Institute of Human Development

Manchester, United Kingdom

Institute of Human Development

Manchester, United Kingdom
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Chen X.,King's College London | Graham J.,University of Manchester | Dabbah M.A.,Roke Manor Research | Petropoulos I.N.,Institute of Human Development | And 2 more authors.
IEEE Transactions on Biomedical Engineering | Year: 2017

Objective: We describe and evaluate an automated software tool for nerve-fiber detection and quantification in corneal confocal microscopy (CCM) images, combining sensitive nerve- fiber detection with morphological descriptors. Method: We have evaluated the tool for quantification of Diabetic Sensorimotor Polyneuropathy (DSPN) using both new and previously published morphological features. The evaluation used 888 images from 176 subjects (84 controls and 92 patients with type 1 diabetes). The patient group was further subdivided into those with (n = 63) and without (n = 29) DSPN. Results: We achieve improved nerve- fiber detection over previous results (91.7% sensitivity and specificity in identifying nerve-fiber pixels). Automatic quantification of nerve morphology shows a high correlation with previously reported, manually measured, features. Receiver Operating Characteristic (ROC) analysis of both manual and automatic measurement regimes resulted in similar results in distinguishing patients with DSPN from those without: AUC of about 0.77 and 72% sensitivity-specificity at the equal error rate point. Conclusion: Automated quantification of corneal nerves in CCM images provides a sensitive tool for identification of DSPN. Its performance is equivalent to manual quantification, while improving speed and repeatability. Significance: CCM is a novel in vivo imaging modality that has the potential to be a noninvasive and objective image biomarker for peripheral neuropathy. Automatic quantification of nerve morphology is a major step forward in the early diagnosis and assessment of progression, and, in particular, for use in clinical trials to establish therapeutic benefit in diabetic and other peripheral neuropathies. © 1964-2012 IEEE.


Rai R.K.,Society for Health and Demographic Surveillance | Singh P.K.,Institute of Human Development | Kumar C.,Central University of Karnataka
Health policy and planning | Year: 2016

Essential maternity care services include providing antenatal, delivery and postnatal care in a continuum to avert excess maternal deaths. This study assesses whether there is any significant difference in the utilization of maternal healthcare services between women from households that experienced any maternal death and women from households that did not experience any maternal death. Data from India's District Level Households and Facility Survey, 2007-08 were used. A sample of 321 women (unweighted) aged 15-49 years residing in households that had experienced maternal death, and 217 737 women (unweighted) of the same age group living in households that did not experience any maternal death were found eligible for the analysis. Results indicate that women belonging to households that experienced maternal deaths were less likely to opt for full antenatal care [odds ratio (OR): 0.56; 95% confidence interval (CI): 0.35-0.88] and postnatal care (OR: 0.82; 95% CI: 0.61-0.91) compared with women from households that did not experience any maternal death. Conversely, women belonging to households experiencing maternal deaths were more likely to utilize skilled birth attendants (OR: 1.31; 95% CI: 1.03-1.73) for their last delivery. This study hopes to draw the attention of program and policy makers to improve the reach of antenatal and postnatal care services, which are considered to be a supply side barrier compared with institutional delivery even by households that have reported maternal death. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


King D.A.,Wellcome Trust Sanger Institute | Fitzgerald T.W.,Wellcome Trust Sanger Institute | Miller R.,Wellcome Trust Sanger Institute | Canham N.,North West London Hospitals NHS Trust | And 6 more authors.
Genome Research | Year: 2014

Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child-mother-father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation. © 2014 Moran et al.


Javed S.,University of Manchester | Petropoulos I.N.,Institute of Human Development | Alam U.,Foundation Medicine | Malik R.A.,Foundation Medicine | Malik R.A.,Cornell College
Therapeutic Advances in Chronic Disease | Year: 2015

Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. © The Author(s), 2014.


Durrington H.J.,Institute of Human Development | Farrow S.N.,Institute of Human Development | Loudon A.S.,University of Manchester | Ray D.W.,Institute of Human Development
Thorax | Year: 2014

It is characteristic of asthma that symptoms worsen overnight, particularly in the early hours of the morning. Nocturnal symptoms in asthma are common and are an important indicator for escalation of treatment. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyper-responsiveness. The molecular apparatus that underpins circadian variations, controlled by so called 'clock' genes, has recently been characterised. Clock genes control circadian rhythms both centrally, in the suprachiasmatic nucleus of the brain and peripherally, within every organ of the body. Here, we will discuss how clock genes regulate circadian rhythms. We will focus particularly on the peripheral lung clock and the peripheral immune clock and discuss how these might relate to both the pathogenesis and treatment of asthma.


