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1.
Int J Drug Policy ; 72: 84-90, 2019 10.
Article in English | MEDLINE | ID: mdl-31351752

ABSTRACT

BACKGROUND: In Australia, Hepatitis C Virus (HCV) treatment is declining, despite broad access to direct-acting antiviral medication. People who inject drugs are proportionally over-represented in emergency department presentations. Emergency department assessment of people who have injected drugs for HCV presents an opportunity to engage this marginalised population with treatment. We describe the outcomes of risk-based screening and point-of-care anti-HCV testing for emergency department patients, and linkage to outpatient antiviral treatment. METHODS: During the three-month study period, consecutive adult patients who presented to the emergency department during the study times were screened for risk factors and offered the OraQuick oral HCV antibody test. Those with reactive results were offered venepuncture in the emergency department for confirmatory testing and direct-acting antiviral treatment in clinic. The main outcome measures were the number and proportion of viremic participants that were linked to the hepatitis clinic, commenced treatment and achieved a sustained viral response. Secondary outcome measures were the proportion (%) of presentations screened that were oral antibody reactive, and the prevalence and type of HCV risk factors. RESULTS: During the study period, 2408 of the 3931 (61%) presentations to the emergency department were eligible for screening. Of these 2408 patients, 1122 (47%) participated, 307 (13%) declined participation and 977 (41%) could not be approached during their time in the emergency department. Among the 1122 participants, 378 (34%) reported at least one risk factor. Subsequently, 368 (97%) of the 378 participants underwent OraQuick anti-HCV test, and 50 (14%) had a reactive result. A risk factor of ever having injected drugs was present in 44 (88%) of participants who were sero-positive. Of the 45 that had blood tested, 30 (67%) were HCV ribonucleic acid (RNA) positive. Three participants died. Of the 27 remaining participants, 10 (37%) commenced treatment and 7 of these 10 (70%) obtained a cure. There was a high rate of homelessness (24%) among anti-HCV positive participants. CONCLUSION: Among emergency department participants with a risk factor for HCV, positive serology was common using a rapid point-of-care test. A history of injecting drug use was identified as the risk factor with highest yield for positive HCV serology, and is suitable as a single screening question. However, linkage to care post ED presentation was low in this marginalised population. There is a need for new pathways to improve the care cascade for marginalised individuals living with HCV infection.


Subject(s)
Emergency Service, Hospital , Hepatitis C/diagnosis , Point-of-Care Systems , Substance Abuse, Intravenous/complications , Adult , Antiviral Agents/administration & dosage , Australia , Female , Follow-Up Studies , Hepacivirus/isolation & purification , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Ill-Housed Persons/statistics & numerical data , Humans , Male , Mass Screening/methods , Mass Screening/statistics & numerical data , Middle Aged , Prospective Studies , RNA, Viral/analysis , Risk Factors , Substance Abuse, Intravenous/epidemiology
2.
Nanoscale ; 10(18): 8547-8559, 2018 May 10.
Article in English | MEDLINE | ID: mdl-29693684

ABSTRACT

Communication between diseased cells and the microenvironment is a complex yet crucial element in progression of varied pathological processes. Recent studies in cancer highlight an important role for small extracellular nanovesicles secreted by cancer cells as modulators of cancer-associated stroma, leading to enhanced angiogenesis and metastatic priming. The intrinsic factors regulating extracellular nanovesicle biogenesis and secretion are therefore relevant in studies of nano-communication in the cancer milieu. We generated prostate cancer cells bearing stable knockdown of several candidate vesicle regulating factors and examined the impact on cell health, vesicle secretion and on communication with fibroblastic stromal cells. We highlight that RAB11B and RAB35 regulate phenotypically distinct nanovesicle populations, each accounting for only around 20% of the total. Depleting RAB35, but not RAB11B leaves a remaining population of vesicles whose phenotype is insufficient for driving fibroblast to myofibroblast differentiation, leading to attenuated motile behaviours in 3D in vitro models. Co-implantation of tumour cells with stromal fibroblasts in xenografts similarly showed that RAB11B knockdown had little effect on growth rates in vivo. In contrast, significant attenuation in growth, and attenuation of myofibroblasts at the tumour site was evident when using RAB35-knockdown cells. The study concludes that a RAB35 regulated nanovesicle sub-population is particularly important for communication between cancer and stromal cells, and is required for generating a tumour-supportive microenvironment.


