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1.  A Review of A Priori Regression Models for Warfarin Maintenance Dose Prediction 
PLoS ONE  2014;9(12):e114896.
A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed.
PMCID: PMC4264860  PMID: 25501765
2.  Thoracic Epidural analgesia versus Rectus Sheath Catheters for open midline incisions in major abdominal surgery within an enhanced recovery programme (TERSC): study protocol for a randomised controlled trial 
Trials  2014;15(1):400.
Thoracic epidural analgesia (TEA) is recommended for post-operative pain relief in patients undergoing major abdominal surgery via a midline incision. However, the effectiveness of TEA is variable with high failure rates reported post-operatively. Common side effects such as low blood pressure and motor block can reduce mobility and hinder recovery, and a number of rare but serious complications can also occur following their use.
Rectus sheath catheters (RSC) may provide a novel alternative approach to somatic analgesia without the associated adverse effects of TEA. The aim of this study is to compare the efficacy of both techniques in terms of pain relief, patient experience, post-operative functional recovery, safety and cost-effectiveness.
This is a single-centre randomised controlled non-blinded trial, which also includes a nested qualitative study. Over a two-year period, 132 patients undergoing major abdominal surgery via a midline incision will be randomised to receive either TEA or RSC for post-operative analgesia. The primary outcome measures pain scores on moving from a supine to a sitting position at 24 hours post wound closure, and the patient experience between groups evaluated through in-depth interviews. Secondary outcomes include pain scores at rest and on movement at other time points, opiate consumption, functional recovery, morbidity and cost-effectiveness.
This will be the first randomised controlled trial comparing thoracic epidurals to ultrasound-guided rectus sheath catheters in adults undergoing elective midline laparotomy. The standardised care provided by an Enhanced Recovery Programme makes this a comparison between two complex pain packages and not simply two analgesic techniques, in order to ascertain if RSC is a viable alternative to TEA.
Trial registration
Current Controlled Trials ISRCTN81223298 (16 January 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-400) contains supplementary material, which is available to authorized users.
PMCID: PMC4223757  PMID: 25336055
Rectus sheath catheters; Rectus sheath block; Analgesia; Epidural; Enhanced recovery; Laparotomy
3.  AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias 
Cell  2011;146(5):10.1016/j.cell.2011.07.032.
AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ∼40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions.
PMCID: PMC3826540  PMID: 21884932
4.  Myeloproliferative Neoplasm Animal Models 
Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow cells into irradiated syngeneic mice established the field of MPN animal modeling and the retroviral bone marrow transplantation (BMT) assay has been used extensively since. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN associated genetic abnormalities on the hematopoietic stem and progenitor cell (HSPC) compartment and xenograft models have allowed the study of primary human MPN-propagating cells in vivo. All models have facilitated the pre-clinical development of MPN therapies. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models. MPN animal models have also been used to investigate additional genetic lesions found in human MPN and to evaluate the bone marrow microenvironment in these diseases. Finally, several genetic lesions, although not common, somatically mutated drivers of MPN in humans induce a MPN phenotype in mice. Future uses for MPN animal models will include modeling compound genetic lesions in MPN and studying myelofibrotic transformation.
PMCID: PMC3459181  PMID: 23009938
Myeloproliferative neoplasms; preclinical murine models; BCR-ABL; JAK2V617F; hematopoietic stem cells; bone marrow microenvironment; myelofibrosis; oncogenes
5.  mTOR Complex 1 Plays Critical Roles in Hematopoiesis and Pten-Loss-Evoked Leukemogenesis 
Cell stem cell  2012;11(3):429-439.
The mammalian target of rapamycin (mTOR)-pathway serves as a key sensor of cellular-energetic state, and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoeisis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, Raptor (regulatory-associated protein of mTOR), in mouse HSC and its loss causes a non-lethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely non-redundant roles with Rictor (rapamycin-insensitive companion of mTOR), in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis, and inform clinical strategies based on chronic mTORC1 inhibition.
PMCID: PMC3743253  PMID: 22958934
6.  The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML 
Inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
PMCID: PMC3549713  PMID: 23277453
7.  Genetic and Pharmacologic Inhibition of β-Catenin Targets Imatinib Resistant Leukemia Stem Cells in CML 
Cell Stem Cell  2012;10(4):412-424.
A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of β-catenin during fetal HSC development leads to impairment of self-renewal while β-catenin is dispensable in fully developed adult HSCs. Whether β-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of β-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of β-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of β-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces β-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting β-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.
