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Aims/hypothesis Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence. Methods UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures. Results MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from <20 per million in Wales and Northern Ireland to >50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million. Conclusions/interpretation Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.

Aims/hypothesis Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual’s probability of having MODY, as a crucial tool for rational genetic testing. Methods We developed prediction models using logistic regression on data from 1,191 patients with MODY ( n  = 594), type 1 diabetes ( n  = 278) and type 2 diabetes ( n  = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. Results The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA 1c , parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA 1c , parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org . Conclusions/interpretation We have developed clinical prediction models that calculate an individual’s probability of having MODY. This allows an improved and more rational approach to determine who should have molecular genetic testing.

Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action. To assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16-0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors. Our results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring pre-natally before the homeostatic feedback loop between glucose and insulin is established.

Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight. The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee. Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=-0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight. Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.

ABSTRACT Purpose: To evaluate the success of contact transscleral cyclophotocoagulation (TDC) in patients with refractory pediatric glaucomas. Methods: Twenty-six eyes of 20 patients with therapyresistant pediatric glaucomas were included in this retrospective study. Subgroup analysis was performed for patients 10 or younger and patients older than 10 at time of first TDC procedure. Diode laser cyclophotocoagulation was applied using a fiber optic G-probe. Follow up until time of failure or for a minimum of 6 months was obtained for all procedures in all eyes. Failure was defined as intraocular pressure (IOP) greater than 21 mm Hg, repeat of TDC due to clinically inadequate IOP control, progression to another procedure, or serious complication. Results: Baseline mean pretreatment IOP was 34.2 ± 10.4 mm Hg (range, 15 to 62 mm Hg). Ten of 26 eyes (38%) were successful 6 months after initial TDC. A mean decrease in IOP of 10.3 ± 14.7 mm Hg was noted after the first procedure (F<0.05). Eighteen eyes (70%) were retreated at least once. The mean decrease in IOP for all patients after all procedures was 12.9 ± 13.4 mm Hg (P<0.001). This represents a mean percent decrease in IOP of 33.2 ± 6.9%. The overall success rate was 50%, including retreated patients. The younger and older subgroups did not differ with regard to overall success, time to failure, or retreatment rate. One patient suffered a retinal detachment. Visual loss was noted in 4 of 22 eyes with reliable visual acuity measurements. Conclusion: TDC is an effective means of decreasing IOP in some patients with refractory pediatric glaucomas. Although the retreatment rate is high, the procedure generally is well tolerated with few complications.

The fetal insulin hypothesis proposes that low birth weight and susceptibility to type 2 diabetes (T2D) could both be two phenotypes of the same genotype. Insulin is a key growth factor in utero, and T2D is characterized by insulin resistance and/or beta-cell dysfunction. Therefore, genetic variants impacting on insulin secretion and action are likely to alter both fetal growth and susceptibility to T2D. There are three lines of evidence in support of this hypothesis. (1) Studies of rare monogenic diabetes have shown mutations in a single gene, such as GCK or KCNJ11, can cause diabetes by reducing insulin secretion, and these mutations are also associated with reduced birth weight. (2) Epidemiological studies have indicated that children born to fathers with diabetes are born smaller. As the father cannot influence the intrauterine environment, this association is likely to reflect genes inherited by the fetus from the father. (3) The most compelling evidence comes from recent genome-wide association studies. Variants in the CDKAL1 and HHEX-IDE genes that predispose to diabetes, if present in the fetus, are associated with reduced birth weight. These data provide evidence for a genetic contribution to the association between low birth weight and susceptibility to T2D. This genetic background is important to take into consideration when investigating the impact of environmental determinants and developing strategies for intervention and prevention.

Anterior chamber lenses have generally been considered to be relatively contraindicated in eyes with glaucoma, due to the increased incidence of associated intraocular pressure elevation in eyes with or without preexisting glaucoma.1,2 Such pressure rises may be influenced, however, by the preoperative status of the anterior chamber angle and the type of anterior chamber lens. Anterior chamber lens implantation in eyes with preoperative anterior synechiae has been associated with corneal endothelial cell loss, fibrous endothelial metaplasia, and angle cicatrization.3 In addition, the anterior chamber lenses reported in early studies were typically rigid, closed-loop designs. Sutured posterior chamber intraocular lenses have the advantage over anterior chamber lenses in glaucomatous eyes with loss of capsular support in that they avoid damage to the anterior chamber angle, with less potential for poor intraocular pressure control.

The clinical features of 100 consecutive cases and the histopathology of six enucleated eyes, all having undergone silicone oil injection for complicated retinal detachments, were studied with regard to the incidence and mechanisms of postoperative intraocular pressure changes. Preoperatively, five patients had glaucoma and 35 had hypotony (7 mm Hg or less). Immediately after surgery, 43 patients had glaucoma and 14 had hypotony, while seven had glaucoma and 39 had hypotony in the late postoperative period (average follow-up of 1 year). In most cases, the mechanism of intraocular pressure change did not appear to be directly related to the presence of silicone, but rather to the preoperative status of the eye and other aspects of the vitreoretinal surgery. When silicone was a factor, the resulting intraocular pressure appeared to represent a balance between mechanisms obstructing aqueous outflow (pupillary block and the reaction to silicone bubbles in the anterior chamber angle) and mechanisms reducing aqueous production (cyclitic membranes and retinal detachment).

Precision medicine drug therapy seeks to maximize efficacy and minimize harm for individual patients. This will be difficult if drug response and side effects are positively associated, meaning that patients likely to respond best are at increased risk of side effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and the risk of side effects (survival outcome) for patients initiating type 2 diabetes therapy. Participants were randomized to metformin (MFN), sulfonylurea (SU), or thiazolidinedione (TZD) therapy in the A Diabetes Outcome Progression Trial (ADOPT) drug efficacy trial (n=4,351). Joint models were parameterized for 1) current HbA1c response (change from baseline in HbA1c) and 2) cumulative HbA1c response (total HbA1c change). With MFN, greater HbA1c response did not increase the risk of gastrointestinal events (HR per 1% absolute greater current response 0.82 [95% CI 0.67, 1.01]; HR per 1% higher cumulative response 0.90 [95% CI 0.81, 1.00]). With SU, greater current response was associated with an increased risk of hypoglycemia (HR 1.41 [95% CI 1.04, 1.91]). With TZD, greater response was associated with an increased risk of edema (current HR 1.45 [95% CI 1.05, 2.01]; cumulative 1.22 [95% CI 1.07, 1.38]) but not fracture. Joint modeling provides a useful framework to evaluate the association between response to a drug and the risk of developing side effects. There may be great potential for widespread application of joint modeling to evaluate the risks and benefits of both new and established medications.