Subject(s)
Extracellular Vesicles/metabolism , Prostatic Neoplasms/metabolism , rab GTP-Binding Proteins/metabolism , Animals , Cell Differentiation , Cell Line, Tumor , Fibroblasts/cytology , Gene Knockdown Techniques , Humans , Male , Mice , Myofibroblasts/cytology , Nanoparticles , Neoplasm Transplantation , Spheroids, Cellular , Stromal Cells/cytology
3.
Conserv Biol ; 32(5): 998-1006, 2018 10.
Article in English | MEDLINE | ID: mdl-29660170

ABSTRACT

Boundary organizations are situated between science, policy, and practice and have a goal of supporting communication and collaboration among these sectors. They have been promoted as a way to improve the effectiveness of conservation efforts by building stronger relationships between scientists, policy makers, industry, and practitioners (Cook et al. 2013). Although their promise has been discussed in theory, the work of and expectations for boundary organizations are less defined in practice. Biodiversity conservation is characterized by complexity, uncertainty, dissent, and tight budgets, so boundary organizations face the challenging task of demonstrating their value to diverse stakeholders. We examined the challenges boundary organizations face when seeking to evaluate their work and thus aimed to encourage more productive conversations about evaluation of boundary organizations and their projects. Although no off-the-shelf solution is available for a given boundary organization, we identified 4 principles that will support effective evaluation for boundary organizations: engage diverse stakeholders, support learning and reflection, assess contribution to change, and align evaluation with assumption and values.


Subject(s)
Conservation of Natural Resources , Biodiversity , Organizations , Policy
5.
Am J Transplant ; 16(1): 235-45, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26317167

ABSTRACT

Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas-kidney allografts for T1D recurrence and its risk factors. With long-term follow-up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D-associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor-recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D-predisposing HLA-DR3/DR4 genotype in the recipient and donor-recipient sharing of HLA-DR alleles, especially HLA-DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.


Subject(s)
Autoantibodies/immunology , Diabetes Mellitus, Type 1/immunology , Graft Rejection/etiology , Kidney Transplantation/adverse effects , Pancreas Transplantation/adverse effects , Postoperative Complications , Adolescent , Adult , Autoantibodies/blood , Child , Child, Preschool , Diabetes Mellitus, Type 1/surgery , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/blood , Graft Rejection/drug therapy , Graft Survival , Humans , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Infant , Kidney Function Tests , Male , Prognosis , Recurrence , Risk Factors , Transplant Recipients , Young Adult
6.
Bone Marrow Transplant ; 50(2): 266-73, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25387093

ABSTRACT

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age- and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1-17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/µL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P=0.035), whereas high pDC/µL PB up to day 60 are associated with higher risk of relapse (P<0.001). The time-trend of DCs/µL PB for days 0-200 is a significant predictor of relapse-free survival for both mDCs (P<0.001) and pDCs (P=0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P=0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT.


Subject(s)
Dendritic Cells/immunology , Graft vs Host Disease , Leukemia , Myelodysplastic Syndromes , Stem Cell Transplantation , Acute Disease , Adolescent , Allografts , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Humans , Leukemia/immunology , Leukemia/mortality , Leukemia/therapy , Male , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Survival Rate
7.
Gen Hosp Psychiatry ; 36(3): 318-24, 2014.
Article in English | MEDLINE | ID: mdl-24630892

