Publications by authors named "Ben Davies"

71 Publications

Recombinant Factor VIIa in Pediatric Cardiac Surgery.

J Cardiothorac Vasc Anesth 2021 Aug 8. Epub 2021 Aug 8.

Department of Anesthesia and Pain Management, The Royal Children's Hospital, Parkville, Australia. Electronic address:

Objectives: Recombinant activated factor VIIa (rVIIa) is used off-label for refractory bleeding after cardiac surgery. This study reviewed the indications, usage rates, and complications of rVIIa.

Design: A retrospective case-control observational study.

Setting: A single quaternary pediatric hospital.

Participants: All children undergoing cardiac surgery with cardiopulmonary bypass over a three-year period.

Interventions: Administration of rVIIa as rescue therapy for refractory bleeding after weaning from cardiopulmonary bypass.

Measurements And Main Results: Onethousand, five hundred fifteen cardiopulmonary bypass procedures were reviewed. Patients receiving rVIIa were each matched to two control patients by age, procedure type, and bypass time. Data collected included weight, crossclamp time, anticoagulant and antifibrinolytic dose, return to the operating room for bleeding, thrombotic events, and extracorporeal membrane oxygenation (ECMO) circuit interventions. Forty-two patients received rVIIa (2.8%). Major systemic thrombotic complications were observed in 19% (controls 12.5%) of patients; 80% of recombinant factor VIIa patients requiring postoperative ECMO had interventions for circuit thrombosis (controls 31.25%); 4.76% of rVIIa recipients required reexploration for intractable bleeding (controls 1.39%).

Conclusions: This study added to understanding regarding the use of recombinant factor VIIa in pediatric cardiac surgery and reported increased thrombotic complications, especially for children who progress to ECMO. Prospective studies to better understand the pathophysiology of coagulopathy and hemorrhage in pediatric cardiac surgery and the role of hemostatic agents, such as rVIIa, are required.
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http://dx.doi.org/10.1053/j.jvca.2021.08.002DOI Listing
August 2021

Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice.

Wellcome Open Res 2020 15;5:15. Epub 2021 Mar 15.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.

The K channel plays a key role in glucose homeostasis by coupling metabolically generated changes in ATP to insulin secretion from pancreatic beta-cells.  Gain-of-function mutations in either the pore-forming (Kir6.2) or regulatory (SUR1) subunit of this channel are a common cause of transient neonatal diabetes mellitus (TNDM), in which diabetes presents shortly after birth but remits within the first few years of life, only to return in later life. The reasons behind this time dependence are unclear. In an attempt to understand the mechanism behind diabetes remission and relapse, we generated mice expressing the common TNDM mutation SUR1-R1183W. We employed Cre/LoxP technology for both inducible and constitutive expression of SUR1-R1183W specifically in mouse beta-cells, followed by investigation of their phenotype using glucose tolerance tests and insulin secretion from isolated islets.  We found that the R1183W mutation impaired inhibition of K channels by ATP when heterologously expressed in human embryonic kidney cells. However, neither induced nor constitutive expression of SUR1-R1183W in mice resulted in changes in blood glucose homeostasis, compared to littermate controls. When challenged with a high fat diet, female mice expressing SUR1-R1183W showed increased weight gain, elevated blood glucose and impaired glycaemic control, but glucose-stimulated insulin secretion from pancreatic islets appeared unchanged. The mouse model of TNDM did not recapitulate the human phenotype. We discuss multiple potential reasons why this might be the case. Based on our findings, we recommend future TNDM mouse models employing a gain-of-function SUR1 mutation should be created using the minimally invasive CRISPR/Cas technology, which avoids many potential pitfalls associated with the Cre/LoxP system.
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http://dx.doi.org/10.12688/wellcomeopenres.15529.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323074PMC
March 2021

The Right Not to Know: some Steps towards a Compromise.

Ethical Theory Moral Pract 2021 Mar 29;24:137-150. Epub 2020 Oct 29.

Uehiro Centre for Practical Ethics, University of Oxford, Oxford OX1 1PT, UK.

There is an ongoing debate in medicine about whether patients have a 'right not to know' pertinent medical information, such as diagnoses of life-altering diseases. While this debate has employed various ethical concepts, probably the most widely-used by both defenders and detractors of the right is autonomy. Whereas defenders of the right not to know typically employ a 'liberty' conception of autonomy, according to which to be autonomous involves doing what one wants to do, opponents of the right not to know often employ a 'duty' understanding, viewing autonomy as involving an obligation to be self-governing. The central contribution of this paper is in showing that neither view of autonomy can reasonably be said to support the extreme stances on the right not to know that they are sometimes taken to. That is, neither can a liberty view properly defend a right not to know without limits, nor can a duty view form the basis of an absolute rejection of the right not to know. While there is still theoretical distance between these two approaches, we conclude that the views are considerably closer on this issue than they first appear, opening the way for a possible compromise.
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http://dx.doi.org/10.1007/s10677-020-10133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611423PMC
March 2021

Precisely Tuned Inhibition of HIF Prolyl Hydroxylases Is Key for Cardioprotection After Ischemia.

