; Ruperto, Nicolino (2020-01-30)
    The Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network is a European Research Network (ERN) that brings together the leading centres for rare immune disorders. On April 2018 an online survey was sent to all RITA members in order to facilitate the harmonization of data collection in rare immune disorders registries. Currently, as many as 52 different registries collect data on rare immune disorders, of whom 30 (58%) are dedicated primarily to autoimmune diseases, 15 (29%) to primary immunodeficiencies and 12 (23%) to autoinflammatory disorders. Improving data on patient safety, outcome, and quality of life measures is warranted to unfold the full potential of RITA registries.
  • Antimicrobial De-Escalation in the ICU: From Recommendations to Level of Evidence.

    Lakbar, Ines; De Waele, Jan J; Tabah, Alexis; Einav, Sharon; Martin-Loeches, Ignacio; Leone, Marc (2020-05-27)
    Antimicrobial de-escalation (ADE) is a component of antimicrobial stewardship (AMS) aimed to reduce exposure to broad-spectrum antimicrobials. In the intensive care unit, ADE is a strong recommendation that is moderately applied in clinical practice. Following a systematic review of the literature, we assessed the studies identified on the topic which included one randomized controlled trial and 20 observational studies. The literature shows a low level of evidence, although observational studies suggested that this procedure is safe. The effects of ADE on the level of resistance of ecological systems and especially on the microbiota are unclear. The reviewers recommend de-escalating antimicrobial treatment in patients requiring long-term antibiotic therapy and considering de-escalation in short-term treatments.
  • Developing a lung nodule management protocol specifically for cardiac CT: Methodology in the DISCHARGE trial.

    Haase, Robert; Dodd, Jonathan D; Kauczor, Hans-Ulrich; Kazerooni, Ella A; Dewey, Marc (2020-06-25)
    Purpose: In this methodology paper we describe the development of a lung nodule management algorithm specifically for patients undergoing cardiac CT. Methods: We modified the Lung-RADS algorithm specifically to manage lung nodules incidentally detected on cardiac CT (Lung-RADS for cardiac CT). We will evaluate the modified algorithm as part of the DISCHARGE trial ( in which patients with suspected coronary artery disease are randomly assigned to cardiac CT or invasive coronary angiography across Europe at 16 sites involving 3546 patients. Patients will be followed for up to four years. Results: The major adjustments to Lung-RADS specifically for cardiac CT relate to 1) incomplete coverage of the lungs by cardiac CT compared with chest CT, and when to order a completion chest CT versus a follow up chest CT, 2) cardiac CT findings will not trigger annual lung-cancer screening, and 3) a lower threshold of at least 10 mm for classifying new ground glass nodules as probably benign (category 3). Conclusions: The DISCHARGE trial will assess a lung nodule management algorithm designed specifically for cardiac CT in patients with stable chest pain across Europe.
  • PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer.

    Luszczak, Sabina; Kumar, Christopher; Sathyadevan, Vignesh Krishna; Simpson, Benjamin S; Gately, Kathy A; Whitaker, Hayley C; Heavey, Susan (2020-01-31)
    PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.
  • Survey on ART and IUI: legislation, regulation, funding and registries in European countries: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE).