PMCID: PMC3339412  PMID: 22482506
9.  CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling 
Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of CDX2-associated AML and observed that PPARγ agonists derepressed KLF4 and were preferentially toxic to CDX2+ leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells, provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer, and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a therapeutic modality in a large proportion of AML patients.
PMCID: PMC3533294  PMID: 23202735
10.  Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study 
PLoS ONE  2011;6(7):e22425.
To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors.
Prospective cohort study.
Alder Hey Children's Hospital, Liverpool, United Kingdom.
378 infants admitted to hospital with a diagnosis of bronchiolitis, of whom 299 (79%) were antigen positive to respiratory syncytial virus (RSV).
Severity of disease during admission, defined as “no need for supplemental oxygen” (reference group), “any need for supplemental oxygen” and “any need for mechanical ventilation”.
Univariate analysis found male sex (p = 0.035) and tobacco smoking by a household member (p<0.001) were associated with need for both supplemental oxygen and mechanical ventilation. Premature birth, low gestation, low birth weight, low admission weight and low corrected age on admission were also associated with need for mechanical ventilation (all p≤0.002). Deprivation scores (IMD 2004) were significantly higher in households where a member smoked compared to non-smoking households (p<0.001). The odds of smoking predicted by deprivation were 7 times higher (95%CI (3.59, 14.03)), when comparing the least and most deprived quintiles of the study population. Family history of atopic disease and deprivation score were not associated with severe disease. Multivariate multinomial logistic regression which initially included all covariates, found household tobacco smoking (adjusted OR = 2.45, 95%CI (1.60, 3.74) predicted need for oxygen supplementation. Household tobacco smoking (adjusted OR = 5.49, (2.78, 10.83)) and weight (kg) on admission (adjusted OR = 0.51, (0.40, 0.65)) were both significant predictors in the final model for mechanical ventilation. The same associations and similar size of effects were found when only children with proven RSV infection were included in analysis.
Low admission weight and householder tobacco smoking increased the risk of severe bronchiolitis in infants admitted to hospital. These effects were independent of a standard deprivation measure. NIHR Study Ref. DHCS/G121/10.
PMCID: PMC3139660  PMID: 21811609
11.  Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells 
Cancer cell  2010;17(6):584-596.
We report a Jak2V617F knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F positive MPN.
The JAK2V617F mutation is a promising candidate for molecularly targeted therapy in MPN. Early data from JAK2 inhibitor clinical trials have called into question the capacity of these compounds to alter the natural history of JAK2V617F mediated MPN. Determining the effect of JAK2 inhibitors on the disease-initiating population requires a model in which the JAK2V617F allele is expressed at physiological levels in hematopoietic stem and progenitor cells, as it is in humans. Our model demonstrates that JAK2V617F causes expansion of erythroid progenitors but that only the HSC compartment can initiate disease in a transplanted mouse. We further demonstrate that the HSC compartment, the definitive target for curative therapy of JAK2V617F mediated MPN, is resistant to treatment with a JAK2 inhibitor.
PMCID: PMC2909585  PMID: 20541703
12.  Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia 
Nature medicine  2010;16(8):903-908.
RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia–associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).
PMCID: PMC3090658  PMID: 20616797
13.  In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus 
mAbs  2010;2(3):335-346.
Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease. Two antibodies, Ab-01 and Ab-02, which differed by only four amino acids in VL CDR3, showed potent inhibition of human and mouse IL-21R in cell-based assays and were evaluated for their pharmacological and pharmacodynamic properties. Ab-01, but not Ab-02, significantly reduced a biomarker of disease (anti-dsDNA antibodies) and IgG deposits in the kidney in the MRL-Faslpr mouse model of lupus, suggesting that anti-IL-21R antibodies may prove useful in the treatment of lupus. Ab-01 also had a consistently higher exposure (AUC0-∞) than Ab-02 following a single dose in rodents or cynomolgus monkeys (2–3-fold or 4–7-fold, respectively). Our data demonstrate that small differences in CDR3 sequences of optimized antibodies can lead to profound differences in in vitro and in vivo properties, including differences in pharmacological activity and pharmacokinetic profiles. The lack of persistent activity of Ab-02 in the MRL-Faslpr mouse lupus model may have been a consequence of faster elimination, reduced potency in blocking the effects of mouse IL-21R, and more potent/earlier onset of the anti-product response relative to Ab-01.
PMCID: PMC2881259  PMID: 20424514
affinity maturation; phage display; monoclonal antibody; autoimmunity; lupus; IL-21; IL-21R; pharmacokinetics; anti-product antibodies
14.  Impaired spine formation and learning in GPCR kinase interacting protein-1 (GIT1) knockout mice 
Brain research  2010;1317:218-226.