Circ Res 2021 Apr 25;128(8):1208-1210. Epub 2021 Feb 25.

Institute of Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany (A.J., A.Z., K.B.-C., A.M.V., D.M.K.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.318216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048377PMC
April 2021

Genome-wide CRISPR/Cas9-knockout in human induced Pluripotent Stem Cell (iPSC)-derived macrophages.

Sci Rep 2021 Feb 19;11(1):4245. Epub 2021 Feb 19.

Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.

Genome engineering using CRISPR/Cas9 technology enables simple, efficient and precise genomic modifications in human cells. Conventional immortalized cell lines can be easily edited or screened using genome-wide libraries with lentiviral transduction. However, cell types derived from the differentiation of induced Pluripotent Stem Cells (iPSC), which often represent more relevant, patient-derived models for human pathology, are much more difficult to engineer as CRISPR/Cas9 delivery to these differentiated cells can be inefficient and toxic. Here, we present an efficient, lentiviral transduction protocol for delivery of CRISPR/Cas9 to macrophages derived from human iPSC with efficiencies close to 100%. We demonstrate CRISPR/Cas9 knockouts for three nonessential proof-of-concept genes-HPRT1, PPIB and CDK4. We then scale the protocol and validate for a genome-wide pooled CRISPR/Cas9 loss-of-function screen. This methodology enables, for the first time, systematic exploration of macrophage involvement in immune responses, chronic inflammation, neurodegenerative diseases and cancer progression, using efficient genome editing techniques.
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http://dx.doi.org/10.1038/s41598-021-82137-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895961PMC
February 2021

Collective deviance: Scaling up subjective group dynamics to superordinate categories reveals a deviant ingroup protection effect.

J Pers Soc Psychol 2021 Jan 21. Epub 2021 Jan 21.

Centre for the Study of Group Processes.

Six experiments examined responses to groups whose attitudes deviated from wider social norms about asylum and immigration (in the United Kingdom), or about taxation levels (in the U.S.). Subjective group dynamics (SGD) theory states that people derogate in-group individuals who deviate from prescriptive in-group norms. This enables members to sustain the subjective validity of those norms and, hence, a positive social identity. Research also shows that in-group deviants who accentuate the difference between the in-group and out-group norm (e.g., extremists) are derogated less than deviants who attenuate that difference (e.g., a member who veers toward the outgroup's norm; Abrams et al., 2000). We hypothesize that these effects and the associated group dynamics should scale up when people evaluate deviant groups that are part of larger in-categories. Consistent with SGD theory, participants in Experiments 1, 2, and 3 derogated an in-category attenuating deviant group and upgraded an out-category attenuating deviant group relative to groups that consolidated or accentuated the respective norms of those categories-thereby reinforcing in-category norms relative to out-category norms. Across all experiments, this pattern of differential evaluation was associated with greater subjective validity of the in-category norm. We also hypothesized a novel Deviant Ingroup Protection (DIP) effect, wherein people should curtail derogation of an in-category deviant group when that group is their own. Consistent with this hypothesis, participants in Experiments 4, 5, and 6 evaluated an accentuating in-group, or an attenuating in-group, equally to or more positively than other in-category groups. Implications for political and organizational entrenchment are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pspi0000356DOI Listing
January 2021

No Blame No Gain? From a No Blame Culture to a Responsibility Culture in Medicine.

J Appl Philos 2020 Aug 10;37(4):646-660. Epub 2020 May 10.

Uehiro Centre for Practical Ethics University of Oxford Littlegate House, St Ebbe's Street Oxford OX1 1PT UK.

Healthcare systems need to consider not only how to prevent error, but how to respond to errors when they occur. In the United Kingdom's National Health Service, one strand of this latter response is the 'No Blame Culture', which draws attention from individuals and towards systems in the process of understanding an error. Defences of the No Blame Culture typically fail to distinguish between someone and holding them responsible. This article argues for a 'responsibility culture', where healthcare professionals are held responsible in cases of foreseeable and avoidable errors. We demonstrate how healthcare professionals can justifiably be held responsible for their errors even though they work in challenging circumstances. We then review the idea of 'responsibility without blame', applying this to cases of error in healthcare. Sensitive to the undesirable effects of blaming healthcare professionals and to the moral significance of holding individuals accountable, we argue that a responsibility culture has significant advantages over a No Blame Culture due to its capacity to enhance patient safety and support medical professionals in learning from their mistakes, while also recognising and validating the legitimate sense of responsibility that many medical professionals feel following avoidable error, and motivating medical professionals to report errors.
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http://dx.doi.org/10.1111/japp.12433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750815PMC
August 2020

Grow the pie, or the resource shuffle? Commentary on Munthe, Fumagalli and Malmqvist.

Authors:
Ben Davies

J Med Ethics 2021 02 17;47(2):98-99. Epub 2020 Dec 17.

Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK

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http://dx.doi.org/10.1136/medethics-2020-107056DOI Listing
February 2021

From Sufficient Health to Sufficient Responsibility.