ABSTRACT

OBJECTIVE: To assess the feasibility and acceptability of routine web-based screening in general hospital settings, and describe the level of common mental disorder. METHOD: A service development platform to integrate mental and physical healthcare was implemented in six specialties (rheumatology, limb reconstruction, hepatitis C, psoriasis, adult congenital heart disease (ACHD), chronic pain) across three general hospitals in London, UK. Under service conditions, patients completed a web-based questionnaire comprising mental and physical patient-reported outcome measures, whilst waiting for their appointment. Feasibility was quantified as the proportion of patients who completed the questionnaire. Acceptability was quantified as the proportion of patients declining screening, and the proportion requiring assistance completing the questionnaire. The prevalence of probable depression and anxiety was expressed as the percentage of cases determined by the Patient Health Questionnaire-9 and Generalised Anxiety Disorder Questionnaire-7. RESULTS: The proportion of patients screened varied widely across specialties (40.1-98.2%). The decline rate was low (0.6-9.7%) and the minority required assistance (11.7-40.4%). The prevalence of probable depression ranged from 60.9% in chronic pain to 6.6% in ACHD. The prevalence of probable anxiety ranged from 25.1% in rheumatology to 11.4% in ACHD. CONCLUSION: Web-based screening is acceptable to patients and can be effectively embedded in routine practice. General hospital patients are at increased risk of common mental disorder, and routine screening may help identify need, inform care and monitor outcomes.


Subject(s)
Delivery of Health Care, Integrated/standards , Hospitals, General/standards , Mental Disorders/diagnosis , Program Evaluation/standards , Delivery of Health Care, Integrated/statistics & numerical data , Feasibility Studies , Hospitals, General/statistics & numerical data , Humans , London/epidemiology , Mental Disorders/epidemiology , Mental Disorders/therapy , Patient Acceptance of Health Care/statistics & numerical data , Prevalence , Program Evaluation/statistics & numerical data
8.
Clin Psychol Rev ; 34(2): 141-57, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24508685

ABSTRACT

Psychological distress, depression and anxiety are common in most physical diseases, and self-help interventions, if effective, might be an important approach to improve outcomes as they are inexpensive to provide to large numbers of patients. The primary aim of this review was to assess randomised controlled trials examining the impact of self-help interventions on symptoms of depression, anxiety and psychological distress in patients with physical illness. Systematic searches of electronic databases resulted in twenty-five eligible studies for meta-analysis (n=4211). The results of the primary meta-analyses revealed a significant improvement in depression symptoms, in favour of the intervention group (SMD=-0.13, 95% CI: -0.25, -0.02, p=0.02, I(2)=50%). There were no significant differences in symptoms of anxiety (SMD=-0.10, 95% CI: -0.24, 0.05, p=0.20, I(2)=63%) or psychological distress (SMD=-0.14, 95% CI: -0.40, 0.12, p=0.30, I(2)=72%) between intervention and control conditions. Several subgroup and sensitivity analyses improved effect sizes, suggesting that optimal mental health outcomes may be obtained in patients without neurological conditions, and with interventions based on a therapeutic model (such as cognitive behavioural therapy), and with stress management components. This review demonstrates that with appropriate design and implementation, self-help interventions may potentially improve symptoms of depression in patients with physical conditions.


Subject(s)
Anxiety/therapy , Depression/therapy , Psychotherapy/methods , Self Care/methods , Stress, Psychological/therapy , Anxiety/psychology , Depression/psychology , Humans , Stress, Psychological/psychology
9.
Hum Reprod ; 28(11): 2930-42, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24041818

