Publications by authors named "Claire Scott"

61 Publications

Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX.

Elife 2021 Jun 24;10. Epub 2021 Jun 24.

Lee Kong Chian School of Medicine, Experimental Medicine Building, Yunnan Garden Campus, 59 Nanyang Drive, Nanyang Technological University, Singapore, Singapore.

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane-bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish mutants show increased HO, NfκB signalling, and IPR -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.
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http://dx.doi.org/10.7554/eLife.66596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291973PMC
June 2021

Audit and feedback with or without training in-practice targeting antibiotic prescribing (TiPTAP): a study protocol of a cluster randomised trial in dental primary care.

Implement Sci 2021 Mar 30;16(1):32. Epub 2021 Mar 30.

Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland.

Background: Antimicrobial resistance is an increasingly serious threat to global public health and patient safety. Overuse of antibiotics has aggravated this issue. Around 7% of all antibiotics in Scotland are prescribed by dentists. Audit and feedback has been shown to decrease these prescriptions, but there is evidence that dentists still prescribe unnecessarily. Our aim is to compare the effectiveness of a theory-informed in-practice training session (TiPTAP) in addition to individualised audit and feedback, with audit and feedback alone for reducing antibiotic prescribing by NHS dentists working in NHS primary care dental practices.

Methods: We will conduct a 2-arm parallel cluster randomised trial: out of 228 practices, 114 will be randomised to the theory-informed in-practice training session targeting antibiotic prescribing and individualised audit and feedback; 114 practices will be randomised to audit and feedback alone. The theory-informed session will include (a) an introductory session including several behaviour change techniques; (b) problem solving discussion, setting and recording action plans; (c) practice-level prescribing feedback discussion. The primary outcome is the number of antibiotic items per 100 NHS treatment claims over a 1-year period post-randomisation for each dentist. Secondary outcomes are the number of amoxicillin 3 g and broad spectrum antibiotics prescribed per 100 NHS treatment claims over a 1-year period; amoxicillin 3 g and broad spectrum antibiotics defined daily doses of antibiotics per 100 claims. Process measures include fidelity, knowledge, and confidence. Primary and secondary outcomes will be obtained using routine data.

Discussion: This study provides the opportunity to robustly assess the effect of adding an in-practice training co-intervention to audit and feedback. Its behaviour change theory-informed content will allow replication of the different components and can inform future training interventions.

Trial Registration: ISRCTN, ISRCTN12345678 . Registered 18 June 2020.
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http://dx.doi.org/10.1186/s13012-021-01098-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007384PMC
March 2021

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

J Med Chem 2021 04 17;64(7):3658-3676. Epub 2021 Mar 17.

Reviral Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2FX, U.K.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01882DOI Listing
April 2021

Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy.

Elife 2020 11 10;9. Epub 2020 Nov 10.

Leeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James' University Hospital, Leeds, United Kingdom.

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or 'viroporins', contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.
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http://dx.doi.org/10.7554/eLife.52555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714397PMC
November 2020

Using the behaviour change technique taxonomy v1 (BCTTv1) to identify the active ingredients of pharmacist interventions to improve non-hospitalised patient health outcomes.

BMJ Open 2020 09 15;10(9):e036500. Epub 2020 Sep 15.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Objectives: The aim of this study was to identify which behaviour change techniques (BCTs) were present in intervention and control groups of randomised controlled trials (RCTs) included in a Cochrane systematic review.

Setting: The RCTs included were conducted in community, primary and/or ambulatory-care settings.

Participants: The data set was derived from 86 RCTs from an interim update of the Cochrane review of the effectiveness of pharmacist services on non-hospitalised patient outcomes.

Primary And Secondary Outcome Measures: The primary outcome was the identification of BCTs scheduled for delivery in intervention and control groups of the RCTs. The secondary outcome measure was to identify which BCTs are not being utilised in intervention and control groups of the RCTs.

Results: The intervention and control groups included 31 and 12 BCTs, respectively. The number of identifiable BCTs/study ranged from 0 to 12 in the intervention groups (mean 3.01 (SD 2.4)) and 0 to 6 in the control groups (mean 0.38 (SD 0.84)). The most commonly identified BCTs in the intervention groups were: instruction on how to perform the behaviour (55%, n=47) (also the most common BCT in control groups); problem solving (29%, n=25); information about health consequences (24%, n=21); social support (practical) (24%, n=21); and social support (unspecified) (23%, n=20) (the second most common BCT in control groups). Thirteen trials had no identifiable BCTs in either group.