J Bioeth Inq 2020 Sep 21;17(3):423-433. Epub 2020 Jul 21.

Uehiro Centre for Practical Ethics, University of Oxford, Suite 8, Littlegate House, St Ebbe's Street, Oxford, OX1 1PT, UK.

The idea of using responsibility in the allocation of healthcare resources has been criticized for, among other things, too readily abandoning people who are responsible for being very badly off. One response to this problem is that while responsibility can play a role in resource allocation, it cannot do so if it will leave those who are responsible below a "sufficiency" threshold. This paper considers first whether a view can be both distinctively sufficientarian and allow responsibility to play a role even for those who will be left with very poor health. It then draws several further distinctions that may affect the application of responsibility at this level. We conclude that a more plausible version of the sufficientarian view is to allow a role for responsibility where failure to do so will leave someone else who is not responsible below the sufficiency threshold. However, we suggest that individuals must exhibit "sufficient responsibility" in order for this to apply, involving both a sufficient level of control and an avoidable failure to respond adequately to reasons for action.
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http://dx.doi.org/10.1007/s11673-020-09992-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557480PMC
September 2020

The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): second EUROMACS Paediatric (Paedi-EUROMACS) report.

Eur J Cardiothorac Surg 2020 06;57(6):1038-1050

Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.

Objectives: A second paediatric report has been generated from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). The purpose of EUROMACS, which is operated by the European Association for Cardio-Thoracic Surgery, is to gather data related to durable mechanical circulatory support for scientific purposes and to publish reports with respect to the course of mechanical circulatory support therapy. Since the first report issued, efforts to increase compliance and participation have been extended. Additionally, the data provided the opportunity to analyse patients of younger age and lower weight.

Methods: Participating hospitals contributed pre-, peri- and long-term postoperative data on mechanical circulatory support implants to the registry. Data for all implants in paediatric patients (≤19 years of age) performed from 1 January 2000 to 1 July 2019 were analysed. This report includes updates of patient characteristics, implant frequency, outcome (including mortality rates, transplants and recovery rates) as well as adverse events including neurological dysfunction, device malfunction, major infection and bleeding.

Results: Twenty-nine hospitals contributed 398 registered implants in 353 patients (150 female, 203 male) to the registry. The most frequent aetiology of heart failure was any form of cardiomyopathy (61%), followed by congenital heart disease and myocarditis (16.4% and 16.1%, respectively). Competing outcomes analysis revealed that a total of 80% survived to transplant or recovery or are ongoing; at the 2-year follow-up examination, 20% died while on support. At 12 months, 46.7% received transplants, 8.7% were weaned from their device and 18.5% died. The 3-month adverse events rate was 1.69 per patient-year for device malfunction including pump exchange, 0.48 for major bleeding, 0.64 for major infection and 0.78 for neurological events.

Conclusions: The overall survival rate was 81.5% at 12 months following ventricular assist device implant. The comparison of survival rates of the early and later eras shows no significant difference. A focus on specific subgroups showed that survival was less in patients of younger age (<1 year of age) (P = 0.01) and lower weight (<20 kg) (P = 0.015). Transplant rates at 6 months continue to be low (33.2%) The fact that the EUROMACS registry is embedded within the European Association for Cardio-Thoracic Surgery Quality Improvement Programme offers opportunities to focus on improving outcomes.
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http://dx.doi.org/10.1093/ejcts/ezaa132DOI Listing
June 2020

'The right not to know and the obligation to know', response to commentaries.

Authors:
Ben Davies

J Med Ethics 2020 05 29;46(5):309-310. Epub 2020 Apr 29.

Uehiro Centre for Practical Ethics, University of Oxford, Oxford OX1 1PT, UK

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http://dx.doi.org/10.1136/medethics-2020-106261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279182PMC
May 2020

The right not to know and the obligation to know.

Authors:
Ben Davies

J Med Ethics 2020 05 29;46(5):300-303. Epub 2020 Apr 29.

Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK

There is significant controversy over whether patients have a 'right not to know' information relevant to their health. Some arguments for limiting such a right appeal to potential burdens on others that a patient's avoidable ignorance might generate. This paper develops this argument by extending it to cases where refusal of relevant information may generate greater demands on a publicly funded healthcare system. In such cases, patients may have an 'obligation to know'. However, we cannot infer from the fact that a patient has an obligation to know that she does not also have a right not to know. The right not to know is held against medical professionals at a formal institutional level. We have reason to protect patients' control over the information that they receive, even if in individual instances patients exercise this control in ways that violate obligations.
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http://dx.doi.org/10.1136/medethics-2019-106009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250654PMC
May 2020

Determining when a hospital admission of an older person can be avoided in a subacute setting: a systematic review and concept analysis.

J Health Serv Res Policy 2020 10 5;25(4):252-264. Epub 2019 Dec 5.

Senior Research Associate, Centre of Academic Primary Care, School of Population Science, University of Bristol, UK.

Objective: To conduct a systematic review of the evidence for when a hospital admission for an older person can be avoided in subacute settings. We examined the definition of admission avoidance and the evidence for the factors that are required to avoid admission to hospital in this setting.