ABSTRACT

STUDY QUESTION: Can the ranked expression levels of a cohort of cumulus cell (CC) genes be used to select MII oocytes with a potential for blastocyst development and live birth? SUMMARY ANSWER: A ranking method containing four (HAS2, FSHR, VCAN, PR) of the eight genes evaluated in this study for identifying good quality MII oocytes provides a significantly better outcome compared with random selection and is equally as good as using all oocytes for ICSI. WHAT IS KNOWN ALREADY: Recent evidence has identified a number of candidate genes in CC that have the potential to serve as markers of oocyte quality; however, a reliable method for selecting MII oocytes with blastocyst and live birth potential remains a challenge. STUDY DESIGN, SIZE, DURATION: A group of 25 patients (<38 years old) underwent rFSH-stimulated ICSI treatment with single embryo replacement (SET). A total of 270 cumulus cell-oocyte complexes (COCs) were recovered and assessed. MATERIALS, SETTING, METHODS: Expression levels of eight candidate genes (HAS2, FSHR, SLC2A4, ALCAM, SFRP2, VCAN, NRP1 and PR), corrected for RPL19, were measured in individual CC masses using multiplex QPCR. Expression levels of individual CC masses were assessed and ranked in relation to oocyte developmental indicators (blastocyst formation and live birth). MAIN RESULTS AND THE ROLE OF CHANCE: From the 25 women, 19 (76%) had achieved a successful live birth delivery following SET. In this population, the selection of MII oocytes according to relative ranking levels of a subset of CC-expressed genes provided a significantly higher chance of identifying a good quality oocyte compared with selecting MII oocytes randomly (blastocyst: 1× MII oocyte: 52 versus 23%, P = 0.008; 3× MII oocytes: 80 versus 52%, P = 0.002; live birth: 1× MII oocyte: 31 versus 15%, P<0.05, 3× MII oocytes: 60 versus 38%, P < 0.05) and a similar chance to that of using all oocytes available after recovery (blastocyst: 80% versus 96%, P = 0.085, live birth: 60% versus 76%, P = 0.206). LIMITATIONS, REASONS FOR CAUTION: The present method was validated only for young (<38 years) women, with male infertility, who had no signs of androgenicity, PCOS or endometriosis and were free of any chronic disease. This is a retrospective study that requires further validation in an unselected population. WIDER IMPLICATIONS OF THE FINDINGS: Results presented in this study could be used to assist the selection of oocytes with high blastocyst developmental potential in frozen oocyte cycles and for the selection of embryos with high developmental potential as early as 18 h after ICSI (2PN stage) in fresh human IVF cycles. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by Fertility Associates Ltd and the New Zealand Government. The authors declare there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


Subject(s)
Cumulus Cells/metabolism , Oocytes/cytology , Single Embryo Transfer/methods , Sperm Injections, Intracytoplasmic , Adult , Embryonic Development/genetics , Female , Gene Expression , Genetic Markers , Humans , Pregnancy , Pregnancy Outcome , Real-Time Polymerase Chain Reaction , Retrospective Studies , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism
10.
Diabetologia ; 56(9): 1964-70, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23712485

ABSTRACT

AIMS/HYPOTHESIS: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. METHODS: A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. RESULTS: Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk. CONCLUSIONS/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.


Subject(s)
Autoantibodies/immunology , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/immunology , HLA-A24 Antigen/genetics , HLA-B18 Antigen/genetics , HLA-B39 Antigen/genetics , HLA-DQ Antigens/genetics , Adolescent , Adult , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Female , Humans , Infant , Infant, Newborn , Male , Risk Assessment , Young Adult
11.
Scand J Immunol ; 77(3): 213-20, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23298344

ABSTRACT

Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key link between the innate and adaptive immune response. Only a few reports with study populations of up to 50 individuals have been published with age-based reference values for DC subpopulations in healthy children. Therefore, we aimed to establish reference ranges in a larger study population of 100 healthy children, which allowed age-matched subgroups. Most previous studies were performed using a dual-platform approach. In this study, a single-platform approach in a lyse no-wash procedure was used. DC subpopulations were defined as follows: CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD33(+) cells as myeloid DCs (mDCs) and CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD123(+) cells as plasmacytoid DCs (pDCs). Reference ranges were established using a semi-parametric regression of age-matched absolute and relative DC counts. We found a significant decline with increasing age in the medians of mDCs (P = 0.0003) and pDCs per µl peripheral blood (PB) (P = 0.004) and in the 50%, 90% and 95% reference ranges. We also identified significantly lower absolute cell counts of mDCs per µl PB in girls than in boys for all age groups (P = 0.0015). Due to the larger paediatric study population and single-platform approach, this study may give a more precise overview of the normal age-matched development of DC subpopulations and may provide a basis for analyzing abnormal DC counts in different illnesses or therapies such as post stem cell transplantation.


