OBJECTIVE: Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known. METHODS: From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, n=141; Norway, n=26; UK, n=34), 108 children had no K(ATP)-channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised. RESULTS: In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type. CONCLUSION: In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.
International research for acute myocardial infarction lacks comparisons of whole health systems. We assessed time trends for care and outcomes in Sweden and the UK.
We used data from national registries on consecutive patients registered between 2004 and 2010 in all hospitals providing care for acute coronary syndrome in Sweden and the UK. The primary outcome was all-cause mortality 30 days after admission. We compared effectiveness of treatment by indirect casemix standardisation. This study is registered with ClinicalTrials.gov, number NCT01359033.
We assessed data for 119,786 patients in Sweden and 391,077 in the UK. 30-day mortality was 7·6% (95% CI 7·4-7·7) in Sweden and 10·5% (10·4-10·6) in the UK. Mortality was higher in the UK in clinically relevant subgroups defined by troponin concentration, ST-segment elevation, age, sex, heart rate, systolic blood pressure, diabetes mellitus status, and smoking status. In Sweden, compared with the UK, there was earlier and more extensive uptake of primary percutaneous coronary intervention (59% vs 22%) and more frequent use of ß blockers at discharge (89% vs 78%). After casemix standardisation the 30-day mortality ratio for UK versus Sweden was 1·37 (95% CI 1·30-1·45), which corresponds to 11,263 (95% CI 9620-12,827) excess deaths, but did decline over time (from 1·47, 95% CI 1·38-1·58 in 2004 to 1·20, 1·12-1·29 in 2010; p=0·01).
We found clinically important differences between countries in acute myocardial infarction care and outcomes. International comparisons research might help to improve health systems and prevent deaths.
Seventh Framework Programme for Research, National Institute for Health Research, Wellcome Trust (UK), Swedish Association of Local Authorities and Regions, Swedish Heart-Lung Foundation.
We assessed changes in advanced cancer incidence and cancer mortality in eight randomized trials of breast cancer screening.
Depending on published data, advanced cancer was defined as cancer > or = 20 mm in size (four trials), stage II+ (four trials), and > or = one positive lymph node (one trial). For each trial, we obtained the estimated relative risk (RR) and 95% CI between the intervention and control groups, for both breast cancer mortality and diagnosis of advanced breast cancer. Using a meta-regression approach, log(RR-mortality) was regressed on log(RR-advanced cancer), weighting each trial by the reciprocal of the square of the standard error of log(RR) for mortality.
RR for advanced breast cancer ranged from 0.69 (95% CI, 0.61 to 0.78) in the Swedish Two-County Trial to 0.97 (95% CI, 0.97 to 1.25) in the Canadian National Breast Screening Study-1 (NBSS-1) trial. Log(RR)s for advanced cancer were highly predictive of log(RR)s for mortality (R(2) = 0.95; P
Since the 1991 Gulf War, more than 10 years and 1 billion dollars of health evaluations and research have been invested in understanding illnesses among Gulf War veterans. We examined the extensive published healthcare utilization data in an effort to summarize what has been learned. Using multiple search techniques, data as of June 2003 from four different national Gulf War health registries and numerous hospitalization and ambulatory care reports were reviewed. Thus far, published reports have not revealed a unique Gulf War syndrome nor identified specific exposures that might explain postwar morbidity. Instead, they have demonstrated that Gulf War veterans have had an increase in multi-symptom condition, injury, and mental health diagnoses. While these diagnoses are similar to those experienced by other comparable military populations, their explanation is not fully understood. New strategies to identify risk factors for, and to reduce, such postdeployment conditions are summarized.
Neonatal bacterial infections are still important causes of perinatal mortality and morbidity, as they were 300 years ago. Queen Anne (1655-1714) underwent 18 pregnancies without producing any successors, probably because the children died of perinatal infection. Some women are unable to produce a specific IgG-antibody against Group B streptococcus (GBS). They may have normal IgM production and are thereby self-protected, while their infants risk developing neonatal GBS septicaemia. Listeria monocytogenes may cause repeated miscarriages, stillbirths and neonatal infections and, even today, is an important cause of perinatal deaths. The miscarriages and neonatal deaths of Queen Anne are believed to have been caused by an asymptomatic listeria monocytogenes infection. The importance of recognizing women at risk for these types of infections is discussed.
Aircraft assisted suicides were studied in the United States, United Kingdom, Germany, and Finland during 1956-2012 by means of literature search and accident case analysis. According to our study the frequency varied slightly between the studies. Overall, the new estimate of aircraft assisted suicides in the United States in a 20-yr period (1993-2012) is 0.33% (95% CI 0.21-0.49) (24/7244). In the detailed accident case analysis, it was found that in five out of the eight cases from the United States, someone knew of prior suicidal ideation before the aircraft assisted fatality. The caveats of standard medico-legal autopsy and accident investigation methods in investigation of suspected aircraft assisted suicides are discussed. It is suggested that a psychological autopsy should be performed in all such cases. Also the social context and possibilities of the prevention of aviation-related suicides were analyzed. In addition, some recent aircraft assisted suicides carried out using commercial aircraft during scheduled services and causing many casualties are discussed.