    Calhaz-Jorge, C; De Geyter, C H; Kupka, M S; Wyns, C; Mocanu, E; Motrenko, T; Scaravelli, G; Smeenk, J; Vidakovic, S; Goossens, V (2020-02-06)
    Study question: How are ART and IUI regulated, funded and registered in European countries? Summary answer: Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding (also available in the 39 countries) varies across and sometimes within countries and national registries are in place in 31 countries. What is known already: Some information devoted to particular aspects of accessibility to ART and IUI is available, but most is fragmentary or out-dated. Annual reports from the European IVF-Monitoring (EIM) Consortium for ESHRE clearly mirror different approaches in European countries regarding accessibility to and efficacy of those techniques. Study design size duration: A survey was designed using the online SurveyMonkey tool consisting of 55 questions concerning three domains-legal, funding and registry. Answers refer to the countries' situation on 31 December 2018. Participants/materials settings methods: All members of EIM plus representatives of countries not yet members of the Consortium were invited to participate. Answers received were checked, and initial responders were asked to address unclear answers and to provide any additional information they considered important. Tables of individual countries resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, asking for a second check. Conflicting information was clarified by direct contact. Main results and the role of chance: Information was received from 43 out of the 44 European countries where ART and IUI are performed. Thirty-nine countries reported specific legislation on ART, and artificial insemination was considered an ART technique in 35 of them. Accessibility is limited to infertile couples in 11 of the 43 countries. A total of 30 countries offer treatments to single women and 18 to female couples. In five countries ART and IUI are permitted for treatment of all patient groups, being infertile couples, single women and same sex couples, male and female. Use of donated sperm is allowed in 41 countries, egg donation in 38, the simultaneous donation of sperm and egg in 32 and embryo donation in 29. Preimplantation genetic testing (PGT) for monogenic disorders or structural rearrangements is not allowed in two countries, and PGT for aneuploidy is not allowed in 11; surrogacy is accepted in 16 countries. With the exception of marital/sexual situation, female age is the most frequently reported limiting criteria for legal access to ART-minimal age is usually set at. 18 years and maximum ranging from 45 to 51 years with some countries not using numeric definition. Male maximum age is set in very few countries. Where permitted, age is frequently a limiting criterion for third-party donors (male maximum age 35 to 55 years; female maximum age 34 to 38 years). Other legal constraints in third-party donation are the number of children born from the same donor (in some countries, number of families with children from the same donor) and, in 10 countries, a maximum number of egg donations. How countries deal with the anonymity is diverse-strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), mixed system (anonymous and non-anonymous donations) and strict non-anonymity.Public funding systems are extremely variable. Four countries provide no financial assistance to patients. Limits to the provision of funding are defined in all the others i.e. age (female maximum age is the most used), existence of previous children, maximum number of treatments publicly supported and techniques not entitled for funding. In a few countries, reimbursement is linked to a clinical policy. The definition of the type of expenses covered within an IVF/ICSI cycle, up to what limit and the proportion of out-of-pocket costs for patients is also extremely dissimilar.National registries of ART and IUI are in place in 31 out of the 43 countries contributing to the survey, and a registry of donors exists in 18 of them. Limitations reasons for caution: The responses were provided by well-informed and committed individuals and submitted to double checking. Since no formal validation was in place, possible inaccuracies cannot be excluded. Also, results are a cross section in time and ART and IUI legislations within European countries undergo continuous evolution. Finally, several domains of ART activity were deliberately left out of the scope of this ESHRE survey. Wider implications of the findings: Results of this survey offer a detailed view of the ART and IUI situation in European countries. It provides updated and extensive answers to many relevant questions related to ART usage at national level and could be used by institutions and policymakers in planning services at both national and European levels. Study funding/competing interests: The study has no external funding, and all costs were covered by ESHRE. There were no competing interests.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.
  • Correction to: Core Rehabilitation Outcome Set for Single Sided Deafness (CROSSSD) study: protocol for an international consensus on outcome measures for single sided deafness interventions using a modified Delphi survey.

    Katiri, Roulla; Hall, Deborah A; Buggy, Nora; Hogan, Nicholas; Horobin, Adele; van de Heyning, Paul; Firszt, Jill B; Bruce, Iain A; Kitterick, Pádraig T (2020-03-17)
    Following the publication of our article [1], the authors have notified us of a typo in the third bullet point of the Consensus Criteria section.
  • Heart University: a new online educational forum in paediatric and adult congenital cardiac care. The future of virtual learning in a post-pandemic world?

    Tretter, Justin T; Windram, Jonathan; Faulkner, Theresa; Hudgens, Michelle; Sendzikaite, Skaiste; Blom, Nico A; Hanseus, Katarina; Loomba, Rohit S; McMahon, Colin J; Zheleva, Bistra; et al. (2020-04-13)
    Online learning has become an increasingly expected and popular component for education of the modern-day adult learner, including the medical provider. In light of the recent coronavirus pandemic, there has never been more urgency to establish opportunities for supplemental online learning. Heart University aims to be "the go-to online resource" for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of paedagogical material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practising provider. In this manuscript, we review the aims, development, current offerings and standing, and future goals of Heart University.
  • Taking guidance from parents involved in a longitudinal birth cohort - the ROLO family advisory committee.

