Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme.

AIMS/HYPOTHESIS: The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly retinopathy screening. METHODS: This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy. RESULTS: The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years. CONCLUSIONS/INTERPRETATION: Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.

A randomized crossover study to assess the effect of an oat-rich diet on glycaemic control, plasma lipids and postprandial glycaemia, inflammation and oxidative stress in Type 2 diabetes.

AIMS: In the UK, lifestyle intervention is first-line management in Type 2 diabetes. It is unclear what type of diet is most efficacious for improving glycaemic control. This study investigated the effects of an oat-enriched diet on glycaemic control, postprandial glycaemia, inflammation and oxidative stress compared with standard dietary advice. METHODS: In a randomized crossover design, 27 volunteers with Type 2 diabetes, managed on diet and lifestyle only, were observed for two consecutive 8-week periods following either the oat-enriched diet or re-enforced standard dietary advice. Volunteers attended at baseline (habitual intake) and 8 and 16 weeks. Measurements included basic clinical measurements and fasted and postprandial (3-h) glucose and insulin in response to a healthy test meal. Markers of inflammation and oxidative stress, including high-sensitivity C-reactive protein, interleukin 6, interleukin 18, tumour necrosis factor-alpha, adiponectin, thiobarbituric acid reactive substances, oxygen radical antioxidant capacity, oxidized LDL and urinary isoprostanes, were also measured at fasting and in the postprandial period. RESULTS: There were no diet-related effects on glycaemic control or glycaemic or insulinaemic responses to the test meal. Total cholesterol (5.1 ± 1.0 vs. 4.9 ± 0.8 mmol/l, P = 0.019) concentrations declined following the oat-enriched diet compared with standard dietary advice. There was a postprandial decline in adiponectin concentration (P = 0.009), but no effect of dietary intervention. None of the measures of oxidative stress or inflammation were altered by the oat-enriched diet compared with standard dietary advice. CONCLUSION: The oat-enriched diet had a modest impact on lipid lowering, but did not impact on oxidative stress or inflammation in these volunteers with Type 2 diabetes.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Inpatient costs for people with type 1 and type 2 diabetes in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group.

AIMS/HYPOTHESIS: The rising prevalence of diabetes worldwide has increased interest in the cost of diabetes. Inpatient costs for all people with diabetes in Scotland were investigated. METHODS: The Scottish Care Information-Diabetes Collaboration (SCI-DC), a real-time clinical information system of almost all diagnosed cases of diabetes in Scotland, UK, was linked to data on all hospital admissions for people with diabetes. Inpatient stay costs were estimated using the 2007-2008 Scottish National Tariff. The probability of hospital admission and total annual cost of admissions were estimated in relation to age, sex, type of diabetes, history of vascular admission, HbA(1c), creatinine, body mass index and diabetes duration. RESULTS: In Scotland during 2005-2007, 24,750 people with type 1 and 195,433 people with type 2 diabetes were identified, accounting for approximately 4.3% of the total Scottish population (5.1 million). The estimated total annual cost of admissions for all people diagnosed with type 1 and type 2 diabetes was £26 million and £275 million, respectively, approximately 12% of the total Scottish inpatient expenditure (£2.4 billion). Sex, increasing age, serum creatinine, previous vascular history and HbA(1c) (the latter differentially in type 1 and type 2) were all associated with likelihood and total annual cost of admission. CONCLUSIONS/INTERPRETATION: Diabetes inpatient expenditure accounted for 12% of the total Scottish inpatient expenditure, whilst people with diabetes account for 4.3% of the population. Of the modifiable risk factors, HbA(1c) was the most important driver of cost in type 1 diabetes.

Do men develop type 2 diabetes at lower body mass indices than women?