Conclusion: The pharmacist interventions presented in this study did not use the full range of available BCTs. Furthermore, the reporting of BCTs was incomplete for both intervention and control groups, thereby limiting the utility and reproducibility of the interventions. Future interventions should be designed and reported using relevant taxonomies and checklists for example, BCT taxonomy and TIDieR (the template for intervention description and replication).
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http://dx.doi.org/10.1136/bmjopen-2019-036500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493093PMC
September 2020

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.

PLoS Pathog 2020 08 11;16(8):e1008716. Epub 2020 Aug 11.

Leeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, St James's University Hospital, University of Leeds, Leeds, West Yorkshire, United Kingdom.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.
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http://dx.doi.org/10.1371/journal.ppat.1008716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418971PMC
August 2020

The association of periodontal disease with the complications of diabetes mellitus. A systematic review.

Diabetes Res Clin Pract 2020 Jul 8;165:108244. Epub 2020 Jun 8.

The University of Sydney School of Dentistry, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

This review investigated the association of periodontal disease with diabetes mellitus (DM) and diabetic complications. PubMed/MEDLINE was searched including search terms "periodontal" OR "periodontitis" AND "diabetic complications" OR "diabetic retinopathy" OR "diabetic nephropathy" OR "diabetic neuropathy" OR "cardiovascular disease diabetes" OR "myocardial infarction diabetes" OR "cerebrovascular disease diabetes" OR "stroke diabetes" OR "peripheral vascular disease diabetes". Fourteen studies included in this review consistently reported an increased risk for diabetic complications including microvascular, macrovascular and death in the presence of periodontal disease. Higher risks for diabetic retinopathy (odds ratios: 2.8-8.7), neuropathy (3.2-6.6), nephropathy (1.9-8.5), cardiovascular complications (1.28-17.7) and mortality (2.3-8.5) were reported for people with diabetes with periodontitis compared to those with diabetes who have no periodontitis. This novel review summarizes current data providing further evidence of a link between poor oral health and DM and its complications. It has also drawn attention to major limitations of the available data linking periodontal disease and diabetic complications.
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http://dx.doi.org/10.1016/j.diabres.2020.108244DOI Listing
July 2020

Behaviour change techniques associated with smoking cessation in intervention and comparator groups of randomized controlled trials: a systematic review and meta-regression.

Addiction 2020 11 16;115(11):2008-2020. Epub 2020 Apr 16.

Health Psychology Group, Institute of Applied Health Sciences, University of Aberdeen, Health Sciences Building, Aberdeen, UK.

Aims: To estimate the strengths of associations between use of behaviour change techniques (BCTs) and clusters of BCTs in behavioural smoking cessation interventions and comparators with smoking cessation rates.

Method: Systematic review and meta-regression of biochemically verified smoking cessation rates on BCTs in interventions and comparators in randomized controlled trials, adjusting for a priori-defined potential confounding variables, together with moderation analyses. Studies were drawn from the Cochrane Tobacco Addiction Group Specialised Register. Data were extracted from published and unpublished (i.e. obtained from study authors) study materials by two independent coders. Adequately described intervention (k = 143) and comparator (k = 92) groups were included in the analyses (n = 43 992 participants). Using bivariate mixed-effects meta-regressions, while controlling for key a priori confounders, we regressed smoking cessation on (a) three BCT groupings consistent with dual-process theory (i.e. associative, reflective motivational and self-regulatory), (b) 17 expert-derived BCT groupings (i.e. BCT taxonomy version 1 clusters) and (c) individual BCTs from the BCT taxonomy version 1.

Results: Among person-delivered interventions, higher smoking cessation rates were predicted by BCTs targeting associative and self-regulatory processes (B = 0.034, 0.041, P < 0.05), and by three individual BCTs (prompting commitment, social reward, identity associated with changed behaviour). Among written interventions, BCTs targeting taxonomy cluster 10a (rewards) predicted higher smoking cessation (B = 0.394, P < 0.05). Moderation effects were observed for nicotine dependence, mental health status and mode of delivery.