Methods: Using defined PICOD criteria, we conducted searches in three databases (Medline, Embase and Cinahl) from January 2006 to February 2018. References were screened by title and abstract followed by full paper screening by two reviewers. Additional studies were searched from the grey literature, experts in the field and forward and backward referencing. Data were narratively described, and concept analysis was used to investigate the definition of admission avoidance.

Results: A total of 17 studies were considered eligible for review; eight provided a definition of admission avoidance and 10 described admission avoidance criteria. We identified three factors which play a key role in admission avoidance in the subacute setting: (1) , which included respiratory infections or pneumonia, urinary tract infections and catheter care, dehydration and associated symptoms, falls and behavioural management, and managing ongoing chronic conditions; (2) , referring to interventions that have used clinical expertise in conjunction with a range of general and geriatric triage tools; in condition-specific interventions, the decision whether to admit or not was based on level of risk determined by defined clinical tools; and (3) , referring to the need for experts to make the initial decision to avoid an admission. Supervision by nurses or physicians was still needed at subacute level, requiring resources such as short-stay beds, intravenous antibiotic treatment or fluids for rehydration and rapid access to laboratory tests.

Conclusion: The review identified a set of criteria for ambulatory care sensitive conditions and common medical scenarios for the older person that can be treated in the subacute setting with appropriate tools and resources. This information can help commissioners and care providers to take on these important elements and deliver them in a locally designed way.
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http://dx.doi.org/10.1177/1355819619886885DOI Listing
October 2020

Solidarity and Responsibility in Health Care.

Public Health Ethics 2019 Jul 4;12(2):133-144. Epub 2019 Jul 4.

Uehiro Chair in Practical Ethics.

Some healthcare systems are said to be grounded in solidarity because healthcare is funded as a form of mutual support. This article argues that health care systems that are grounded in solidarity have the right to penalise some users who are responsible for their poor health. This derives from the fact that solidary systems involve both rights and obligations and, in some cases, those who avoidably incur health burdens violate obligations of solidarity. Penalties warranted include direct patient contribution to costs, and lower priority treatment, but not typically full exclusion from the healthcare system. We also note two important restrictions on this argument. First, failures of solidary obligations can only be assumed under conditions that are conducive to sufficiently autonomous choice, which occur when patients are given 'Golden Opportunities' to improve their health. Second, because poor health does not occur in a social vacuum, an insistence on solidarity as part of healthcare is legitimate only if all members of society are held to similar standards of solidarity. We cannot insist upon, and penalise failures of, solidarity only for those who are unwell, and who cannot afford to evade the terms of public health.
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http://dx.doi.org/10.1093/phe/phz008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655468PMC
July 2019

Systemic silencing of PHD2 causes reversible immune regulatory dysfunction.

J Clin Invest 2019 06 4;129(9):3640-3656. Epub 2019 Jun 4.

Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity.
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http://dx.doi.org/10.1172/JCI124099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715380PMC
June 2019

Successful lung donation at the age of 6 weeks: Challenges and lessons learned.

Pediatr Transplant 2019 06 23;23(4):e13419. Epub 2019 Apr 23.

Royal Papworth Hospital, Cambridge, UK.

A clinical case of successful procurement and transplantation of bilateral lungs from 6-week-old infant with sepsis secondary to bacterial meningitis is reported. Forty-one-day-old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO 50.4 kPa (378 mm Hg), pCO 4.9 kPa (37 mm Hg), on FiO 100%, PEEP 5 cm H O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram-stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4-month-old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6-week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.
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http://dx.doi.org/10.1111/petr.13419DOI Listing
June 2019

Permanent pacemaker implantation after pediatric heart transplantation: Risk factors, indications, and outcomes.

Clin Transplant 2019 04 6;33(4):e13503. Epub 2019 Mar 6.

Great Ormond Street Hospital for Children Foundation Trust, London, UK.

Background: Permanent pacemaker (PPM) placement in adults following orthotopic heart transplantation (OHT) has been well documented. However, studies concerning the need for PPM implantation in pediatric heart transplant recipients are less common.

Methods: Institutional transplant and pacing databases as well as patient medical records were reviewed for all pediatric patients undergoing OHT (n = 314; all with bicaval connection) at our institution between January 2000 and March 2018.

Results: A total of 16 patients (5.1%) were implanted with a pacemaker after transplantation. Donor age was the only significant risk factor for post-transplant PPM implantation, with a median age of 28.5 years (7.0-49.0) in the pacing group vs 15.5 years (0.4-56.0) in the non-pacing group (P = 0.009). Indication for pacemaker insertion was more often complete heart block (CHB) (12/16, 75%) than sinus node dysfunction (SND) (4/16, 25%). There was no significant difference in mortality between recipients who received a PPM and those who did not (log-rank test; P = 0.345).