AIMS/HYPOTHESIS: To describe the associations between age, sex and BMI at diagnosis of type 2 diabetes, and test the hypothesis that men are diagnosed with diabetes at lower average BMI than women of similar age. METHODS: Linear regression was used to estimate and compare the relationship between age and BMI at diagnosis among 51,920 men and 43,137 women included in a population-based diabetes register in Scotland for whom an index BMI measurement was taken within 1 year of diabetes diagnosis. We also examined HbA(1c) values by sex within the same timescale. RESULTS: Mean BMI closest to date of diagnosis of type 2 diabetes mellitus was 31.83 kg/m(2) (SD 5.13) in men and 33.69 kg/m(2) (SD 6.43) in women. The inverse relationship between age and BMI at diagnosis of type 2 diabetes mellitus was significantly steeper in women than in men (slope estimate in men -0.12 kg/m(2) per year [95% CI -0.13, -0.12] women -0.18 kg/m(2) per year [95% CI -0.18, -0.17], p < 0.0001 for formal test of interaction). Mean BMI difference was most marked at younger ages and narrowed with advancing age. However, HbA(1c) levels within 1 year of diagnoses were broadly similar in men and women. CONCLUSIONS/INTERPRETATION: Men are diagnosed with type 2 diabetes at lower BMI than women across the age range. This observation may help explain why type 2 diabetes is more common among middle-aged men in populations of European extraction. Whether the same pattern is also observed in other ethnic groups requires confirmation.

A national approach to diabetes foot risk stratification and foot care.

The Scottish Diabetes Foot Action Group (SDG) has developed and introduced a national strategy plan for diabetic foot care across Scotland. This has involved the implementation of an evidence-based national foot screening and risk stratification programme that has already covered 61% of the population in just the first two years. Nationally agreed patient information foot leaflets and professional education material have been introduced, and a consensus for antibiotic use in the diabetic foot has been published. Information on multidisciplinary specialist foot services has been collected, indicating that 58% of Health Board areas have consultants with dedicated sessions in their job plan to a foot clinic, and 42% had integrated orthotic involvement. The SDG aims to increase these figures. Work has been undertaken to support local podiatry networks and improve communication between the specialist centre and the community. At a national level the SDG is working with Foot in Diabetes UK (FDUK) to recognize key podiatry skills by developing core competencies and a competency framework for the diabetes podiatrist and diabetes orthotist. The annual Scottish Diabetes Survey indicates some improvement in amputation rates with prevalence decreasing from 0.8% to 0.5%, and improved recording of foot ulceration at a national level. This national strategy has helped highlight the importance and difficulties facing diabetes foot care and should help to continue to improve the quality of care of people with diabetes who have foot-related problems.

Severe hypoglycaemia during pregnancy in women with Type 1 diabetes is common and planning pregnancy does not decrease the risk.

AIMS: The aim of this study was to identify risk factors for severe hypoglycaemia (SH) in pregnancy in Type 1 diabetes, including associations with pregnancy planning and glycaemic control. METHODS: Clinical data including details of the pregnancy and its outcome, glycaemic control, frequency of SH and evidence of pregnancy planning were collected prospectively as part of a national audit of 160 pregnancies in women with Type 1 diabetes. RESULTS: An episode of SH was experienced by 29.4% of women at some point during the pregnancy, with the percentage of women experiencing SH decreasing from 21.9% in the first trimester to 18.1% in trimester 2 and 10.9% in trimester 3. Longer duration of diabetes was associated with increased frequency of SH during pregnancy (r = 0.191, P = 0.012). A greater fall in glycated haemoglobin (HbA(1c)) between pre-pregnancy and the first trimester was not associated with increased risk of SH in trimester 1. Planned pregnancies had better glycaemic control but higher risk of SH in trimester 1 (P = 0.047). Women with pre-pregnancy retinopathy and current smokers had an increased risk of SH in trimester 3 (P = 0.029, P = 0.033). CONCLUSIONS: SH is common during pregnancy and particularly in the first trimester. Planning pregnancy does not decrease the risk of SH. Improvements in glycaemic control at the start of pregnancy do not appear to increase the risk of SH. Education of women and their partners about the risks of SH and its management is essential when planning pregnancy.

Glycaemic control and body mass index in late-adolescents and young adults with Type 1 diabetes mellitus: a population-based study.

