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1.  Older Adults’ Outdoor Walking: Inequalities in Neighbourhood Safety, Pedestrian Infrastructure and Aesthetics 
Older adults living in high-deprivation areas walk less than those living in low-deprivation areas. Previous research has shown that older adults’ outdoor walking levels are related to the neighbourhood built environment. This study examines inequalities in perceived built environment attributes (i.e., safety, pedestrian infrastructure and aesthetics) and their possible influences on disparities in older adults’ outdoor walking levels in low- and high-deprivation areas of Birmingham, United Kingdom. It applied a mixed-method approach, included 173 participants (65 years and over), used GPS technology to measure outdoor walking levels, used questionnaires (for all participants) and conducted walking interviews (with a sub-sample) to collect data on perceived neighbourhood built environment attributes. The results show inequalities in perceived neighbourhood safety, pedestrian infrastructure and aesthetics in high- versus low-deprivation areas and demonstrate that they may influence disparities in participants’ outdoor walking levels. Improvements of perceived neighbourhood safety, pedestrian infrastructure and aesthetic in high-deprivation areas are encouraged.
PMCID: PMC5201320  PMID: 27898023
physical activity; walking; deprivation; built environment; older adults; perception; inequalities; GPS
2.  Assessment of red blood cell deformability in type 2 diabetes mellitus and diabetic retinopathy by dual optical tweezers stretching technique 
Scientific Reports  2016;6:15873.
A pilot cross sectional study was conducted to investigate the role of red blood cells (RBC) deformability in type 2 diabetes mellitus (T2DM) without and with diabetic retinopathy (DR) using a dual optical tweezers stretching technique. A dual optical tweezers was made by splitting and recombining a single Nd:YAG laser beam. RBCs were trapped directly (i.e., without microbead handles) in the dual optical tweezers where they were observed to adopt a “side-on” orientation. RBC initial and final lengths after stretching were measured by digital video microscopy, and a Deformability index (DI) calculated. Blood from 8 healthy controls, 5 T2DM and 7 DR patients with respective mean age of 52.4yrs, 51.6 yrs and 52 yrs was analysed. Initial average length of RBCs for control group was 8.45 ± 0.25 μm, 8.68 ± 0.49 μm for DM RBCs and 8.82 ± 0.32 μm for DR RBCs (p < 0.001). The DI for control group was 0.0698 ± 0.0224, and that for DM RBCs was 0.0645 ± 0.03 and 0.0635 ± 0.028 (p < 0.001) for DR group. DI was inversely related to basal length of RBCs (p = 0.02). DI of RBC from DM and DR patients was significantly lower in comparison with normal healthy controls. A dual optical tweezers method can hence be reliably used to assess RBC deformability.
PMCID: PMC4792142  PMID: 26976672
3.  A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis 
Molecular Therapy  2015;23(11):1722-1733.
FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression.
PMCID: PMC4817942  PMID: 26234505
4.  Variation in CAD Secondary Prevention Prescription among Outpatient Cardiology Practices: Insights from the NCDR® 
This study assesses practice variation of secondary prevention medication prescription among coronary artery disease (CAD) patients treated in outpatient practices participating in the NCDR® PINNACLE Registry®.
Among patients with CAD, secondary prevention with a combination of beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and statins reduces cardiac mortality and myocardial infarction (MI). Accordingly, every CAD patient should receive the combination of these medications for which they are eligible. However, little is known about current prescription patterns of these medications and the variation in use among outpatient cardiology clinics.
Using data from NCDR® PINNACLE Registry®, a national outpatient cardiology practice registry, we assessed medication prescription patterns among eligible CAD patients between July 2008 and December 2010. Overall rates of prescription and variation by practice were calculated, adjusting for patient characteristics.
Among 156,145 CAD patients in 58 practices, 103,830 (66.5%) were prescribed the optimal combination of medications for which they were eligible. The median rate of optimal combined prescription by practice was 73.5% and varied from 28.8% to 100%. After adjustment for patient factors, the practice median rate ratio for prescription was 1.25 (95% CI 1.2,1.32), indicating a 25% likelihood that 2 random practices would differ in treating identical CAD patients.
Among a national registry of CAD patients treated in outpatient cardiology practices, over one-third of patients failed to receive their optimal combination of secondary prevention medications. Significant variation was observed across practices, even after adjusting for patient characteristics, suggesting that quality improvement efforts may be needed to support more uniform practice.
PMCID: PMC3990248  PMID: 24184238
CAD; Outpatient Practice; Secondary Prevention
5.  Practice-level Variation in Use of Recommended Medications Among Outpatients With Heart Failure: Insights From the NCDR PINNACLE Program 
Circulation. Heart failure  2013;6(6):1132-1138.