Conclusions: Increasing donor age is associated with increased PPM placement following pediatric heart transplantation. Interestingly, a high proportion of CHB patients recovered sinus rhythm, and long-term outcomes for paced patients are similar to other heart transplant recipients.
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http://dx.doi.org/10.1111/ctr.13503DOI Listing
April 2019

Frailty assessment in primary health care and its association with unplanned secondary care use: a rapid review.

BJGP Open 2018 Apr 10;2(1):bjgpopen18X101325. Epub 2018 Apr 10.

Research Fellow, Centre for Academic Primary Care, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: The growing frail, older population is increasing pressure on hospital services. This is directing the attention of clinical commissioning groups towards more comprehensive approaches to managing frailty in the primary healthcare environment.

Aim: To review the literature on whether assessment of frailty in primary health care leads to a reduction in unplanned secondary care use.

Design & Setting: A rapid review involving a systematic search of Medline and Medline In-Process.

Method: Relevant data were extracted following the iterative screening of titles, abstracts, and full texts to identify studies in the primary or community healthcare setting which assessed the effect of frailty on unplanned secondary care use between January 2005-June 2016.

Results: The review included 11 primary studies: nine observational studies; one randomised controlled trial (RCT); and one non-randomised controlled trial (nRCT). Eight out of nine observational studies reported a positive association between frailty and secondary care utilisation. The RCT and nRCT reported conflicting findings.

Conclusion: Older people identified as frail in a primary healthcare setting were more likely to be admitted to hospital. Based on the limited and equivocal trial evidence, it is not possible to draw firm conclusions regarding appropriate tools for the identification and management of frail older people at risk of hospital admission.
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http://dx.doi.org/10.3399/bjgpopen18X101325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181074PMC
April 2018

Parental Feeding Beliefs and Practices and Household Food Insecurity in Infancy.

Acad Pediatr 2019 Jan - Feb;19(1):80-89. Epub 2018 Sep 21.

Department of Pediatrics and Duke Center for Childhood Obesity Research (SN Ravanbakht, CT Wood, and EM Perrin), Duke University Medical Center, Durham, NC. Electronic address:

Objective: Food insecurity is associated with childhood obesity possibly mediated through caregiver feeding practices and beliefs. We examined if caregiver feeding practices differed by household food security status in a diverse sample of infants. We hypothesized that feeding practices differ based on food security status.

Patients And Methods: Included in the baseline cross-sectional analysis of data from a randomized controlled trial to prevent obesity were 842 caregivers of 2-month-old infants presenting for well-child care at 4 academic institutions. Food insecurity exposure was based on an affirmative answer to 1 of 2 items in a 2-item validated questionnaire. Chi-square tests examined the association between parent feeding practices and food security status. Logistic regression adjusted for covariates. Differences in caregiver feeding practices by food security status and race/ethnicity were explored with an interaction term (food security status x race/ethnicity).

Results: Forty-three percent of families screened as food insecure. In adjusted logistic regression, parents from food-insecure households were more likely to endorse that "the best way to make an infant stop crying is to feed him or her" (adjusted odds ratio [aOR], 1.72; 95% confidence interval [CI], 1.28-2.29) and "when my baby cries, I immediately feed him or her" (aOR, 1.40; 95% CI, 1.06-1.83). Food-insecure caregivers less frequently endorsed paying attention to their baby when he or she is full or hungry (OR, 0.57; 95% CI, 0.34-0.96). Racial/ethnic differences in beliefs and behaviors were observed by food security status.

Conclusions: During early infancy, feeding practices differed among caregivers by household food security status. Further research is needed to examine whether these practices are associated with increased risk of obesity and obesity-related morbidity.
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http://dx.doi.org/10.1016/j.acap.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599601PMC
February 2020

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

J Am Soc Nephrol 2018 07 13;29(7):1849-1858. Epub 2018 Apr 13.

Centre for Nephrology and.

For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. analysis showed that the particular mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. In this novel genetic disorder, fully penetrant heterozygous missense mutations in trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
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http://dx.doi.org/10.1681/ASN.2017111179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050927PMC
July 2018

Long-Term Outcome of Interrupted Arch Repair With Direct Anastomosis and Homograft Augmentation Patch.

Ann Thorac Surg 2018 06 13;105(6):1819-1826. Epub 2018 Feb 13.

Department of Cardiac Surgery, Birmingham Children's Hospital, Birmingham, United Kingdom. Electronic address:

Background: This study analyzed outcomes of interrupted aortic arch (IAA) repair using a standardized technique to interpret the role of the arch repair on late outcomes in a complex and heterogeneous group of patients.

Methods: This single institution study covered the period from 1988 to 2015. A total of 120 cases of IAA were divided into four groups: IAA with ventricular septal defect (VSD) (n = 38), IAA with a Norwood or Damus-Kaye-Stansel procedure (n = 41), IAA with truncus arteriosus (n = 24), and a miscellaneous group (n = 17). Arch repair was performed using a standard technique of direct anastomosis with homograft patch augmentation.