Conclusions: Among person-delivered behavioural smoking cessation interventions, specific behaviour change techniques and clusters of techniques are associated with higher success rates.
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http://dx.doi.org/10.1111/add.15056DOI Listing
November 2020

Do pharmacy intervention reports adequately describe their interventions? A template for intervention description and replication analysis of reports included in a systematic review.

BMJ Open 2019 12 19;9(12):e025511. Epub 2019 Dec 19.

The Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Introduction: Scientific progress and translation of evidence into practice is impeded by poorly described interventions. The Template for Intervention Description and Replication (TIDieR) was developed to specify the minimal intervention elements that should be reported.

Objectives: (1) To assess the extent to which outpatient pharmacy interventions were adequately reported. (2) To examine the dimension(s) across which reporting quality varies. (3) To examine trial characteristics that predict better reporting.

Methods: The sample comprised 86 randomised controlled trials identified in a Cochrane review of the effectiveness of pharmacist interventions on patient health outcomes. Duplicate, independent application of a modified 15-item TIDieR checklist was undertaken to assess the intervention reporting. The reporting/non-reporting of TIDieR items was analysed with principal component analysis to evaluate the dimensionality of reporting quality and regression analyses to assess predictors of reporting quality RESULTS: In total, 422 (40%) TIDieR items were fully reported, 395 (38%) were partially reported and 231 (22%) were not reported. A further 242 items were deemed not applicable to the specific trials. Reporting quality loaded on one component which accounted for 26% of the variance in TIDieR scores. More recent trials reported a slightly greater number of TIDieR items (0.07 (95% CI 0.02 to 0.13) additional TIDieR items per year of publication). Trials reported an 0.09 (95% CI 0.04 to 0.14) additional TIDieR items per unit increase in impact factor (IF) of the journal in which the main report was published.

Conclusions: Most trials lacked adequate intervention reporting. This diminished the applied and scientific value of their research. The standard of intervention reporting is, however, gradually increasing and appears somewhat better in journals with higher IFs. The use of the TIDieR checklist to improve reporting could enhance the utility and replicability of trials, and reduce research waste.
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http://dx.doi.org/10.1136/bmjopen-2018-025511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937059PMC
December 2019

Aggressive skin lesions in pigs.

Vet Rec 2019 04;184(17):529-530

Minsterworth, Gloucester GL2 8JG.

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http://dx.doi.org/10.1136/vr.l1859DOI Listing
April 2019

Enhancing Behavior Change Technique Coding Methods: Identifying Behavioral Targets and Delivery Styles in Smoking Cessation Trials.

Ann Behav Med 2019 05;53(6):583-591

Health Psychology Group, Institute of Applied Health Sciences, University of Aberdeen, Health Sciences Building, Foresterhill Campus, Aberdeen, UK.

Background: The behavior change technique (BCT) taxonomy v1 is often used in systematic reviews for identifying active components of interventions. Its utility could be enhanced by linking BCTs to specific target behaviors and qualifying BCT delivery style.

Purpose: To determine whether behavioral targets and delivery styles of BCTs can be coded reliably and to determine the utility of coding these characteristics.

Methods: As part of a large systematic review of 142 smoking cessation trials, two researchers independently coded publicly and privately held intervention and comparator group materials, specifying the behavioral target (quitting, abstinence, medication adherence, or treatment engagement) and delivery style (tailored vs. not tailored; active participation vs. passive receipt) of each BCT.

Results: Researchers coded 3,843 BCTs, which were reliably attributed to behavioral targets (AC1 = 0.92, PABAK = 0.91). Tailoring (AC1 = 0.80, PABAK = 0.74) and participation (AC1 = 0.71, PABAK = 0.64) were also coded reliably. There was considerable variability between groups in quitting and abstinence BCTs (ranges: 0-41; 0-18) and in tailoring and participation (ranges: 0-20; 0-32), but less variability for medication adherence and treatment engagement (ranges: 0-6; 0-7).

Conclusions: Behavioral targets and delivery styles of BCTs can be reliably identified and occur with sufficient frequency in smoking cessation trials for inclusion in quantitative syntheses (e.g., meta-regression analyses). Systematic reviewers could consider adopting these methods to evaluate the impact of intervention components targeting different behaviors, as well as the benefits of different BCT delivery styles.
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http://dx.doi.org/10.1093/abm/kay068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499411PMC
May 2019

Pharmacist services for non-hospitalised patients.

Cochrane Database Syst Rev 2018 09 4;9:CD013102. Epub 2018 Sep 4.

Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Background: This review focuses on non-dispensing services from pharmacists, i.e. pharmacists in community, primary or ambulatory-care settings, to non-hospitalised patients, and is an update of a previously-published Cochrane Review.

Objectives: To examine the effect of pharmacists' non-dispensing services on non-hospitalised patient outcomes.

Search Methods: We searched CENTRAL, MEDLINE, Embase, two other databases and two trial registers in March 2015, together with reference checking and contact with study authors to identify additional studies. We included non-English language publications. We ran top-up searches in January 2018 and have added potentially eligible studies to 'Studies awaiting classification'.

Selection Criteria: Randomised trials of pharmacist services compared with the delivery of usual care or equivalent/similar services with the same objective delivered by other health professionals.

Data Collection And Analysis: We used standard methodological procedures of Cochrane and the Effective Practice and Organisation of Care Group. Two review authors independently checked studies for inclusion, extracted data and assessed risks of bias. We evaluated the overall certainty of evidence using GRADE.

Main Results: We included 116 trials comprising 111 trials (39,729 participants) comparing pharmacist interventions with usual care and five trials (2122 participants) comparing pharmacist services with services from other healthcare professionals. Of the 116 trials, 76 were included in meta-analyses. The 40 remaining trials were not included in the meta-analyses because they each reported unique outcome measures which could not be combined. Most trials targeted chronic conditions and were conducted in a range of settings, mostly community pharmacies and hospital outpatient clinics, and were mainly but not exclusively conducted in high-income countries. Most trials had a low risk of reporting bias and about 25%-30% were at high risk of bias for performance, detection, and attrition. Selection bias was unclear for about half of the included studies.Compared with usual care, we are uncertain whether pharmacist services reduce the percentage of patients outside the glycated haemoglobin target range (5 trials, N = 558, odds ratio (OR) 0.29, 95% confidence interval (CI) 0.04 to 2.22; very low-certainty evidence). Pharmacist services may reduce the percentage of patients whose blood pressure is outside the target range (18 trials, N = 4107, OR 0.40, 95% CI 0.29 to 0.55; low-certainty evidence) and probably lead to little or no difference in hospital attendance or admissions (14 trials, N = 3631, OR 0.85, 95% CI 0.65 to 1.11; moderate-certainty evidence). Pharmacist services may make little or no difference to adverse drug effects (3 trials, N = 590, OR 1.65, 95% CI 0.84 to 3.24) and may slightly improve physical functioning (7 trials, N = 1329, mean difference (MD) 5.84, 95% CI 1.21 to 10.48; low-certainty evidence). Pharmacist services may make little or no difference to mortality (9 trials, N = 1980, OR 0.79, 95% CI 0.56 to 1.12, low-certaintly evidence).Of the five studies that compared services delivered by pharmacists with other health professionals, no studies evaluated the impact of the intervention on the percentage of patients outside blood pressure or glycated haemoglobin target range, hospital attendance and admission, adverse drug effects, or physical functioning.

Authors' Conclusions: The results demonstrate that pharmacist services have varying effects on patient outcomes compared with usual care. We found no studies comparing services delivered by pharmacists with other healthcare professionals that evaluated the impact of the intervention on the six main outcome measures. The results need to be interpreted cautiously because there was major heterogeneity in study populations, types of interventions delivered and reported outcomes.There was considerable heterogeneity within many of the meta-analyses, as well as considerable variation in the risks of bias.
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http://dx.doi.org/10.1002/14651858.CD013102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513292PMC
September 2018

Ten-minute chat.

Authors:
Claire Scott

Vet Rec 2017 May;180(21):i-ii

Claire Scott is a fourth-year student at the Royal Veterinary College. She has embarked on rotations and completed several of her required extramural studies weeks, including one spent with .
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http://dx.doi.org/10.1136/vr.j2557DOI Listing
May 2017

Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization.

Clin Cancer Res 2017 Aug 21;23(15):4086-4094. Epub 2017 Feb 21.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.

Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline status, three-biomarker homologous recombination deficiency (HRD) score, methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort. Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome ( < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy ( < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with , and mutations being most common (90%, 25%, and 35%, respectively). mutations were enriched among the LT responders. methylation was not associated with response duration. High myriad HRD score (>42) and/or mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and mutation. Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly defects. The type of mutation warrants further investigation. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2615DOI Listing
August 2017

Interventions to improve antibiotic prescribing practices for hospital inpatients.