AIMS: Studies of children with diabetes up to the age of 15 years report deteriorating glycaemic control in the early teenage years. The aim was to investigate glycaemia and body mass index in older teenagers and young adults. METHOD: A Scottish, regional, population-based, cross-sectional study of 255 young people (117 female, 138 male) with Type 1 diabetes, aged 15-25 years (mean +/-sd 19.8 +/- 2.8 years, diabetes duration: 8.8 +/- 5.4 years) registered on a diabetes database. Glycaemic control, body mass index (BMI) and insulin regimens were assessed in three age groups [group 1 (n = 96) 15-18 years; group 2 (n = 74) 18.1-22 years; and group 3 (n = 85) 22.1-25 years]. RESULTS: Subjects in the oldest age group had a significantly lower mean HbA(1c) than those in the youngest age group (8.8 +/- 1.7 vs. 9.9 +/- 1.9%; P < 0.001). Mean BMI was higher in group 3 (25.2 +/- 3.4 kg/m(2)) compared with group 1 (23.9 +/- 3.1 kg/m(2); P < 0.001). HbA(1c )levels were higher in the younger subjects and women. Lower HbA(1c) levels were associated with a higher BMI (r = -0.324, P < 0.001) in men only. Overall, 74% took three or more injections a day, of whom 60% were on basal/bolus therapy. The proportion on basal/bolus insulin therapy increased with age and duration of diabetes. CONCLUSION: Compared with adolescents, young adults with Type 1 diabetes have better glycaemic control and higher BMI. This was associated with lower insulin requirements.

Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558.

Two of the cytosolic NADPH oxidase components, p47-phox and p67-phox, translocate to the plasma membrane in normal neutrophils stimulated with phorbol myristate acetate (PMA). We have now studied the translocation process in neutrophils of patients with chronic granulomatous disease (CGD), an inherited syndrome in which the oxidase system fails to produce superoxide due to lesions affecting any one of its four known components: the gp91-phox and p22-phox subunits of cytochrome b558 (the membrane-bound terminal electron transporter of the oxidase), p47-phox, and p67-phox. In contrast to normal cells, neither p47-phox nor p67-phox translocated to the membrane in PMA-stimulated CGD neutrophils which lack cytochrome b558. In one patient with a rare X-linked form of CGD caused by a Pro----His substitution in gp91-phox, but whose neutrophils have normal levels of this mutant cytochrome b558, translocation was normal. In two patients with p47-phox deficiency, p67-phox failed to translocate, whereas p47-phox was detected in the particulate fraction of PMA-stimulated neutrophils from two patients deficient in p67-phox. Our data suggest that cytochrome b558 or a closely linked factor provides an essential membrane docking site for the cytosolic oxidase components and that it is p47-phox that mediates the assembly of these components on the membrane.

Birth weight and maternal glycated haemoglobin in pregnancies complicated by type 1 diabetes.

AIM: To re-examine the relationships between birth weight and maternal glycated haemoglobin (HbAlc) concentration at different time points in pregnancies complicated by pre-gestational type 1 diabetes. METHODS: A dataset was collected prospectively on all deliveries in Scotland to women with pre-gestational type 1 diabetes occurring during two 12 month periods (01/04/98 to 31/03/99 and 01/04/03 to 31/03/04). Relationships between standardised measures of birth weight and HbAlc at each time point were examined using correlation analysis. RESULTS: Standardised birth weights (Z scores) were calculated for 338 singleton live born infants. HbA1c concentrations were available for: 204 women (pre-pregnancy), 297 women (1st trimester), 314 women (2nd trimester) and 303 women (3rd trimester). Standardised birth weight showed a unimodal distribution shifted to the right relative to a reference population (Mean, +1.62 S.D). There was a significant negative correlation between pre-pregnancy HbAlc and birth weight (Spearman's Rho -0.138; p=0.049). CONCLUSIONS: Standardised birth weights of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic control and birth weight, but the previously described paradoxical inverse relationship between pre-pregnancy glycaemic control and birth weight has been confirmed using a larger dataset.