Subject(s)
Dendritic Cells/cytology , Dendritic Cells/immunology , Adolescent , Age Factors , Antigens, CD/immunology , Antigens, CD/metabolism , Cell Count , Child , Child, Preschool , Dendritic Cells/metabolism , Female , Flow Cytometry , HLA-DR Antigens/immunology , HLA-DR Antigens/metabolism , Humans , Infant , Infant, Newborn , Interleukin-3 Receptor alpha Subunit/immunology , Interleukin-3 Receptor alpha Subunit/metabolism , Leukocyte Common Antigens/immunology , Leukocyte Common Antigens/metabolism , Leukocyte Immunoglobulin-like Receptor B1 , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Male , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Regression Analysis , Sex Factors
12.
Clin Exp Immunol ; 171(1): 82-90, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23199327

ABSTRACT

In first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA(+) , GADA(+) , IA-2A(+) and/or ZnT8A(+) relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19 and 20-39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A(+) and/or ZnT8A(+) relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10-39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.


Subject(s)
Autoantibodies/blood , Cation Transport Proteins/immunology , Diabetes Mellitus, Type 1/immunology , Disease Progression , Prediabetic State/blood , Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology , Adolescent , Autoantibodies/economics , Belgium , Blood Glucose/immunology , Child , Child, Preschool , Diabetes Mellitus, Type 1/blood , Family , Female , Glutamate Decarboxylase/immunology , Humans , Insulin/immunology , Male , Prediabetic State/immunology , Registries , Risk , Zinc Transporter 8
13.
Br J Nutr ; 108(9): 1714-20, 2012 Nov 14.
Article in English | MEDLINE | ID: mdl-22947201

ABSTRACT

Improving health through better nutrition of the population may contribute to enhanced efficiency and sustainability of healthcare systems. A recent expert meeting investigated in detail a number of methodological aspects related to the discipline of nutrition economics. The role of nutrition in health maintenance and in the prevention of non-communicable diseases is now generally recognised. However, the main scope of those seeking to contain healthcare expenditures tends to focus on the management of existing chronic diseases. Identifying additional relevant dimensions to measure and the context of use will become increasingly important in selecting and developing outcome measurements for nutrition interventions. The translation of nutrition-related research data into public health guidance raises the challenging issue of carrying out more pragmatic trials in many areas where these would generate the most useful evidence for health policy decision-making. Nutrition exemplifies all the types of interventions and policy which need evaluating across the health field. There is a need to start actively engaging key stakeholders in order to collect data and to widen health technology assessment approaches for achieving a policy shift from evidence-based medicine to evidence-based decision-making in the field of nutrition.


Subject(s)
Clinical Trials as Topic/economics , Diet/economics , Nutrition Disorders/prevention & control , Biomedical Technology/economics , Costs and Cost Analysis/methods , Evidence-Based Medicine/economics , Humans , Nutrition Disorders/economics , Nutrition Policy
15.
Br J Anaesth ; 108(6): 998-1005, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22466819

ABSTRACT

BACKGROUND: Continuous wound infiltration (CWI), i.v. patient-controlled analgesia (i.v.-PCA), and epidural analgesia (EDA) are analgesic techniques commonly used for pain relief after open abdominal surgery. The aim of this study was to evaluate the cost-effectiveness of these techniques. METHODS: A decision analytic model was developed, including values retrieved from clinical trials and from an observational prospective cohort of 85 patients. Efficacy criteria were based on pain at rest (VAS ≤ 30/100 mm at 24 h). Resource use and costs were evaluated from medical record measurements and published data. Probabilistic sensitivity analysis (PSA) was performed. RESULTS: When taking into account all resources consumed, the CWI arm (€ 6460) is economically dominant when compared with i.v.-PCA (€ 7273) and EDA (€ 7500). The proportion of patients successfully controlled for their postoperative pain management are 77.4%, 53.9%, and 72.9% for CWI, i.v.-PCA, and EDA, respectively, demonstrating the CWI procedure to be both economically and clinically dominant. PSA reported that CWI remains cost saving in 70.4% of cases in comparison with EDA and in 59.2% of cases when compared with PCA. CONCLUSIONS: Device-related costs of using CWI for pain management after abdominal laparotomy are partly counterbalanced by a reduction in resource consumption. The cost-effectiveness analysis suggests that CWI is the dominant treatment strategy for managing postoperative pain (i.e. more effective and less costly) in comparison with i.v.-PCA. When compared with EDA, CWI is less costly with almost equivalent efficacy. This economic evaluation may be useful for clinicians to design algorithms for pain management after major abdominal surgery.