Cochrane Database Syst Rev 2017 02 9;2:CD003543. Epub 2017 Feb 9.

Research Department of Primary Care and Population Health, University College London, Upper Floor 3, Royal Free Hospital, Rowland Hill Street, London, UK, NW3 2PF.

Background: Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients.

Objectives: To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015.

Selection Criteria: We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention.

Data Collection And Analysis: Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria.

Main Results: This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias.More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention.The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence).Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence).There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomesWe analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect.

Authors' Conclusions: We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions.
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http://dx.doi.org/10.1002/14651858.CD003543.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464541PMC
February 2017

New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report.

Mol Syndromol 2016 Jul 2;7(3):160-3. Epub 2016 Jun 2.

Centre for Cell Biology and Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

GAPO syndrome is a very rare genetic disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy (GAPO). To date, only 30 cases have been described worldwide. Recently, gene alterations in the ANTXR1 gene have been reported to be causative of this disorder, and an autosomal recessive pattern has been observed. This gene encodes a matrix-interacting protein that works as an adhesion molecule. In this report, we describe 2 homozygous siblings diagnosed with GAPO syndrome carrying a new missense mutation. This mutation produces the substitution of a glutamine in position 137 for a leucine (c.410A>T, p.Q137L).
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http://dx.doi.org/10.1159/000446619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988245PMC
July 2016

Ion Channel Function and Cross-Species Determinants in Viral Assembly of Nonprimate Hepacivirus p7.

J Virol 2016 05 29;90(10):5075-5089. Epub 2016 Apr 29.

Institute for Experimental Virology, TWINCORE, Hannover, Germany

Unlabelled: Nonprimate hepacivirus (NPHV), the closest homolog of hepatitis C virus (HCV) described to date, has recently been discovered in horses. Even though the two viruses share a similar genomic organization, conservation of the encoded hepaciviral proteins remains undetermined. The HCV p7 protein is localized within endoplasmic reticulum (ER) membranes and is important for the production of infectious particles. In this study, we analyzed the structural and functional features of NPHV p7 in addition to its role during virus assembly. Three-dimensional homology models for NPHV p7 using various nuclear magnetic resonance spectroscopy (NMR) structures were generated, highlighting the conserved residues important for ion channel function. By applying a liposome permeability assay, we observed that NPHV p7 exhibited liposome permeability features similar to those of HCV p7, indicative of similar ion channel activity. Next, we characterized the viral protein using a p7-based trans-complementation approach. A similar subcellular localization pattern at the ER membrane was observed, although production of infectious particles was likely hindered by genetic incompatibilities with HCV proteins. To further characterize these cross-species constraints, chimeric viruses were constructed by substituting different regions of HCV p7 with NPHV p7. The N terminus and transmembrane domains were nonexchangeable and therefore constitute a cross-species barrier in hepaciviral assembly. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious trans-complemented viral particles. In conclusion, comparison of NPHV and HCV p7 revealed structural and functional homology of these proteins, including liposome permeability, and broadly acting determinants that modulate hepaciviral virion assembly and contribute to the host-species barrier were identified.

Importance: The recent discovery of new relatives of hepatitis C virus (HCV) enables for the first time the study of cross-species determinants shaping hepaciviral pathogenesis. Nonprimate hepacivirus (NPHV) was described to infect horses and represents so far the closest homolog of HCV. Both viruses encode the same viral proteins; however, NPHV protein functions remain poorly understood. In this study, we aimed to dissect NPHV p7 on a structural and functional level. By using various NMR structures of HCV p7 as templates, three-dimensional homology models for NPHV p7 were generated, highlighting conserved residues that are important for ion channel function. A p7-based trans-complementation approach and the construction of NPHV/HCV p7 chimeric viruses showed that the N terminus and transmembrane domains were nonexchangeable. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious viral particles. These results identify species-specific constraints as well as exchangeable determinants in hepaciviral assembly.
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http://dx.doi.org/10.1128/JVI.00132-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859704PMC
May 2016

Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population.

Gastroenterology 2016 05 10;150(5):1171-1182. Epub 2016 Feb 10.

Department of Surgery, Mitsui Kinen Hospital, Tokyo, Japan.

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer.

Methods: We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2. Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells.