A comparison of skeletal uptakes of three diphosphonates by whole-body retention: concise communication.

Twenty normal volunteers had measurements of 24-hr whole-body retention (WBR) of three structurally related Tc-99m-labeled phosphonate skeletal imaging agents: (1-hydroxyethylidene) diphosphonate (HEDP), methylene diphosphonate (MDP), and hydroxymethylene diphosphonate (HMDP). The average WBR values, reflecting skeletal uptake, were 18.4, 30.3, and 36.6%, respectively. These results clearly illustrate that slight alterations in diphosphonate molecular structure have a significant effect upon specificity for osseous tissue, and thus may affect skeletal image quality and the usefulness of the WBR technique in diagnosing metabolic bone disease.

Relapse of Graves' disease after medical therapy: predictive value of thyroidal technetium-99m uptake and serum thyroid stimulating hormone receptor antibody levels.

In 49 patients with Graves' disease, the 20-min thyroidal uptake of 99mTc and serum levels of thyroid stimulating hormone (TSH) receptor antibody were estimated at presentation and at intervals during a 1-yr course of carbimazole and triiodothyronine. In the 12 mo after cessation of therapy, 29 patients developed recurrent thyrotoxicosis. Thyroidal 99mTc uptake had a poor predictive value for recurrence of thyrotoxicosis, both at presentation and during therapy. A very high level of TSH receptor antibody was present in seven patients at presentation, all of whom relapsed on withdrawing therapy. An abnormal value of TSH receptor antibody at the end of the course of medical therapy was present in 24/29 (83%) patients who relapsed and in 1/20 (5%) patients who remained euthyroid 1 yr after stopping antithyroid drugs.

Management of the pregnant diabetic patient.

The prognosis in diabetic pregnancy has greatly improved as a result of patient education and the availability of home blood glucose monitoring techniques enabling the implementation of good metabolic control pre-pregnancy, antenatal and intrapartum. These in turn have made possible the benefits to the offspring of vaginal delivery at term. Screening for gestational diabetes is important and the prognosis is also good where maternal normoglycaemia is achieved. All diabetic pregnancies should be cared for in specialist units under the supervision of an integrated team comprising an obstetrician, diabetologist and paediatrician, and for optimal results care should start prior to conception.

V79 survival following simultaneous or sequential irradiation by 15-MeV neutrons and 60Co photons.

A unique tandem source irradiation facility, composed of an intense d-T neutron source and a 60Co teletherapy unit, was used to investigate biological responses for different neutron/photon configurations. V79 Chinese hamster cells, attached as monolayers in log-phase growth, were irradiated at 37 degrees C by either 14.8-MeV neutrons, 60Co, or a mixture of 40% neutrons and 60% photons in simultaneous or sequential application. Measurements of cell survival indicate an increased effectiveness in cell killing for simultaneously administered neutrons and photons compared to that measured or predicted for sequentially applied beam modalities. An understanding of the magnitude of these interactive effects is important both for calculating accurate effective doses for neutron radiotherapy of deep-seated tumors, for which the photon component is appreciable, and for determination of environmental hazards to people occupationally exposed to mixtures of photons and neutrons.

Synchroton-produced ultrasoft X rays: equivalent cell survival at the isoattenuating energies 273 eV and 860 eV.

In this paper we report on survival of Chinese hamster V79 and mouse C3H 10T1/2 cells after irradiation with synchrotron-produced 273 eV and 860 eV ultrasoft X rays. These two energies, which are available by multilayer monochromatization of the synchrotron output spectrum, exhibit equal attenuation within living cells. Such an isoattenuating energy pair allows the direct examination of how biological effectiveness varies with the energy of the ultrasoft X rays. In comparing survival results, we find similar biological effectiveness of these two energies for both the C3H 10T1/2 and the V79 cells. These results are not consistent with previous findings of increasing RBE with decreasing ultrasoft X-ray energies. In addition, after correcting for mean nuclear dose based on measurements of cell thickness obtained with confocal microscopy, we find no significant differences in survival between the two ultrasoft X-ray energies and 250 kVp X rays. These results suggest that RBE does not increase with decreasing energy of ultrasoft X rays between 860 eV and 273 eV. The possible impact of our results on past results for ultrasoft X rays is discussed.