Results: IAAs were predominantly type B (n = 81, 68%), and type A (n = 34, 28%), with a significant association of type B with truncus arteriosus and of type A with an aortopulmonary window (p < 0.01). Survival was similar in all groups. The incidence of catheter or surgical reintervention was 18% (confidence interval [CI], 10% to 25%) at 5 years and 18% (CI, 10% to 25%) at 10 years, with catheter reintervention more common and occurring before 18 months. Surgical reintervention occurred in 7% (CI, 2% to 13%) at 5 and 10 years and at 10 years the reintervention rate was lower in the group with truncus arteriosus (0%) and in the group with a Norwood or Damus-Kaye-Stansel procedure (5%). There was no bronchial obstruction or aortic aneurysm. The Cox proportional hazard model showed that weight at surgery <2.5 kg and era of surgery were predictive of outcome, with surgical mortality rates in all variants dropping to 8.3% in the last 15 years of the study.

Conclusions: Repair of IAA using direct anastomosis and patch augmentation is applicable to all variants and provides good long-term arch patency. Survival is strongly associated with weight at surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2018.01.035DOI Listing
June 2018

A randomised trial of the influence of racial stereotype bias on examiners' scores, feedback and recollections in undergraduate clinical exams.

BMC Med 2017 10 25;15(1):179. Epub 2017 Oct 25.

Centre for Health Education Scholarship, Faculty of Health, University of British Columbia, Vancouver, Canada.

Background: Asian medical students and doctors receive lower scores on average than their white counterparts in examinations in the UK and internationally (a phenomenon known as "differential attainment"). This could be due to examiner bias or to social, psychological or cultural influences on learning or performance. We investigated whether students' scores or feedback show influence of ethnicity-related bias; whether examiners unconsciously bring to mind (activate) stereotypes when judging Asian students' performance; whether activation depends on the stereotypicality of students' performances; and whether stereotypes influence examiner memories of performances.

Methods: This is a randomised, double-blinded, controlled, Internet-based trial. We created near-identical videos of medical student performances on a simulated Objective Structured Clinical Exam using British Asian and white British actors. Examiners were randomly assigned to watch performances from white and Asian students that were either consistent or inconsistent with a previously described stereotype of Asian students' performance. We compared the two examiner groups in terms of the following: the scores and feedback they gave white and Asian students; how much the Asian stereotype was activated in their minds (response times to Asian-stereotypical vs neutral words in a lexical decision task); and whether the stereotype influenced memories of student performances (recognition rates for real vs invented stereotype-consistent vs stereotype-inconsistent phrases from one of the videos).

Results: Examiners responded to Asian-stereotypical words (716 ms, 95% confidence interval (CI) 702-731 ms) faster than neutral words (769 ms, 95% CI 753-786 ms, p < 0.001), suggesting Asian stereotypes were activated (or at least active) in examiners' minds. This occurred regardless of whether examiners observed stereotype-consistent or stereotype-inconsistent performances. Despite this stereotype activation, student ethnicity had no influence on examiners' scores; on the feedback examiners gave; or on examiners' memories for one performance.

Conclusions: Examiner bias does not appear to explain the differential attainment of Asian students in UK medical schools. Efforts to ensure equality should focus on social, psychological and cultural factors that may disadvantage learning or performance in Asian and other minority ethnic students.
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http://dx.doi.org/10.1186/s12916-017-0943-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655938PMC
October 2017

Red supergiants as supernova progenitors.

Authors:
Ben Davies

Philos Trans A Math Phys Eng Sci 2017 Oct;375(2105)

Astrophysics Research Institute, Liverpool John Moores University, Liverpool Science Park ic2, 146 Brownlow Hill, Liverpool L3 5RF, UK

It is now well-established from pre-explosion imaging that red supergiants (RSGs) are the direct progenitors of Type-IIP supernovae. These images have been used to infer the physical properties of the exploding stars, yielding some surprising results. In particular, the differences between the observed and predicted mass spectrum has provided a challenge to our view of stellar evolutionary theory. However, turning what is typically a small number of pre-explosion photometric points into the physical quantities of stellar luminosity and mass requires a number of assumptions about the spectral appearance of RSGs, as well as their evolution in the last few years of life. Here I will review what we know about RSGs, with a few recent updates on how they look and how their appearance changes as they approach supernova.This article is part of the themed issue 'Bridging the gap: from massive stars to supernovae'.
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http://dx.doi.org/10.1098/rsta.2016.0270DOI Listing
October 2017

Delivery and Receipt of a Self-Determination-Theory-Based Extracurricular Physical Activity Intervention: Exploring Theoretical Fidelity in Action 3:30.

J Sport Exerc Psychol 2016 Aug 13;38(4):381-395. Epub 2016 Oct 13.

