Matthew N. Cooper

Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia.

CONTEXTnThe Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function.nnnOBJECTIVEnTo investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls.nnnDESIGNnComparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples.nnnSETTINGnUnrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained.nnnPARTICIPANTSnPatients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality.nnnMAIN OUTCOME MEASURESnIn this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample.nnnRESULTSnIn the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened.nnnCONCLUSIONSnIn a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.

Long-term outcome of insulin pump therapy in children with type 1 diabetes assessed in a large population-based case-control study.

Aims/hypothesisWe determined the impact of insulin pump therapy on long-term glycaemic control, BMI, rate of severe hypoglycaemia and diabetic ketoacidosis (DKA) in children.MethodsPatients on pump therapy at a single paediatric tertiary hospital were matched to patients treated by injections on the basis of age, duration of diabetes and HbA1c at the time of pump start. HbA1c, anthropometric data, episodes of severe hypoglycaemia and rates of hospitalisation for DKA were collected prospectively.ResultsA total of 345 patients on pump therapy were matched to controls on injections. The mean age, duration of diabetes at pump start and length of follow-up were 11.4 (±u20093.5), 4.1 (±u20093.0) and 3.5 (±u20092.5) years, respectively. The mean HbA1c reduction in the pump cohort was 0.6% (6.6xa0mmol/mol). This improved HbA1c remained significant throughout the 7xa0years of follow-up. Pump therapy reduced severe hypoglycaemia from 14.7 to 7.2 events per 100 patient-years (pu2009<u20090.001). In contrast, severe hypoglycaemia increased in the non-pump cohort over the same period from 6.8 to 10.2 events per 100 patient-years. The rate of hospitalisation for DKA was lower in the pump cohort (2.3 vs 4.7 per 100 patient-years, pu2009=u20090.003) over the 1,160 patient-years of follow-up.Conclusions/interpretationThis is the longest and largest study of insulin pump use in children and demonstrates that pump therapy provides a sustained improvement in glycaemic control, and reductions of severe hypoglycaemia and hospitalisation for DKA compared with a matched cohort using injections.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison

Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries.

A distinct subset of chemokines dominates the mucosal chemokine response in inflammatory bowel disease

Background :u2002Inflammatory bowel disease (IBD) is characterised by intense mucosal recruitment of activated leukocytes. Chemokines determine inflammatory leukocyte recruitment and retention.

Reducing Rates of Severe Hypoglycemia in a Population-Based Cohort of Children and Adolescents With Type 1 Diabetes Over the Decade 2000–2009

OBJECTIVE To examine rates of severe hypoglycemia (SH) in a large population-based cohort of children with type 1 diabetes and relationships to HbA1c. RESEARCH DESIGN AND METHODS Data from 1,683 children (mean [SD] age at diagnosis 10.5 [4.2]; range 1–18 years) from 2000 to 2009 were analyzed from the Western Australian Childrens Diabetes Database. Rates of SH were related to HbA1c using negative binomial regression. RESULTS A total of 7,378 patient-years of data and 780 SH events were recorded. The rate of SH per 100 patient-years peaked at 17.3 in 2001 and then declined from 2004 to a nadir of 5.8 in 2006. HbA1c <7% was not associated with higher risk of SH (incidence rate ratio 1.2 [95% CI 0.9–1.6], P = 0.29) compared with HbA1c of 8–9%. CONCLUSIONS In a sample of youth with type 1 diabetes, there has been a decrease in rates of SH and a weaker relationship with glycemic control than previously observed.

Complement Factor H Y402H and C-Reactive Protein Polymorphism and Photodynamic Therapy Response in Age-Related Macular Degeneration