The G-protein coupled receptor (GPCR)-kinase interacting proteins 1 and 2 (GIT1 and GIT2) are scaffold proteins with ADP-ribosylating factor GTPase activity. GIT1 and GIT2 control numerous cellular functions and are highly expressed in neurons, endothelial cells and vascular smooth muscle cells (VSMC). GIT1 promotes dendritic spine formation, growth and motility in cultured neurons, but its role in brain in vivo is unknown. By using global GIT1 knockout mice (GIT1 KO), we show that deletion of GIT1 results in markedly reduced dendritic length and spine density in the hippocampus by 36.7 % (p < 0.0106*) and 35.1% (p< 0.0028*) respectively compared to WT controls. This correlated with their poor adaptation to new environments as shown by impaired performance on tasks dependent on learning. We also studied the effect of GIT1 gene deletion on brain microcirculation. In contrast to findings in systemic circulation, GIT1 KO mice had an intact blood-brain barrier and normal regional cerebral blood flow as determined with radiotracers. Thus, our data suggest that GIT1 plays an important role in brain in vivo by regulating spine density involved in synaptic plasticity that is required for processes involved in learning.
PMCID: PMC2861918  PMID: 20043896
G-protein coupled receptor kinase interacting protein 1, GIT1; spine formation; cytoskeleton dynamics; brain morphology; blood brain barrier; BBB
15.  Electronic brachytherapy as adjuvant therapy for early stage breast cancer: a retrospective analysis 
OncoTargets and therapy  2011;4:13-20.
This multicenter, retrospective study evaluated treatment and clinical outcomes of patients with early stage breast cancer who received adjuvant high-dose rate (HDR) electronic brachytherapy (EBT) treatment post-lumpectomy using the Axxent® EBT system. Dosimetric data from the EBT treatment plans were compared with those based on iridium-192 HDR brachytherapy.
Material and methods:
Medical records of 63 patients with early stage breast cancer (Tis, T1a, T1b, T1c, and T2) who were treated post-lumpectomy with EBT alone or in combination with external beam radiation therapy were reviewed. The prescribed EBT dose was 34 Gy (10 fractions over 5 days, 3.4 Gy each) to 1 cm from the balloon surface. Dosimetry data from 12 patients were compared with these of treatment plans using an iridium-192 source prepared for the same 12 patients.
The majority of patients (90.5%) were older than 50 years and had one or more risk factors for breast cancer (80.6%). Tumor sizes were 0.1 cm to 3.5 cm (mean 1.3 cm). Median follow-up was 7 months (1 to 18 months) post-EBT. Balloon applicators were implanted 0 to 85 days (mean 13.4 days) post-lumpectomy/re-excision. The most common adverse events were erythema, rash dermatitis, and pain or breast tenderness. No recurrences were reported. Dosimetric analyses demonstrated comparable target coverage, increased high-dose regions, and a significantly reduced dose to the ipsilateral breast and lungs as well as the heart with EBT as compared with the iridium-192 treatment plans.
This retrospective, multicenter study showed that postsurgical adjuvant radiation therapy for early stage breast cancer can be administered using the EBT system with similar toxicity outcomes to those reported with iridium-192 brachytherapy. EBT offers a convenient, portable, nonisotope alternative to HDR brachytherapy using iridium-192.
PMCID: PMC3084303  PMID: 21552411
electronic brachytherapy; breast cancer; radiation therapy
16.  Use of electronic brachytherapy to deliver postsurgical adjuvant radiation therapy for endometrial cancer: a retrospective multicenter study 
OncoTargets and therapy  2010;3:197-203.
This retrospective, multicenter study evaluated the feasibility and safety of high-dose rate electronic brachytherapy (EBT) as a postsurgical adjuvant radiation therapy for endometrial cancer.
Medical records were reviewed from 41 patients (age 40–89 years) with endometrial cancer (Federation of International Gynecology and Obstetrics stages IA–IIIC) treated at nine centers between April 2008 and October 2009. Treatment included intracavitary vaginal EBT alone (n = l6) at doses of 18.0–24.0 Gy in 3–4 fractions and EBT in combination with external beam radiation therapy (EBRT, n = 25) at a total radiation dose range of 40.0–80.4 Gy. Doses were prescribed to a depth of 5 mm from the applicator surface and to the upper third (n = 15) and the upper half (n = 26) of the vagina.