Subject(s)
Abdomen/surgery , Analgesia, Epidural/economics , Analgesia, Patient-Controlled/economics , Morphine/administration & dosage , Pain, Postoperative/drug therapy , Adult , Aged , Cohort Studies , Cost-Benefit Analysis , Female , Health Care Costs , Humans , Male , Middle Aged , Probability , Prospective Studies
16.
Diabetologia ; 55(7): 1978-84, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22526605

ABSTRACT

AIMS/HYPOTHESIS: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. METHODS: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. RESULTS: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. CONCLUSIONS/INTERPRETATION: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.


Subject(s)
Autoantibodies/genetics , Cation Transport Proteins/genetics , Diabetes Mellitus, Type 1/genetics , Insulin Antibodies/genetics , Polymorphism, Single Nucleotide , Cation Transport Proteins/immunology , Child , Diabetes Mellitus, Type 1/immunology , Female , Genetic Predisposition to Disease , Genotype , Humans , Insulin Antibodies/immunology , Male , Zinc Transporter 8
17.
Diabetologia ; 55(7): 2026-31, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22526607

ABSTRACT

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cation Transport Proteins/immunology , Diabetes Mellitus, Type 1/immunology , Epitopes, T-Lymphocyte/immunology , HLA-A2 Antigen/immunology , Adolescent , Adult , Animals , Autoantibodies/genetics , CD4-Positive T-Lymphocytes/immunology , Cation Transport Proteins/genetics , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Epitope Mapping , Epitopes, T-Lymphocyte/genetics , Female , HLA-A2 Antigen/genetics , Humans , Infant , Male , Mice , Mice, Transgenic , Middle Aged , Zinc Transporter 8
18.
Diabetologia ; 55(2): 413-20, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22095238

ABSTRACT

AIMS/HYPOTHESIS: The appearance of autoantibodies (Abs) before diabetes onset has mainly been studied in young children. However, most patients develop type 1 diabetes after the age of 15 years. In first-degree relatives aged under 40 years, we investigated the frequency of seroconversion to (persistent) Ab positivity, progression to diabetes and baseline characteristics of seroconverters according to age. METHODS: Abs against insulin (IAA), glutamate decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured during follow-up of 7,170 first-degree relatives. RESULTS: We identified 379 (5.3%) relatives with positivity for IAA, GADA, IA-2A and/or ZnT8A (Ab(+)) at first sampling and 224 (3.1%) at a later time point. Most seroconversions occurred after the age of 10 years (63%). During follow-up, Abs persisted more often in relatives initially Ab(+) (76%) than in seroconverters (53%; p < 0.001). In both groups diabetes developed at a similar pace and almost exclusively with Ab persistence (136 of 139 prediabetic individuals). For both groups, progression was more rapid if Abs appeared before the age of 10 years. Baseline characteristics at seroconversion did not vary significantly according to age. CONCLUSIONS/INTERPRETATION: Seroconversion to (persistent) Ab(+) occurs regardless of age. Although the progression rate to diabetes is higher under age 10 years, later seroconverters (up to age 40 years) have similar characteristics when compared with age-matched initially Ab(+) relatives and generate an important minority of prediabetic relatives, warranting their identification and, eventually, enrolment in prevention trials.