1 University of Bristol.

The implementation, fidelity, and receipt of a self-determination-theory-based after-school physical activity intervention (Action 3:30) delivered by teaching assistants (TAs) was examined using a mixed-methods process evaluation. Physical activity motivation and need satisfaction were reported by 539 participants at baseline, the end of intervention, and 4-month follow-up. Pupil- and TA-reported autonomy-support and teaching efficacy were collected alongside interviews with 18 TAs and focus groups with 60 participants. Among intervention boys there were small increases in identified, introjected, and external motivation and no differences in need satisfaction. Among girls, intrinsic and identified motivation and autonomy and relatedness were lower in the intervention group. Qualitative evidence for fidelity was moderate, and boys reported greater need satisfaction than girls. TAs provided greater structure than involvement or autonomy-support and felt least efficacious when facing school-based challenges. The findings highlight the refinements needed to enhance theoretical fidelity and intervention effectiveness for boys and girls.
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http://dx.doi.org/10.1123/jsep.2015-0217DOI Listing
August 2016

Cost-effectiveness of telehealth for patients with depression: evidence from the Healthlines randomised controlled trial.

BJPsych Open 2016 Jul 9;2(4):262-269. Epub 2016 Aug 9.

MD, Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, UK.

Background: Depression is a prevalent long-term condition that is associated with substantial resource use. Telehealth may offer a cost-effective means of supporting the management of people with depression.

Aims: To investigate the cost-effectiveness of a telehealth intervention ('Healthlines') for patients with depression.

Method: A prospective patient-level economic evaluation conducted alongside a randomised controlled trial. Patients were recruited through primary care, and the intervention was delivered via a telehealth service. Participants with a confirmed diagnosis of depression and PHQ-9 score ≥10 were recruited from 43 English general practices. A series of up to 10 scripted, theory-led, telephone encounters with health information advisers supported participants to effect a behaviour change, use online resources, optimise medication and improve adherence. The intervention was delivered alongside usual care and was designed to support rather than duplicate primary care. Cost-effectiveness from a combined health and social care perspective was measured by net monetary benefit at the end of 12 months of follow-up, calculated from incremental cost and incremental quality-adjusted life years (QALYs). Cost-consequence analysis included cost of lost productivity, participant out-of-pocket expenditure and the clinical outcome.

Results: A total of 609 participants were randomised - 307 to receive the Healthlines intervention plus usual care and 302 to receive usual care alone. Forty-five per cent of participants had missing quality of life data, 41% had missing cost data and 51% of participants had missing data on either cost or utility, or both. Multiple imputation was used for the base-case analysis. The intervention was associated with incremental mean per-patient National Health Service/personal social services cost of £168 (95% CI £43 to £294) and an incremental QALY gain of 0.001 (95% CI -0.023 to 0.026). The incremental cost-effectiveness ratio was £132 630. Net monetary benefit at a cost-effectiveness threshold of £20 000 was -£143 (95% CI -£164 to -£122) and the probability of the intervention being cost-effective at this threshold value was 0.30. Productivity costs were higher in the intervention arm, but out-of-pocket expenses were lower.

Conclusions: The Healthlines service was acceptable to patients as a means of condition management, and response to treatment after 4 months was higher for participants randomised to the intervention. However, the positive average intervention effect size was modest, and incremental costs were high relative to a small incremental QALY gain at 12 months. The intervention is not likely to be cost-effective in its current form.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) licence.
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http://dx.doi.org/10.1192/bjpo.bp.116.002907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995177PMC
July 2016

Comparison of high glucose concentration blood and crystalloid cardioplegia in paediatric cardiac surgery: a randomized clinical trial.

Interact Cardiovasc Thorac Surg 2016 05 31;22(5):553-60. Epub 2016 Jan 31.

School of Medicine, University of Belgrade, Belgrade, Serbia Department of Urology, University Children's Hospital, Belgrade, Serbia.

Objectives: This study investigates the effects of high glucose content on patients undergoing cold crystalloid versus cold blood cardioplegia in terms of early clinical results, functional myocardial recovery and ischaemia-reperfusion injury in patients undergoing repair of acyanotic cardiac lesions.

Methods: Patients were randomly assigned to receive either crystalloid (n = 31) or blood cardioplegia (n = 31). Early clinical results were assessed. Changes in left ventricular fractional shortening, arterial blood lactate levels, central venous saturation, cardiac Troponin I release and blood glucose concentration were measured during the first 24 h after ischaemia.

Results: There was no significant difference in clinical outcomes and postoperative complication rates between groups. The postoperative changes in left ventricular function, lactate levels, central venous saturation and Troponin I were not significantly different between groups. The use of crystalloid cardioplegia was associated with significant increases in serum glucose compared with blood cardioplegia.

Conclusions: A high glucose content blood cardioplegia does not show any advantage compared with crystalloid cardioplegia in terms of clinical outcomes, functional recovery and the degree of ischaemic injury in infants and children undergoing repair of acyanotic heart lesions. High glucose concentration of the cardioplegic solution might potentiate ischaemia-reperfusion injury and diminish the beneficial effects of blood cardioplegia.
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http://dx.doi.org/10.1093/icvts/ivv391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892136PMC
May 2016

Open Access Could Transform Drug Discovery: A Case Study of JQ1.

Expert Opin Drug Discov 2016 ;11(3):321-32

c Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences , University of Oxford , Oxford , UK.

Introduction: The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the lengthy transition times during development. Open access is an emerging model of open innovation that places no restriction on the use of information and has the potential to accelerate the development of new drugs.