Results: A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5' thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6) factors. Many tumors contained mutations in genes that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7); epigenetic processes (MLL2, EP300, CREBBP, TET2); and the NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase signaling pathways (PIK3CA, EGFR, ERBB2). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes.

Conclusions: We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
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http://dx.doi.org/10.1053/j.gastro.2016.01.035DOI Listing
May 2016

Viroporins: structure, function and potential as antiviral targets.

J Gen Virol 2015 Aug 28;96(8):2000-2027. Epub 2015 May 28.

Leeds Institute of Cancer & Pathology and Leeds CRUK Clinical Centre, Faculty of Medicine and Health, St James's University Hospital, University of Leeds, Beckett Street, Leeds LS9 7TF, UK.

The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.
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http://dx.doi.org/10.1099/vir.0.000201DOI Listing
August 2015

Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads.

Am J Hum Genet 2015 Mar 12;96(3):440-7. Epub 2015 Feb 12.

Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China. Electronic address:

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375526PMC
March 2015

mTOR signalling, embryogenesis and the control of lung development.

Semin Cell Dev Biol 2014 Dec 5;36:68-78. Epub 2014 Oct 5.

School of Psychology & Neuroscience, Westburn Lane, St Andrews KY16 9JP, UK.

The existence of a nutrient sensitive "autocatakinetic" regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford-Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development.
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http://dx.doi.org/10.1016/j.semcdb.2014.09.023DOI Listing
December 2014

Discovery in genetic skin disease: the impact of high throughput genetic technologies.

Genes (Basel) 2014 Aug 4;5(3):615-34. Epub 2014 Aug 4.

Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.

The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, such as harlequin ichthyosis, Olmsted syndrome, and exfoliative ichthyosis, which have provided unique insights into the structure and function of the skin. In addition, through genome wide association studies we now have an understanding of how low penetrance variants contribute to inflammatory skin diseases such as psoriasis vulgaris and atopic dermatitis, and how they contribute to underlying pathophysiological disease processes. In this review we discuss strategies used to unravel the genes underlying both monogenic and complex trait skin diseases in the last 10 years and the implications on mechanistic studies, diagnostics, and therapeutics.
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http://dx.doi.org/10.3390/genes5030615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198921PMC
August 2014

Profile of Gaze Dysfunction following Cerebrovascular Accident.

ISRN Ophthalmol 2013 10;2013:264604. Epub 2013 Oct 10.

Worcestershire Acute Hospitals NHS Trust, Worcester WR5 1DD, UK.

Aim. To evaluate the profile of ocular gaze abnormalities occurring following stroke. Methods. Prospective multicentre cohort trial. Standardised referral and investigation protocol including assessment of visual acuity, ocular alignment and motility, visual field, and visual perception. Results. 915 patients recruited: mean age 69.18 years (SD 14.19). 498 patients (54%) were diagnosed with ocular motility abnormalities. 207 patients had gaze abnormalities including impaired gaze holding (46), complete gaze palsy (23), horizontal gaze palsy (16), vertical gaze palsy (17), Parinaud's syndrome (8), INO (20), one and half syndrome (3), saccadic palsy (28), and smooth pursuit palsy (46). These were isolated impairments in 50% of cases and in association with other ocular abnormalities in 50% including impaired convergence, nystagmus, and lid or pupil abnormalities. Areas of brain stroke were frequently the cerebellum, brainstem, and diencephalic areas. Strokes causing gaze dysfunction also involved cortical areas including occipital, parietal, and temporal lobes. Symptoms of diplopia and blurred vision were present in 35%. 37 patients were discharged, 29 referred, and 141 offered review appointments. 107 reviewed patients showed full recovery (4%), partial improvement (66%), and static gaze dysfunction (30%). Conclusions. Gaze dysfunction is common following stroke. Approximately one-third of patients complain of visual symptoms, two thirds show some improvement in ocular motility.
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http://dx.doi.org/10.1155/2013/264604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914228PMC
February 2014

A prospective profile of visual field loss following stroke: prevalence, type, rehabilitation, and outcome.

Biomed Res Int 2013 9;2013:719096. Epub 2013 Sep 9.

Department of Health Services Research, Whelan Building, University of Liverpool, Brownlow Hill, Liverpool L69 3GB, UK.

Aims: To profile site of stroke/cerebrovascular accident, type and extent of field loss, treatment options, and outcome.