Median follow-up was 3.8 (range 0.5–12.0) months. All 41 patients received the intended dose of radiation as prescribed. Adverse events occurred in 13 of 41 patients and were mild to moderate (Grade 1–2), consisting primarily of vaginal mucositis, rectal mucosal irritation and discomfort, and temporary dysuria and diarrhea. There were no Grade 3 adverse events in the EBT-only treatment group. One patient, who was being treated with the combination of EBT and EBRT for recurrent endometrial cancer, had a Grade 3 adverse event. No recurrences have been reported to date.
Electronic brachytherapy provides a feasible treatment option for postoperative adjuvant vaginal brachytherapy as sole radiation therapy and in combination with EBRT for primary endometrial cancer. Early and late toxicities were mild to moderate.
PMCID: PMC2962306  PMID: 21049086
endometrial cancer; electronic brachytherapy; radiation therapy
17.  The Global Mental Health Assessment Tool-validation in Hindi: A validity and feasibility study 
Indian Journal of Psychiatry  2010;52(4):316-319.
A computer-assisted interview, the Global Mental Health Assessment Tool-validation (GMHAT/PC) has been developed to assist general practitioners and other health professionals to make a quick, convenient, yet reasonably comprehensive standardized mental health assessment. GMHAT/PC has been translated into various languages including Hindi. This is the first study conducted in India, using the Hindi version GMHAT/PC of the series of studies assessing its validity in different cultures.
The study aims to assess the feasibility of using a computer assisted diagnostic interview by health professionals and to examine the level of agreement between the Hindi version GMHAT/PC diagnosis and psychiatrists’ ICD-10 based clinical diagnosis.
Cross-sectional validation study.
Psychiatric clinic of a General Hospital and an out patient (Neurology) clinic in the Teaching General Hospital in Jaipur, India.
Materials and Methods:
All consecutive patients attending the psychiatric out patient clinic were interviewed using GMHAT/PC and psychiatrists made a diagnosis applying ICD-10 criteria for a period of six weeks. A small sample of subjects was interviewed in a similar way in a Neurology clinic for four weeks.
The mean duration of interview was under 17 minutes. Most patients were pleased that they were asked about every aspect of their mental health. The agreement between psychologists’ GMHAT/PC interview diagnoses and psychiatrists’ clinical diagnoses was excellent (Kappa 0.96, sensitivity 1.00, and specificity 0.94).
GMHAT/PC Hindi version detected mental disorders accurately and it was feasible to use GMHAT/PC in Indian settings.
PMCID: PMC3025156  PMID: 21267364
GMHAT; mental health assessment; primary care mental health; psychiatric diagnosis
18.  Linkage of survey data with district‐level lung cancer registrations: a method of bias reduction in ecological studies 
To investigate a stratified ecological method for reducing ecological bias in studies that use aggregate data, by incorporating information on individual‐level risk factors into the analysis.
Cross‐sectional study investigating associations between socioeconomic risk factors and lung cancer in the north of England, using 1991 UK Census Small Area Statistics and Sample of Anonymised Records with lung cancer registrations from three regional cancer registries for 1993–6.
Setting and patients
92 local authority districts in the north of England containing over three million people aged 45–74 years.
Generally, groups considered more socioeconomically disadvantaged had an increased risk of lung cancer across districts. In the standard ecological analysis, effects for non‐car ownership, social class III manual, social class IV/V and socioeconomic inactivity were insignificant, suggesting ecological bias. In the stratified ecological analysis these effects became significant (rate ratio (RR) 2.23, 95% confidence interval (CI) 1.79 to 2.78, p<0.001; RR 1.35, 95% CI 1.04 to 1.74, p = 0.022; RR 2.36, 95% CI 1.86 to 2.99, p<0.001; and RR 0.72, 95% CI 0.53 to 0.98, p = 0.039, respectively), and spuriously large positive effects for the social class III non‐manual (RR 20.29) and unemployment groups (RR 147.53) reduced to a more reasonable level (RR 1.92, 95% CI 1.46 to 2.52, p<0.001; and RR 2.36, 95% CI 1.22 to 4.55, p = 0.011, respectively).
Stratified ecological analysis incorporating information on individual‐level covariates reduced the bias seen in a standard ecological analysis. The method is straightforward to apply and allows the linkage of health data with data from any large‐scale complex survey where district of residence is known.
PMCID: PMC2465495  PMID: 17108309
19.  Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells 
The Journal of Clinical Investigation  2009;119(11):3437-3449.
Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood–spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood–spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor–1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.