Areas Covered: To date, no quantitative assessment has yet taken place to determine the effects and viability of open access on the process of drug translation. This need is addressed within this study. The literature and intellectual property landscapes of the drug candidate JQ1, which was made available on an open access basis when discovered, and conventionally developed equivalents that were not are compared using the Web of Science and Thomson Innovation software, respectively.

Expert Opinion: Results demonstrate that openly sharing the JQ1 molecule led to a greater uptake by a wider and more multi-disciplinary research community. A comparative analysis of the patent landscapes for each candidate also found that the broader scientific diaspora of the publically released JQ1 data enhanced innovation, evidenced by a greater number of downstream patents filed in relation to JQ1. The authors' findings counter the notion that open access drug discovery would leak commercial intellectual property. On the contrary, JQ1 serves as a test case to evidence that open access drug discovery can be an economic model that potentially improves efficiency and cost of drug discovery and its subsequent commercialization.
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http://dx.doi.org/10.1517/17460441.2016.1144587DOI Listing
October 2016

Production of Highly Monolayer Enriched Dispersions of Liquid-Exfoliated Nanosheets by Liquid Cascade Centrifugation.

ACS Nano 2016 Jan 12;10(1):1589-601. Epub 2016 Jan 12.

CRANN & AMBER Research Centers, Trinity College Dublin , Dublin 2, Ireland.

While liquid exfoliation is a powerful technique to produce defect-free nanosheets in large quantities, its usefulness is limited by broad nanosheet thickness distributions and low monolayer contents. Here we demonstrate liquid processing techniques, based on iterative centrifugation cascades, which can be designed to achieve either highly efficient nanosheet size-selection and/or monolayer enrichment. The resultant size-selected dispersions were used to establish quantitative metrics to determine monolayer volume fraction, as well as mean nanosheet size and thickness, from standard spectroscopic measurements. Such metrics allowed us to design and optimize centrifugation cascades to enrich liquid exfoliated WS2 dispersions up to monolayer contents of 75%. Monolayer-rich dispersions show relatively bright photoluminescence with narrow line widths (<35 meV) indicating the high quality of the nanosheets. The enriched dispersions display extinction spectra with distinct features, which also allow the direct estimation of monolayer contents.
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http://dx.doi.org/10.1021/acsnano.5b07228DOI Listing
January 2016

Fair Innings and Time-Relative Claims.

Authors:
Ben Davies

Bioethics 2016 07 10;30(6):462-8. Epub 2015 Dec 10.

Greg Bognar has recently offered a prioritarian justification for 'fair innings' distributive principles that would ration access to healthcare on the basis of patients' age. In this article, I agree that Bognar's principle is among the strongest arguments for age-based rationing. However, I argue that this position is incomplete because of the possibility of 'time-relative' egalitarian principles that could complement the kind of lifetime egalitarianism that Bognar adopts. After outlining Bognar's position, and explaining the attraction of time-relative egalitarianism, I suggest various ways in which these two kinds of principle could interact. Since various options have very different implications for age-based rationing, proponents of such a rationing scheme must take a position on time-relative egalitarianism to complement a lifetime prioritarian view like Bognar's.
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http://dx.doi.org/10.1111/bioe.12234DOI Listing
July 2016

The role of physical activity and psychological coping strategies in the management of painful diabetic neuropathy--A systematic review of the literature.

Physiotherapy 2015 Dec 22;101(4):319-26. Epub 2015 Apr 22.

Faculty of Health and Applied Sciences, University of the West of England, Blackberry Hill, Bristol BS16 1DD, UK; Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1 1RL, UK.

Background: Diabetes is rising in prevalence; painful diabetic neuropathy (PDN) is one complication of diabetes. PDN is primarily managed with medication but analgesic failure is common and people remain in pain and distress. It is unclear whether pain management strategies are appropriate for PDN.

Objectives: To establish the effectiveness of physical activity and psychological coping strategies for PDN.

Design: Systematic literature review.

Data Sources: Ten online databases.

Eligibility Criteria (participants And Interventions): Controlled trials reporting specific results for PDN, investigating, (a) physical activity or (b) psychological coping strategies and measuring pain as an outcome. The search was restricted to published research with no restriction on language or date of publication.

Study Appraisal Methods: Methodological quality and risk of bias assessed with Cochrane collaboration and NICE checklist for randomised controlled trials.

Results: Of 1306 titles identified, four studies met the inclusion criteria. Two trials investigated physical activity and two investigated psychological coping interventions. Studies showed pain measures improved or did not worsen compared to controls, but methodological quality was moderate and results need cautious interpretation.

Limitations: The studies were of small sample size and used a diverse range of outcome measures. There is high risk of bias from lack of blinding and attrition at follow up.

Conclusions And Implications Of Key Findings: The research literature in this area is sparse and inconsistent, despite the pressing clinical challenge of PDN. Firm conclusions cannot be drawn from the studies included. Further high quality research is required to match treatment provision to patient requirements.
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http://dx.doi.org/10.1016/j.physio.2015.04.003DOI Listing
December 2015
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