    Walsh, N M; O'Brien, E C; Geraghty, A A; Byrne, D F; Whelan, A; Reilly, S; Murray, S; Reilly, C; Adams, E; Farnan, P M; et al. (2020-04-28)
    Background: The ROLO Study (Randomised cOntrol trial of a Low glycaemic index diet in pregnancy to prevent macrosomia) was a randomised control trial conducted between 2007 and 2011 to examine if a low glycaemic index (GI) diet could reduce the incidence of macrosomia. The ROLO Family Advisory Committee is a self-selected group of parents who are involved in the longitudinal follow-up of the ROLO Study. The committee was established in 2017 and the goal is to achieve a partnership between ROLO families and researchers, leading to improved research quality, relevance, and outcomes. This research method is termed "Public and patient involvement (PPI)" and describes how researchers collaborate and engage with the public in order to make research more relevant to them. Methods: The ROLO study mothers and children have been prospectively followed-up at multiple time points post-pregnancy. In October 2017, all women were invited to join the ROLO Family Advisory Committee via email or via advertisement on the ROLO Study Facebook page. Fathers and other guardians of the study children were also invited to join. Two annual meetings with the research team and parents were held in 2018 and 2019. The meetings were recorded, transcribed verbatim by researchers, and thematically analysed. Results: Parents provided opinions on the areas they felt should be explored within the ROLO study using information that was collected up to the current follow-up point. They also shared views on research interests which were of importance to them. These topics included; child mental health, fussy eating in childhood and healthy eating policies in schools. Mothers were much more concerned about factors which influenced their child's health rather than their own. Incorporating an element of PPI to this study was found to be a positive learning experience for participants and researchers. Conclusion: The involvement of parents has enriched the research agenda at the UCD Perinatal Research Centre. We will continue to engage with the parents of the ROLO Study and plan to involve the children to explore their opinions at the next opportunity.
  • Difficult Airway Society guidelines for awake tracheal intubation (ATI) in adults.

    Ahmad, I; El-Boghdadly, K; Bhagrath, R; Hodzovic, I; McNarry, A F; Mir, F; O'Sullivan, E P; Patel, A; Stacey, M; Vaughan, D (2019-11-14)
    Awake tracheal intubation has a high success rate and a favourable safety profile but is underused in cases of anticipated difficult airway management. These guidelines are a comprehensive document to support decision making, preparation and practical performance of awake tracheal intubation. We performed a systematic review of the literature seeking all of the available evidence for each element of awake tracheal intubation in order to make recommendations. In the absence of high-quality evidence, expert consensus and a Delphi study were used to formulate recommendations. We highlight key areas of awake tracheal intubation in which specific recommendations were made, which included: indications; procedural setup; checklists; oxygenation; airway topicalisation; sedation; verification of tracheal tube position; complications; management of unsuccessful awake tracheal intubation; post-tracheal intubation management; consent; and training. We recognise that there are a range of techniques and regimens that may be effective and one such example technique is included. Breaking down the key practical elements of awake tracheal intubation into sedation, topicalisation, oxygenation and performance might help practitioners to plan, perform and address complications. These guidelines aim to support clinical practice and help lower the threshold for performing awake tracheal intubation when indicated.
  • Speech Sound Disorders in Children: An Articulatory Phonology Perspective.