Subject(s)
Autoantibodies/chemistry , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/immunology , Prediabetic State/immunology , Adolescent , Adult , Age Factors , Autoantibodies/immunology , Cation Transport Proteins/chemistry , Cation Transport Proteins/immunology , Child , Child, Preschool , Disease-Free Survival , Family Health , Female , Glutamate Decarboxylase/chemistry , Glutamate Decarboxylase/immunology , Humans , Insulin/chemistry , Insulin/immunology , Male , Time Factors , Zinc Transporter 8
19.
Diabetes Metab Res Rev ; 27(8): 887-90, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22069279

ABSTRACT

BACKGROUND: Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ-specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15-1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early diagnosis of ABG/pernicious anaemia is essential for the prevention and/or treatment before manifestations of chronic disease become irreversible. Parietal cell autoantibody detection via enzyme-linked immunosorbent assay is currently the most widely used biomarker of disease with diagnosis confirmed by subsequent immunohistochemistry via biopsy. METHODS: To improve the assay we designed a specific, molecularly defined radioimmunoprecipitation assay for early detection of ABG, targeting its major antigen, the gastric H+/K+ ATPase 4A subunit ATP4A. RESULTS: The major antigenic domain in ATP4A was tested against a panel of sera from new onset patients with T1DM which tested positive for the gold standard T1DM autoantibodies (IAA, IA2A, GAD65A, and ZnT8A). Significant immunoreactivity to ATP4A was measured (25%) while 6% of first-degree relatives of subjects with T1DM who were sero-negative for T1DM autoantigens were positive for ATP4A autoantibodies. ATP4A antibody prevalence increased with age of onset of T1DM, which is atypical of other T1DM autoantibodies. Immunoreactivity to ATP4A, unlike that of T1DM antigens, demonstrates a significant gender bias in newly diagnosed individuals with T1DM. CONCLUSION: Although the utility of the assay as a biomarker for T1DM is likely limited, it may serve as an improved indicator of ABG.


Subject(s)
Autoantibodies/blood , Diabetes Mellitus, Type 1/immunology , Gastritis, Atrophic/immunology , H(+)-K(+)-Exchanging ATPase/immunology , Protein Subunits/immunology , Anemia, Pernicious/immunology , Autoantibodies/immunology , Autoimmune Diseases/immunology , Diabetes Mellitus, Type 1/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male
20.
BJOG ; 118(12): 1477-83, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21790956

ABSTRACT

OBJECTIVE: To discuss different methods for evaluating fetal growth and population-based birthweight standards relevant to different uses: either in antenatal care or in epidemiology. DESIGN: Population-based cohort study. SETTING: Routinely collected data in Scotland. POPULATION: A total of 540,849 singletons born after 24 weeks between 1980 and 2003. METHODS: The performance of a fetal growth standard and a population-based birthweight standard are compared in two ways. First, we consider the accuracy of estimated risks of stillbirth at any point during the remaining pregnancy, a measure that is relevant in antenatal care. Second, the rates of stillbirth at each gestation, which are measures relevant in epidemiology, are compared with the actual rates. MAIN OUTCOME MEASURES: Standard measures of screening and diagnostic performance: sensitivity, specificity, and positive and negative predictive values. RESULTS: In clinical care, the evidence points towards using fetal growth standards: sensitivity at term is about 30%, increasing to 43% for preterm births (24-31 weeks of gestation), compared with about 29% across all ages under the birthweight standard. Positive predictive values are about 1% across gestations. For epidemiology, the evidence is not so clear-cut: preterm, the population birthweight standard has higher sensitivity and specificity, but this is not the case in the full-term weeks. CONCLUSIONS: The performance of fetal growth and birthweight standards should be evaluated in different ways, depending on whether they are intended for use in antenatal care or in epidemiological investigations.


Subject(s)
Birth Weight , Fetal Development , Growth Charts , Prenatal Diagnosis/methods , Stillbirth , Cohort Studies , Epidemiologic Studies , Female , Humans , Infant, Newborn , Infant, Small for Gestational Age , Predictive Value of Tests , Pregnancy , Prenatal Care , Reference Values , Scotland , Sensitivity and Specificity
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