Measurements and Monte Carlo calculations to determine the absolute detector response of radiochromic film for brachytherapy dosimetry.

GafChromic (MD-55-2) radiochromic film has become increasingly popular for medical applications and has proven to be useful for brachytherapy dosimetry. To measure the absolute dose near a brachytherapy source, the response of the proposed detector in the measurement conditions relative to the response of the detector in calibration conditions must be known. MD-55-2 radiochromic film has been exposed in four different photon beams, a 30 and 40 kVp tungsten anode x-ray beam, a 75 kVp orthovoltage therapy beam, and a 60Co teletherapy beam to measure the relative detector response. These measurements were combined with coupled photon/electron Monte Carlo transport calculations to determine the absolute detector response. The Los Alamos National Laboratory Monte Carlo transport code MCNP4B2 was used. The measured relative response of this batch of MD-55-2 film varies from 8.79 mOD/Gy, measured for the 60Co beam, by as much as 42% for the low-energy x-ray beams. However, the absolute detector response varies from 4.32 mOD/Gy for the 60Co beam by, at most, only 6.3%. In this work we demonstrate that the absolute detector response of MD-55-2 radiochromic film is a constant and independent of beam quality. Further, this work shows that MCNP4B2 accurately simulates the energy response and geometry artifacts of the radiochromic film.

Performance characteristics of A 150 plastic-equivalent gases in A 150 plastic proportional counters for 14.8-MeV neutrons.

Two recently developed A 150 plastic-equivalent gas mixtures have been tested for suitability in proportional counter applications. Methane- and propane-based "tissue-equivalent" gases were also included for comparison purposes. Event-size weighted dose distributions were measured in a 14.8-MeV neutron beam. Resolution was found to be independent of gas mixture. Moreover the gains of the two A 150 mixtures were the same, and comparable to that of the methane-based gas mixture. The ionization yield per event size was also independent of the hydrogenous gas mixture employed. Neutron doses determined with the proportional counter were in reasonable agreement with those obtained from an ionization chamber.

Measurement of dose distributions of linear energy transfer in matter irradiated by fast neutrons.

A detector has been developed and used to measure dose distributions versus linear energy transfer to thin gas targets in spherical geometry from fast neutron irradiation of tissue-equivalent plastic and carbon. The detector is a hemispherical proportional counter with a Cs(T1) scintillator at the center of the hemisphere. The coincidence of the proportional counter signals constrain the measurements to charged particles traversing the radius of the hemisphere. The charged particle energy deposition distributions are directly measured for a known pathlength. The A-150 kerma factor was measured at a neutron energy of 14.8 MeV and is in agreement with tabulated values. The carbon kerma factor measurements are less than the tabulated value at 14.8 MeV. The alpha-particle production in carbon was measured for neutron energies from 14.1 to 14.8 MeV and is compared with existing data.

Calibration of 192Ir high-dose-rate afterloading systems.

A method is described for calibration of 192Ir high-dose-rate (HDR) brachytherapy afterloading systems. Since NIST does not offer calibration of ionization chambers with the gamma-ray spectrum of iridium-192, an interpolation procedure is employed, using calibrations above (137Cs, 662 keV) and below (250 kVcp, 146-keV x rays) the exposure-weighted average 192Ir energy of 397 keV. The same total wall + cap thickness must be used for both calibrations, and for the 192Ir measurements. A wall + cap thickness of 0.3 g/cm2 is recommended to assure charged particle equilibrium and to exclude secondary electrons emitted from the source encapsulation. Procedures are described for determining the corrections for source-chamber distance and room scatter during the source calibration in inverse-square-law geometry. A new well-type ionization chamber has been designed specifically for convenient routine use with the HDR afterloading system. It can be calibrated by means of a previously calibrated 192Ir source, and offers a simple means for verifying the decay rate and for calibrating 192Ir replacement sources.