Methods: Prospective multicentre cohort trial. Standardised referral and investigation protocol of visual parameters.

Results: 915 patients were recruited with a mean age of 69 years (SD 14). 479 patients (52%) had visual field loss. 51 patients (10%) had no visual symptoms. Almost half of symptomatic patients (n = 226) complained only of visual field loss: almost half (n = 226) also had reading difficulty, blurred vision, diplopia, and perceptual difficulties. 31% (n = 151) had visual field loss as their only visual impairment: 69% (n = 328) had low vision, eye movement deficits, or visual perceptual difficulties. Occipital and parietal lobe strokes most commonly caused visual field loss. Treatment options included visual search training, visual awareness, typoscopes, substitutive prisms, low vision aids, refraction, and occlusive patches. At followup 15 patients (7.5%) had full recovery, 78 (39%) had improvement, and 104 (52%) had no recovery. Two patients (1%) had further decline of visual field. Patients with visual field loss had lower quality of life scores than stroke patients without visual impairment.

Conclusions: Stroke survivors with visual field loss require assessment to accurately define type and extent of loss, diagnose coexistent visual impairments, and offer targeted treatment.
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http://dx.doi.org/10.1155/2013/719096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782154PMC
June 2014

Birt-Hogg-Dube syndrome is a novel ciliopathy.

Hum Mol Genet 2013 Nov 19;22(21):4383-97. Epub 2013 Jun 19.

Department of Dermatology and GROW School for Oncology and Developmental Biology.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder where patients are predisposed to kidney cancer, lung and kidney cysts and benign skin tumors. BHD is caused by heterozygous mutations affecting folliculin (FLCN), a conserved protein that is considered a tumor suppressor. Previous research has uncovered multiple roles for FLCN in cellular physiology, yet it remains unclear how these translate to BHD lesions. Since BHD manifests hallmark characteristics of ciliopathies, we speculated that FLCN might also have a ciliary role. Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. Alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. In three-dimensional culture, abnormal expression of FLCN disrupts polarized growth of kidney cells and deregulates canonical Wnt signalling. Our findings further suggest that BHD-causing FLCN mutants may retain partial functionality. Thus, several BHD symptoms may be due to abnormal levels of FLCN rather than its complete loss and accordingly, we show expression of mutant FLCN in a BHD-associated renal carcinoma. We propose that BHD is a novel ciliopathy, its symptoms at least partly due to abnormal ciliogenesis and canonical Wnt signalling.
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http://dx.doi.org/10.1093/hmg/ddt288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792695PMC
November 2013

Hand hygiene: a way out of the deadlock.

Aust Health Rev 2012 Nov;36(4):363-4

School of Medicine, University of Tasmania, Bag 96, Clinical School, Hobart, TAS 7000, Australia.

Hospital-acquired infection costs money and lives. Improving compliance with hand hygiene is proving an intractable problem as initial gains often lack sustainability. A growing field of research suggests that health service managers may have a critical role in dealing with this issue, which crosses all professional boundaries.
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http://dx.doi.org/10.1071/AH11105DOI Listing
November 2012

Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction.

Cell Tissue Res 2013 Feb 4;351(2):281-8. Epub 2012 Aug 4.

Centre for Cutaneous Research, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 2AT, UK.

Harlequin ichthyosis (HI) is a devastating autosomal recessive congenital skin disease. It has been vital to elucidate the biological importance of the protein ABCA12 in skin-barrier permeability, following the discovery that ABCA12 gene mutations can result in this rare disease. ATP-binding cassette transporter A12 (ABCA12) is a member of the subfamily of ATP-binding cassette transporters and functions to transport lipid glucosylceramides (GlcCer) to the extracellular space through lamellar granules (LGs). GlcCer are hydrolysed into hydroxyceramides extracellularly and constitute a portion of the extracellular lamellar membrane, lipid envelope and lamellar granules. In HI skin, loss of function of ABCA12 due to null mutations results in impaired lipid lamellar membrane formation in the cornified layer, leading to defective permeability of the skin barrier. In addition, abnormal lamellar granule formation (distorted shape, reduced in number or absent) could further cause aberrant production of LG-associated desquamation enzymes, which are likely to contribute to the impaired skin barrier in HI. This article reviews current opinions on the patho-mechanisms of ABCA12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies.
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http://dx.doi.org/10.1007/s00441-012-1474-9DOI Listing
February 2013
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