    Namasivayam, Aravind Kumar; Coleman, Deirdre; O'Dwyer, Aisling; van Lieshout, Pascal (2020-01-28)
    Speech Sound Disorders (SSDs) is a generic term used to describe a range of difficulties producing speech sounds in children (McLeod and Baker, 2017). The foundations of clinical assessment, classification and intervention for children with SSD have been heavily influenced by psycholinguistic theory and procedures, which largely posit a firm boundary between phonological processes and phonetics/articulation (Shriberg, 2010). Thus, in many current SSD classification systems the complex relationships between the etiology (distal), processing deficits (proximal) and the behavioral levels (speech symptoms) is under-specified (Terband et al., 2019a). It is critical to understand the complex interactions between these levels as they have implications for differential diagnosis and treatment planning (Terband et al., 2019a). There have been some theoretical attempts made towards understanding these interactions (e.g., McAllister Byun and Tessier, 2016) and characterizing speech patterns in children either solely as the product of speech motor performance limitations or purely as a consequence of phonological/grammatical competence has been challenged (Inkelas and Rose, 2007; McAllister Byun, 2012). In the present paper, we intend to reconcile the phonetic-phonology dichotomy and discuss the interconnectedness between these levels and the nature of SSDs using an alternative perspective based on the notion of an articulatory "gesture" within the broader concepts of the Articulatory Phonology model (AP; Browman and Goldstein, 1992). The articulatory "gesture" serves as a unit of phonological contrast and characterization of the resulting articulatory movements (Browman and Goldstein, 1992; van Lieshout and Goldstein, 2008). We present evidence supporting the notion of articulatory gestures at the level of speech production and as reflected in control processes in the brain and discuss how an articulatory "gesture"-based approach can account for articulatory behaviors in typical and disordered speech production (van Lieshout, 2004; Pouplier and van Lieshout, 2016). Specifically, we discuss how the AP model can provide an explanatory framework for understanding SSDs in children. Although other theories may be able to provide alternate explanations for some of the issues we will discuss, the AP framework in our view generates a unique scope that covers linguistic (phonology) and motor processes in a unified manner.
  • Medical Management of Patients After Atypical Femur Fractures: a Systematic Review and Recommendations From the European Calcified Tissue Society.

    van de Laarschot, Denise M; McKenna, Malachi J; Abrahamsen, Bo; Langdahl, Bente; Cohen-Solal, Martine; Guañabens, Núria; Eastell, Richard; Ralston, Stuart H; Zillikens, M Carola
    Context: Atypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing. Evidence acquisition: We performed a systematic review to evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF. Evidence synthesis: We retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient. Conclusions: There is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion.
  • Development and use of health outcome descriptors: a guideline development case study.

    Baldeh, Tejan; Saz-Parkinson, Zuleika; Muti, Paola; Santesso, Nancy; Morgano, Gian Paolo; Wiercioch, Wojtek; Nieuwlaat, Robby; Gräwingholt, Axel; Broeders, Mireille; Duffy, Stephen; et al. (2020-06-05)
    Background: During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed 'health outcome descriptors' for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. Methods: We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. Results: Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. Conclusions: Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.
  • Histone Acetylation as a Regenerative Target in the Dentine-Pulp Complex.

    Yamauchi, Yukako; Cooper, Paul Roy; Shimizu, Emi; Kobayashi, Yoshifumi; Smith, Anthony J; Duncan, Henry Fergus (2020-02-06)
    If dental caries (or tooth decay) progresses without intervention, the infection will advance through the dentine leading to severe pulpal inflammation (irreversible pulpitis) and pulp death. The current management of irreversible pulpits is generally root-canal-treatment (RCT), a destructive, expensive, and often unnecessary procedure, as removal of the injurious stimulus alone creates an environment in which pulp regeneration may be possible. Current dental-restorative-materials stimulate repair non-specifically and have practical limitations; as a result, opportunities exist for the development of novel therapeutic strategies to regenerate the damaged dentine-pulp complex. Recently, epigenetic modification of DNA-associated histone 'tails' has been demonstrated to regulate the self-renewal and differentiation potential of dental-stem-cell (DSC) populations central to regenerative endodontic treatments. As a result, the activities of histone deacetylases (HDAC) are being recognised as important regulators of mineralisation in both tooth development and dental-pulp-repair processes, with HDAC-inhibition (HDACi) promoting pulp cell mineralisation in vitro and in vivo. Low concentration HDACi-application can promote de-differentiation of DSC populations and conversely, increase differentiation and accelerate mineralisation in DSC populations. Therapeutically, various HDACi solutions can release bioactive dentine-matrix-components (DMCs) from the tooth's extracellular matrix; solubilised DMCs are rich in growth factors and can stimulate regenerative processes such as angiogenesis, neurogenesis, and mineralisation. The aim of this mini-review is to discuss the role of histone-acetylation in the regulation of DSC populations, while highlighting the importance of HDAC in tooth development and dental pulp regenerative-mineralisation processes, before considering the potential therapeutic application of HDACi in targeted biomaterials to the damaged pulp to stimulate regeneration.
  • Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study.