PURPOSEnTo investigate the association between complement factor H (CFH) and C-reactive protein (CRP) genotypes and response to photodynamic therapy (PDT) treatment for neovascular age-related macular degeneration (AMD).nnnDESIGNnRetrospective cohort study.nnnPARTICIPANTSnThe study cohort consisted of 273 neovascular AMD patients treated with PDT.nnnMETHODSnGenotypes were determined for the common T-->C single nucleotide polymorphism (SNP) in exon 9 of the CFH gene (rs1061170; Y402H), as well as 9 selected tagging SNPs across the CRP gene (rs2808635, rs1417938, rs1800947, rs1130864, rs1205, rs3093077, rs876538, rs876537, and rs1572970). Visual acuity outcome after PDT was retrospectively calculated and patients were classified as PDT-positive responders or PDT-negative responders. Logistic regression analysis was used to evaluate the association between individual SNPs and PDT treatment response while adjusting for relevant covariates.nnnMAIN OUTCOME MEASURESnResponse to PDT treatment defined by visual acuity; genotypes of CFH Y402H and CRP polymorphism.nnnRESULTSnOf the 273 patients, 75 had a positive response after PDT treatment. The frequency of CC genotype of the CFH Y402H polymorphism in the PDT-positive response group was lower than in the negative PDT response group (26.4% vs 31.6%) but this difference failed to reach statistical significance. Two CRP SNPs (rs2808635 and rs876538) were significantly associated with PDT treatment response. Positive treatment response was seen in individuals homozygous for the minor allele of the rs2808635 (GG; odds ratio [OR], 3.92; 95% confidence interval [CI], 1.40-10.97; P = 0.048) and rs876538 (AA; OR, 6.49; 95% CI, 1.65-25.47; P = 0.048) variants after adjusting for relevant covariates. The remaining 7 CRP genetic variants did not reveal any significant association with treatment response.nnnCONCLUSIONSnOur data did not show significant association between the CFH Y402H polymorphism and PDT treatment response for neovascular AMD; however, CRP genetic variants were associated with a positive response to PDT treatment for neovascular AMD.

Hypoglycaemia, fear of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents.

To evaluate the association between fear of hypoglycaemia, episodes of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents.

Excessive daytime sleepiness increases the risk of motor vehicle crash in obstructive sleep apnea

STUDY OBJECTIVESn(1) To describe the incidence rate of motor vehicle crashes (MVCs) in patients with obstructive sleep apnea (OSA); and (2) to investigate MVC risk factors in OSA patients.nnnMETHODSnA retrospective case-series observational study was conducted using data from the West Australian Sleep Health Study at a tertiary hospital-based sleep clinic. Participants were patients (N = 2,673) referred for assessment of suspected sleep disordered breathing. Questionnaire data were collected including age, sex, years of driving, near-misses and MVCs, sleepiness, and consumption of alcohol and caffeinated drinks. Overnight laboratory-based polysomnography was performed using standard methodology.(1) Poisson univariate and negative binomial multivariable regression models were used to investigate associations between risk factors and MVC and near-miss risk in patients with untreated OSA.nnnRESULTSnIn patients with untreated OSA, the crash rate was 0.06 MVC/person-year compared with the general community crash rate of 0.02 MVC/person-year. The rate ratio comparing very sleepy men with normal men was 4.68 (95% CI 3.07, 7.14) for near-misses and 1.27 (95% CI 1.00, 1.61) for crashes, after adjusting for confounders. In women there was a significant association with sleepiness score (p = 0.02) but no dose effect across quartiles.nnnCONCLUSIONSnUntreated OSA is associated with an increased risk of near-misses in men and women and an increased risk of MVCs in very sleepy men. There is a strong association between excessive daytime sleepiness and increased report of near-misses. Our data support the observation that it is those patients with increased sleepiness regardless of OSA severity who are most at risk.

High prevalence of undiagnosed obstructive sleep apnoea in the general population and methods for screening for representative controls

PurposeUndiagnosed obstructive sleep apnoea (OSA) in the community makes comparisons of OSA subjects with control samples from the general population problematic. This study aims to estimate undiagnosed moderate to severe OSA in a general population sample and to determine the capacity of questions from the Berlin questionnaire (BQ) to identify subjects without diagnosed OSA of this severity.MethodsUsing a general population sample (nu2009=u2009793) with no history of OSA, case and control status for moderate–severe OSA was determined by home-based nasal flow and oximetry-derived apnoea–hypopnoea index using a cut-off value of ≥15 events/h to define cases. The diagnostic accuracy of the complete BQ and its component questions in identifying cases was assessed by calculating sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and post-test probabilities.ResultsThe age-standardised prevalence estimate of moderate–severe OSA was 9.1xa0% (12.4xa0% in men, 5.7xa0% in women). Sensitivity of the BQ in this population was 54xa0%, and specificity, 70xa0%. A combination of questions regarding snoring frequency and hypertension provided maximal post-test probability of OSA and greatest post-screen sample size.ConclusionsUndiagnosed OSA is highly prevalent in the Western Australian general population. While the complete BQ is a sub-optimal screening instrument for the general population, snoring frequency or hypertension can be used to screen out moderate–severe OSA from general population samples with limited reduction in sample size. As there are few general population samples available for epidemiological or genetic studies of OSA and its associated phenotypes, these results may usefully inform future case–control studies.

A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes

Aims/hypothesisSevere hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes.MethodsSubjects were identified from a population-based register containing data on >99% of patients (<16xa0years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3xa0months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year.ResultsClinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA1c <7% [53xa0mmol/mol]) compared with the cohort average (HbA1c 8–9% [64–75xa0mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12–18xa0years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9).Conclusions/interpretationIn this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.