The objective of this study is to examine practice-level variation in rates of guideline-recommended treatment for outpatients with heart failure and reduced ejection fraction (HFREF), and to examine the association between treatment variation and practice site, independent of patient factors.
Methods and Results
Cardiology practices participating in the NCDR PINNACLE registry from July 2008 – December 2010 were evaluated. Practice rates of treatment with angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) and beta blockers (BB) and an optimal combined treatment measure were determined for patients with HFREF and no documented contraindications. Multivariable hierarchical regression models were adjusted for demographics, insurance status and comorbidities. A median rate ratio (MRR) was calculated for each therapy, which describes the likelihood that the treatment of a patient with given comorbidities would differ at two randomly selected practices. We identified 12,556 patients from 45 practices. The unadjusted practice-level prescription rates ranged from 44% to 100% for ACEI/ARB (median 85%; interquartile range [IQR] 75%–89%), from 49%–100% for BB (median of 92%; IQR 83%–95%) and from 37%–100% for optimal combined treatment (median of 79%; IQR 66%–85%). The adjusted MRR was 1.11 (95% confidence interval [CI] 1.08–1.18) for ACEI/ARB therapy, 1.08 (95% CI 1.05–1.15) for BB therapy and 1.17 (1.13–1.26) for optimal combined treatment.
Variation in the use of guideline-recommended medications for patients with HFREF exists in the outpatient setting. Addressing practice-level differences may be an important component of improving quality of care for patients with HFREF.
PMCID: PMC3894058  PMID: 24130004
heart failure; registry; drugs
6.  Age at diagnosis predicts deterioration in glycaemic control among children and adolescents with type 1 diabetes 
Poor glycemic control early in the course of type 1 diabetes mellitus (T1DM) increases the risk for microvascular complications. However, predictors of deteriorating control after diagnosis have not been described, making it difficult to identify high-risk patients and proactively provide aggressive interventions.
We examined whether diagnostic age, gender, and race were associated with deteriorating glycemic control during the first 5 years after diagnosis.
2218 pediatric patients with T1DM.
We conducted a longitudinal cohort study of pediatric patients with T1DM from the Midwest USA, 1993–2009, evaluating within-patient glycated hemoglobin (HbA1c) trajectories constructed from all available HbA1c values within 5 years of diagnosis.
52.6% of patients were male; 86.1% were non-Hispanic Caucasian. The mean diagnostic age was 9.0±4.1 years. The mean number of HbA1c values/year/participant was 2.4±0.9. HbA1c trajectories differed markedly across age groups, with older patients experiencing greater deterioration than their younger counterparts (p<0.001). HbA1c trajectories, stratified by age, varied markedly by race (p for race×diagnostic age <0.001). Non-Hispanic African-American patients experienced higher initial HbA1c (8.7% vs 7.6% (71.6 vs 59.6 mmol/mol); p<0.001), and greater deterioration in HbA1c than non-Hispanic Caucasian patients across diagnostic ages (rise of 2.04% vs 0.99% per year (22.3 vs 10.8 mmol/mol/year); p<0.0001).
Older diagnostic age and black race are major risk factors for deterioration in glycemic control early in the course of T1DM. These findings can inform efforts to explore the reasons behind these differences and develop preventive interventions for high-risk patients.
PMCID: PMC4212563  PMID: 25452876
Type 1; Adolescents / Children; Age of Diabetes Onset; Glycemic Control
7.  Stability assessment on a library scale: a rapid method for the evaluation of the commutability and insertion of residues in C-terminal loops of the CH3 domains of IgG1-Fc 
Antigen-binding Fc fragments (Fcab) are generated by engineering the C-terminal loop regions in the CH3 domain of human immunoglobulin G class 1-crystallizable fragment (IgG1-Fc). For an optimum library design with high percentage of well-folded clones for efficient binder selection, information about the correlation between primary structure and stability is needed. Here, we present a rapid method that allows determination of the overall stability of whole libraries of IgG1-Fc on the surface of yeast by flow cytometry. Libraries of IgG1-Fc mutants with distinct regions in AB-, CD- and EF-loops of the CH3 domains randomized or carrying therein insertions of five additional residues were constructed, incubated at increasing temperatures and probed for residual binding of generic Fc ligands. Calculated temperatures of half-maximal irreversible denaturation of the libraries gave a clear hierarchy of tolerance to randomization of distinct loop positions. Experimental data were evaluated by a computational approach and are discussed with respect to the structure of IgG1-Fc and variation in sequence and length of these loops in homologous Fc proteins. Generally, the described method allows for quick assessment of the effects of randomization of distinct regions on the foldability and stability of a yeast-displayed protein library.