    Nolan, Beatrice; Mahlangu, Johnny; Pabinger, Ingrid; Young, Guy; Konkle, Barbara A; Barnes, Chris; Nogami, Keiji; Santagostino, Elena; Pasi, K John; Khoo, Liane; et al. (2020-03-30)
    Introduction: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. Aim: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. Conclusion: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.
  • Optimum nutritional strategies for cardiovascular disease prevention and rehabilitation (BACPR).

    Butler, Tom; Kerley, Conor P; Altieri, Nunzia; Alvarez, Joe; Green, Jane; Hinchliffe, Julie; Stanford, Dell; Paterson, Katherine (2020-02-25)
    Nutrition has a central role in both primary and secondary prevention of cardiovascular disease yet only relatively recently has food been regarded as a treatment, rather than as an adjunct to established medical and pharmacotherapy. As a field of research, nutrition science is constantly evolving making it difficult for patients and practitioners to ascertain best practice. This is compounded further by the inherent difficulties in performing double-blind randomised controlled trials. This paper covers dietary patterns that are associated with improved cardiovascular outcomes, including the Mediterranean Diet but also low-carbohydrate diets and the potential issues encountered with their implementation. We suggest there must be a refocus away from macronutrients and consideration of whole foods when advising individuals. This approach is fundamental to practice, as clinical guidelines have focused on macronutrients without necessarily considering their source, and ultimately people consume foods containing multiple nutrients. The inclusion of food-based recommendations aids the practitioner to help the patient make genuine and meaningful changes in their diet. We advocate that the cardioprotective diet constructed around the traditional Mediterranean eating pattern (based around vegetables and fruits, nuts, legumes, and unrefined cereals, with modest amounts of fish and shellfish, and fermented dairy products) is still important. However, there are other approaches that can be tried, including low-carbohydrate diets. We encourage practitioners to adopt a flexible dietary approach, being mindful of patient preferences and other comorbidities that may necessitate deviations away from established advice, and advocate for more dietitians in this field to guide the multi-professional team.
  • Cannabinoids in the Older Person: A Literature Review.

    Beedham, William; Sbai, Magda; Allison, Isabel; Coary, Roisin; Shipway, David (2020-01-13)
    Introduction: Medical cannabinoids have received significant mainstream media attention in recent times due to an evolving political and clinical landscape. Whilst the efficacy of cannabinoids in the treatment of some childhood epilepsy syndromes is increasingly recognized, medical cannabinoids may also have potential clinical roles in the treatment of older adults. Prescribing restrictions for medical cannabinoids in certain jurisdictions (including the UK) has recently been relaxed. However, few geriatricians have the detailed knowledge or awareness of the potential risks or rewards of utilizing cannabinoids in the older person; even fewer geriatricians have direct experience of using these drugs in their own clinical practice. Older persons are more likely to suffer from medical illness representing potential indications for medical cannabinoids (e.g., pain); equally they may be more vulnerable to any adverse effects. Aim: This narrative literature review aims to provide a brief introduction for the geriatrician to the potential indications, evidence-base, contra-indications and side effects of medical cannabinoids in older people. Methods: A search was conducted of CENTRAL, Medline, Embase, CINAHL and psycINFO, Cochrane and Web of Science databases. Reference lists were hand searched. Abstracts and titles were screened, followed by a full text reading of relevant articles. Results: 35 studies were identified as relevant for this narrative review. Conclusions: Cannabinoids demonstrate some efficacy in the treatment of pain and chemotherapy-related nausea; limited data suggest potential benefits in the treatment of spasticity and anxiety. Risks of cannabinoids in older patients appear to be moderate, and their frequency comparable to other analgesic drug classes. However, the quality of research is weak, and few older patients have been enrolled in cannabinoid studies. Dedicated research is needed to determine the efficiency and safety of cannabinoids in older patients.
  • Correction to: Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain.

    Rieckmann, Nina; Neumann, Konrad; Feger, Sarah; Ibes, Paolo; Napp, Adriane; Preuß, Daniel; Dreger, Henryk; Feuchtner, Gudrun; Plank, Fabian; Suchánek, Vojtěch; et al. (2020-06-29)

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