Owen L.J.,University of Manchester | Owen L.J.,Institute of Human Development | Keevil B.G.,University of Manchester | Keevil B.G.,Institute of Human Development
Annals of Clinical Biochemistry | Year: 2013

Background: Supported liquid extraction (SLE) techniques are relatively new compared to other sample preparation approaches such as solid phase extraction (SPE), liquid-liquid extraction (LLE) and protein precipitation (PPE). We investigated the use of SLE as an alternative to SPE for the liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement of aldosterone. Methods: Samples (n1/483) were analysed by the routine method using SPE. The same samples were subsequently analysed using two different SLE 96-well plate devices (Thermo and Biotage) with methyl-tertiary butyl ether extraction. A direct comparison of the three extraction techniques on two different mass spectrometers was also performed. Results: Both results using SLE plates gave excellent agreement with the results from the SPE analysis. The area counts obtained with the Biotage plates were considerably higher than those obtained using the Thermo plate. Conclusions: SLE is an acceptable alternative to SPE for the LC-MS/MS analysis of aldosterone. Using SLE reduces the time required for sample preparation. © UHSM 2013.


Fresquet M.,University of Manchester | Jowitt T.A.,University of Manchester | Gummadova J.,University of Manchester | Collins R.,University of Manchester | And 5 more authors.
Journal of the American Society of Nephrology | Year: 2015

Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides fromthe ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of thismajor epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies. Copyright © 2015 by the American Society of Nephrology.


Tan S.Z.,Institute of Human Development | Tan S.Z.,University of Manchester | Au L.,University of Manchester
Eye (Basingstoke) | Year: 2016

PurposeTo evaluate the safety, efficacy, and the cost of combined phacoemulsification and single iStent insertion in open angle glaucoma (OAG) at 3-years follow-up.MethodsThis was a prospective, uncontrolled, interventional case series. All subjects underwent single iStent implantation combined with cataract surgery by a single surgeon and were followed up over 3 years. Primary outcome measures were the reduction in intraocular pressure (IOP) and number of glaucoma drops at 1, 2, and 3 years. The costs of the procedure vs the cost of continuation of glaucoma drops were calculated and compared in patients who completed 3-years follow-up.ResultsForty-one patients were included in the study and thirty-six patients completed 3-years follow-up. Mean pre-op IOP was 21.2 mm Hg on 2.1 medications. Mean IOP was reduced to 15.9 mm Hg on 0.5 drops, 16.1 mm Hg on 1.0 drops, and 17.1 mm Hg (P<0.001) on 1.3 drops (P<0.001) at 1, 2, and 3 years, respectively. The overall cost of combined cataract surgery and iStent was estimated to be £829.32 more in total than conservative management with brand name eye drops over 3 years (£7.70 per patient per year) and £14 176.9 more if generic drops were used. (£131.3 per patient per year).ConclusionsCombined phaco-iStent proved to be a safe and effective way of managing patients with OAG over our 3-year follow-up period. The cost-effectiveness of the procedure may vary depending on whether brand name or generic eye drops are used. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Petropoulos I.N.,Institute of Human Development
Investigative ophthalmology & visual science | Year: 2014

To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy. One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods. Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P < 0.001) and CNFD (P < 0.0001), and CNFL (P < 0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r = 0.9, P < 0.0001), CNFL (r = 0.89, P < 0.0001), and CNBD (r = 0.75, P < 0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy. Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy.


Petropoulos I.N.,Institute of Human Development | Alam U.,Central Manchester NHS Foundation Trust | Fadavi H.,Institute of Human Development | Marshall A.,Central Manchester NHS Foundation Trust | And 8 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy. Methods. One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/ T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods. Results. Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P < 0.001) and CNFD (P < 0.0001), and CNFL (P < 0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r = 0.9, P < 0.0001), CNFL (r = 0.89, P < 0.0001), and CNBD (r = 0.75, P < 0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy. Conclusions. Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

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