PMCID: PMC3785252  PMID: 24006374
Fcab; IgG1-Fc; library design; loop engineering; therapeutic antibody; thermal denaturation; yeast surface display
8.  Bioinformatics Training Network (BTN): a community resource for bioinformatics trainers 
Briefings in Bioinformatics  2011;13(3):383-389.
Funding bodies are increasingly recognizing the need to provide graduates and researchers with access to short intensive courses in a variety of disciplines, in order both to improve the general skills base and to provide solid foundations on which researchers may build their careers. In response to the development of ‘high-throughput biology’, the need for training in the field of bioinformatics, in particular, is seeing a resurgence: it has been defined as a key priority by many Institutions and research programmes and is now an important component of many grant proposals. Nevertheless, when it comes to planning and preparing to meet such training needs, tension arises between the reward structures that predominate in the scientific community which compel individuals to publish or perish, and the time that must be devoted to the design, delivery and maintenance of high-quality training materials. Conversely, there is much relevant teaching material and training expertise available worldwide that, were it properly organized, could be exploited by anyone who needs to provide training or needs to set up a new course. To do this, however, the materials would have to be centralized in a database and clearly tagged in relation to target audiences, learning objectives, etc. Ideally, they would also be peer reviewed, and easily and efficiently accessible for downloading. Here, we present the Bioinformatics Training Network (BTN), a new enterprise that has been initiated to address these needs and review it, respectively, to similar initiatives and collections.
PMCID: PMC3357490  PMID: 22110242
Bioinformatics; training; end users; bioinformatics courses; learning bioinformatics
9.  Hygrochastic capsule dehiscence supports safe site strategies in New Zealand alpine Veronica (Plantaginaceae) 
Annals of Botany  2010;106(3):405-412.
Background and Aims
Hygrochasy is a capsule-opening mechanism predominantly associated with plants in arid habitats, where it facilitates spatially and temporally restricted dispersal. Recently, hygrochastic capsules were described in detail for the first time in alpine Veronica in New Zealand. The aim of the present study was to investigate whether hygrochastic capsules are an adaptation of alpine Veronica to achieve directed dispersal to safe sites. We expect that by limiting dispersal to rainfall events, distances travelled by seeds are short and confine them to small habitat patches where both seedlings and adults have a greater chance of survival.
Dispersal distances of five hygrochastic Veronica were measured under laboratory and field conditions and the seed shadow was analysed. Habitat patch size of hygrochastic Veronica and related non-hygrochastic species were estimated and compared.
Key Results
Dispersal distances achieved by dispersal with raindrops did not exceed 1 m but weather conditions could influence the even distribution of seeds around the parent plant. Compared with related Veronica species, hygrochastic Veronica mostly grow in small, restricted habitat patches surrounded by distinctly different habitats. These habitat patches provide safe sites for seeds due to their microtopography and occurrence of adult cushion plants. Non-hygrochastic Veronica can be predominantly found in large habitats without clearly defined borders and can be spread over long distances along rivers.
The results suggest that hygrochasy is a very effective mechanism of restricting seed dispersal to rainfall events and ensuring short-distance dispersal within a small habitat patch. It appears that it is an adaptation for directed dispersal to safe sites that only exist within the parent habitat.
PMCID: PMC2924830  PMID: 20587583
Dispersal; habitat patch; hygrochasy; New Zealand Alps; ombrohydrochory; safe sites; Veronica
10.  Accuracy of comparing bone quality to chocolate bars for patient information purposes: observational study 
BMJ : British Medical Journal  2007;335(7633):1285-1287.
Objective To test whether standard information for patients using Crunchie and Aero chocolate bars to explain bone health and risk of fracture is robust.
Design Observational study.
Setting Domestic kitchen in rural west Wales.
Participants 10 Crunchie bars and 10 Aero bars.
Main outcome measure Fracture after falls from varying heights.
Results Both Crunchie and Aero bars exhibited the same T and Z scores for bone density. Crunchie bars had a lower chocolate mass index than the Aero bars. Crunchie bars are more liable to fracture.
Conclusions Using Crunchie and Aero chocolate bars to explain bone structure to patients may be visually attractive but oversimplifies the situation.