PMCID: PMC2769191  PMID: 19841542
20.  Activated protein C promotes neovascularization and neurogenesis in post-ischemic brain via protease activated receptor 1 
Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early post-ischemic APC application activates the cellular protein C pathway in brain endothelium and neurons which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 days, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 days post-ischemia, APC multiple-dosing (0.8 mg/kg i.p.) at 6-72 h or 72-144 h enhanced comparably cerebral perfusion in the ischemic border by about 40% as shown by in vivo lectin-FITC angiography, blocked blood-brain barrier leakage of serum proteins and increased the number of endothelial replicating cells by 4.5-4.7-fold. APC multi-dosing at 6-72 h or 72-144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40-50% and migration of newly formed neuroblasts from the SVZ towards the ischemic border by about 2-fold. APC's effects on neovascularization and neurogenesis were mediated by protease activated receptor-1 and were independent of APC's reduction of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair, i.e., neovascularization and neurogenesis, suggesting a significant extension of the therapeutic window for APC intervention in post-ischemic brain.
PMCID: PMC2742231  PMID: 19036971
activated protein C; serine protease; transient cerebral ischemia; neuroprotection; neurogenesis; angiogenesis
21.  Mental health diagnosis by nurses using the Global Mental Health Assessment Tool: a validity and feasibility study 
The Global Mental Health Assessment Tool — Primary Care Version (GMHAT/PC) has been developed to assist health professionals to make a quick and comprehensive standardised mental health assessment. It has proved to be a reliable and valid tool in a previous study involving GPs. Its use by other health professionals may help in detecting and managing mental disorders in primary care and general health settings.
To assess the feasibility of using a computer-assisted diagnostic interview by nurses and to examine the level of agreement between the GMHAT/PC diagnosis and psychiatrists' clinical diagnosis.
Design of study
Cross-sectional validation study.
Primary care, general healthcare (cardiac rehabilitation clinic), and community mental healthcare settings.
A total of 215 patients between the ages of 16 and 75 years were assessed by nurses and psychiatrists in various settings: primary care centre (n = 54), cardiac rehabilitation centre (n = 98), and community mental health clinic (n = 63). The time taken for the interview, and feedback from patients and interviewers were indicators of feasibility, and the kappa coefficient (κ), sensitivity, and specificity of the GMHAT/PC diagnosis were measures of validity.
Mean duration of interview was under 15 minutes. The agreement between nurses' GMHAT/PC interview-based diagnosis and psychiatrists' International Classification of Diseases (ICD)–10 criteria-based clinical diagnosis was 80% (κ = 0.76, sensitivity = 0.84, specificity = 0.92).
The GMHAT/PC can assist nurses to make accurate mental health assessment and diagnosis in various healthcare settings and it is acceptable to patients.
PMCID: PMC2418993  PMID: 18505618
diagnosis; computer-assisted; mental disorders; mental health services; psychiatric diagnosis
22.  Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I131 KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma 
BMC Cancer  2009;9:66.
Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I131 in pancreatic cancer (ISRCTN 16857581).
Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death.
Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3).
The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis.
Dose limiting toxicity for KAb201 with I131 by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.
PMCID: PMC2656541  PMID: 19243606
23.  apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain 
The Journal of Clinical Investigation  2008;118(12):4002-4013.
Neurotoxic amyloid β peptide (Aβ) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Aβ accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Aβ clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Aβ binding to apoE4 redirected the rapid clearance of free Aβ40/42 from the LDL receptor–related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Aβ-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Aβ-apoE2 and Aβ-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Aβ-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Aβ were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate Aβ clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.
PMCID: PMC2582453  PMID: 19033669
24.  PAMFOnline: Integrating EHealth with an Electronic Medical Record System 
The Institute of Medicine stressed the need for continuous healing relationships, yet the delivery of health care has traditionally been confined to the physician office or hospital. We implemented an eHealth application tightly integrated with our electronic medical record system that provides patients with a convenient, continuously available communication channel to their physician’s office. Patients can view summary data from their medical record, including the results of diagnostic tests, and request medical advice, prescription renewals, appointments, or updates to their demographic information. We have found that patients embrace this new communication channel and are using the service appropriately. Patients especially value electronic messaging with their physicians and timely access to their test results. While initially concerned about an increase in work, physicians have found that use of electronic messaging can be an efficient method for handling non-urgent communication with their patients. Online tools for patients, when integrated with an electronic medical record, can provide patients with better access to health information, improve patient satisfaction, and improve operational efficiency.
PMCID: PMC1479999  PMID: 14728252
25.  Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses 
Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.
Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.
Setting UK National Health Service.
Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.
Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.
Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained.
Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.
PMCID: PMC3204867  PMID: 22042753

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