PMCID: PMC2151161  PMID: 18156229
11.  A multi-compartment vascular model for inferring arteriole dilation and cerebral metabolic changes during functional activation 
Functional hemodynamic responses, measured by methods such as fMRI or optical imaging, are the composite, downstream results of underlying variations in cerebral oxygen consumption and the dilation of arteriole vessels, which follow from changes in neuronal activity. The separation of metabolic and vascular effects is an actively growing area of interest, motivated by increasing evidence of the role of neural-metabolic-vascular coupling in health and disease. However, this coupling cannot be easily or directly observed in vivo. Vascular modeling plays an important role by relating these underlying physiological responses to the hemodynamic variables measured with non-invasive imaging. In this paper, we describe a multi-compartment model of the cerebral vascular and oxygen transport dynamics associated with stimulus driven neuronal activation. The unique formulation of this model allows both the estimation of the dynamic arteriole dilation and metabolic processes associated with the functional response to stimuli, and also enables us to infer details of the structural and baseline properties of the vascular anatomy, such as baseline oxygen consumption, blood flow, and resting hemoglobin concentrations. We apply this model to multimodal optical spectroscopic and laser speckle imaging of the rat somato-sensory cortex during nine conditions of whisker stimulation. We estimate baseline blood flows to be 94(±15) mL/100g/min and baseline oxygen consumption to be 6.7(±1.3) mL O2/100g/min. We calculate parametric, linear increases in the arteriole dilation (R2=0.96) and CMRO2 (R2=0.87) responses over the nine conditions. We find that our model more accurately describes these observed oxygenation changes when compared to a single compartment model.
PMCID: PMC2586902  PMID: 17200678
13.  Introduction of a Carboxyl Group in the First Transmembrane Helix of Escherichia coli F1Fo ATPase Subunit c and Cytoplasmic pH Regulation 
Journal of Bacteriology  2001;183(5):1524-1530.
The multicopy subunit c of the H+-transporting F1Fo ATP synthase of Escherichia coli folds across the membrane as a hairpin of two hydrophobic α helices. The subunits interact in a front-to-back fashion, forming an oligomeric ring with helix 1 packing in the interior and helix 2 at the periphery. A conserved carboxyl, Asp61 in E. coli, centered in the second transmembrane helix is essential for H+ transport. A second carboxylic acid in the first transmembrane helix is found at a position equivalent to Ile28 in several bacteria, some the cause of serious infectious disease. This side chain has been predicted to pack proximal to the essential carboxyl in helix 2. It appears that in some of these bacteria the primary function of the enzyme is H+ pumping for cytoplasmic pH regulation. In this study, Ile28 was changed to Asp and Glu. Both mutants were functional. However, unlike the wild type, the mutants showed pH-dependent ATPase-coupled H+ pumping and passive H+ transport through Fo. The results indicate that the presence of a second carboxylate enables regulation of enzyme function in response to cytoplasmic pH and that the ion binding pocket is aqueous accessible. The presence of a single carboxyl at position 28, in mutants I28D/D61G and I28E/D61G, did not support growth on a succinate carbon source. However, I28E/D61G was functional in ATPase-coupled H+ transport. This result indicates that the side chain at position 28 is part of the ion binding pocket.
PMCID: PMC95036  PMID: 11160082
14.  The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation 
Gut  2014;64(1):11-19.
Knowledge of the cellular mechanisms involved in homeostasis of human squamous oesophagus in the steady state and following chronic injury is limited. We aimed to better understand these mechanisms by using a functional 3D approach.
Proliferation, mitosis and the expression of progenitor lineage markers were assessed in normal squamous oesophagus from 10 patients by immunofluorescence on 3D epithelial whole mounts. Cells expressing differential levels of epithelial and progenitor markers were isolated using flow cytometry sorting and characterised by qPCR and IF. Their self-renewing potential was investigated by colony forming cells assays and in vitro organotypic culture models.
Proliferation and mitotic activity was highest in the interpapillary basal layer and decreased linearly towards the tip of the papilla (p<0.0001). The orientation of mitosis was random throughout the basal layer, and asymmetric divisions were not restricted to specific cell compartments. Cells sorted into distinct populations based on the expression of epithelial and progenitor cell markers (CD34 and EpCAM) showed no difference in self-renewal in 2D culture, either as whole populations or as single cells. In 3D organotypic cultures, all cell subtypes were able to recapitulate the architecture of the tissue of origin and the main factor determining the success of the 3D culture was the number of cells plated, rather than the cell type.
Oesophageal epithelial cells demonstrate remarkable plasticity for self-renewal. This situation could be viewed as an ex vivo wounding response and is compatible with recent findings in murine models.
PMCID: PMC4283695  PMID: 24572143

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