An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

Guidelines for the management of pregnancy in women with cystic fibrosis.

Women with cystic fibrosis (CF) now regularly survive into their reproductive years in good health and wish to have a baby. Many pregnancies have been reported in the literature and it is clear that whilst the outcome for the baby is generally good and some mothers do very well, others find either their CF complicates the pregnancy or is adversely affected by the pregnancy. For some, pregnancy may only become possible after transplantation. Optimal treatment of all aspects of CF needs to be maintained from the preconceptual period until after the baby is born. Clinicians must be prepared to modify their treatment to accommodate the changing physiology during pregnancy and to be aware of changing prescribing before conception, during pregnancy, after birth and during breast feeding. This supplement offers consensus guidelines based on review of the literature and experience of paediatricians, adult and transplant physicians, and nurses, physiotherapists, dietitians, pharmacists and psychologists experienced in CF and anaesthetist and obstetricians with experience of CF pregnancy. It is hoped they will provide practical guidelines helpful to the multidisciplinary CF teams caring for pregnant women with CF.

Composition of nasal airway surface liquid in cystic fibrosis and other airway diseases determined by X-ray microanalysis.

The ionic composition of the airway surface liquid (ASL) in healthy individuals and in patients with cystic fibrosis (CF) has been debated. Ion transport properties of the upper airway epithelium are similar to those of the lower airways and it is easier to collect nasal ASL from the nose. ASL was collected with ion exchange beads, and the elemental composition of nasal fluid was determined by X-ray microanalysis in healthy subjects, CF patients, CF heterozygotes, patients with rhinitis, and with primary ciliary dyskinesia (PCD). In healthy subjects, the ionic concentrations were approximately isotonic. In CF patients, CF heterozygotes, rhinitis, and PCD patients, [Na] and [Cl] were significantly higher compared when compared with those in controls. [K] was significantly higher in CF and PCD patients compared with that in controls. Severely affected CF patients had higher ionic concentrations in their nasal ASL than in patients with mild or moderate symptoms. Female CF patients had higher levels of Na, Cl, and K than male patients. As higher salt concentrations in the ASL are also found in other patients with airway diseases involving chronic inflammation, it appears likely that inflammation-induced epithelial damage is important in determining the ionic composition of the ASL.

Exhaled carbon monoxide is not elevated in patients with asthma or cystic fibrosis.

Increased levels of exhaled carbon monoxide (fractional concentration of CO in expired gas (FE,CO)), measured with an electrochemical sensor, have been reported in patients with inflammatory airway disorders, such as asthma, rhinitis and cystic fibrosis. This study aimed to evaluate these findings by using a fast-response nondisperse infrared (NDIR) analyser, and to compare these measurements with the fractional concentration of nitric oxide in exhaled air (FE,NO). Thirty-two steroid-naïve asthmatics, 24 steroid-treated asthmatics (16 patients with allergic rhinitis, nine patients with cystic fibrosis), and 30 nonsmoking healthy controls were included. CO measurements with the NDIR analyser were performed simultaneously with nitric oxide (NO) analysis (chemiluminescence technique). After 15 s of breath-hold, single-breath exhalations over 10 s were performed at two flow rates and end-tidal plateau concentrations were registered. An electrochemical CO sensor was used independently with an exhalation to residual volume, after a 15 s breath-hold. None of the two CO analysers gave a significant increase in FE,CO in the groups of patients with inflammatory airway disorders compared to controls. FE,NO was significantly elevated in steroid-naïve asthmatics and subjects with allergic rhinitis, but not in steroid-treated asthmatics and subjects with cystic fibrosis. Reducing exhalation flow rate by 50% gave a two-fold increase in FE,NO, while FE,CO was unaffected. A significant increase was seen in FE.CO, but not in FE,NO, when comparing with and without a 10 s breath-hold. In conclusion, the fractional concentration of carbon monoxide in expired gas was not increased in any of the patient groups, while the fractional concentration of nitric oxide in expired gas was significantly elevated in patients with steroid-naïve asthma and allergic rhinitis. Moreover, carbon monoxide was unaffected by flow rate but increased with breath-hold, suggesting an origin in the alveoli rather than the conducting airways.

Predictors of deterioration of lung function in cystic fibrosis.

The severity of lung disease in cystic fibrosis (CF) may be related to the type of mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and to environmental and immunological factors. Since pulmonary disease is the main determinant of morbidity and mortality in CF, it is important to identify factors that can explain and predict this variation. The aim of this longitudinal study of the whole Swedish CF population over age 7 years was to correlate genetic and clinical data with the rate of decline in pulmonary function. The statistical analysis was performed using the mixed model regression method, supplemented with calculation of relative risks for severe lung disease in age cohorts.The severity of pulmonary disease was to some extent predicted by CFTR genotype. Furthermore, the present investigation is the first long-term study showing a significantly more rapid deterioration of lung function in patients with concomitant diabetes mellitus. Besides diabetes mellitus, pancreatic insufficiency and chronic Pseudomonas colonization were found to be negative predictors of pulmonary function. In contrast to several other reports, we found no significant differences in lung function between genders. Patients with pancreatic sufficiency have no or only a slight decline of lung function with age once treatment is started, but an early diagnosis in this group is desirable.

Lung function changes in relation to menstrual cycle in females with cystic fibrosis.

Oestrogen and progesterone have been shown to have impact on cystic fibrosis transmembrane conductance regulator (CFTR) gene expression, tone of smooth muscle in the airways, immune response, exhaled nitric oxide and cytology in the tracheobronchial epithelium. The aim of this investigation was to study the influence of menstrual cyclicity on airway symptoms among cystic fibrosis (CF) females. Twelve CF women (mean age 30 years, mean Shwachman score 85) kept daily records during three menstrual cycles of lung function, sputum quality and need for intravenous antibiotics. Paired t-test was used as a statistical method to compare the airway symptoms between the time of ovulation (high levels of oestrogen and low levels of progesterone), the luteal phase (high levels of oestrogen and progesterone) and menstruation (low levels of oestrogens and progesterone). Forced expiratory volume in 1 sec (FEV1) was significantly higher during the luteal phase (66% of predicted) compared to during ovulation (63%) and menstruation (61%) (P<0.01). Forced vital capacity (FVC) showed the same pattern, being significantly higher during the luteal phase compared with during menstruation (mean 75% vs. 70%, P<0.01). In conclusion, lung function changes were found during menstrual cycles in women with cystic fibrosis. These changes are probably related to changes in progesterone levels during the menstrual cycles. This result warrants further studies to understand the complexity of CF lung disease in women.

Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden.

Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better nutritional development and other advantages compared with those in a nonscreened group. The two-tier immunoreactive trypsinogen (IRT)/DNA screening protocol has been found superior to the single-tier IRT approach, improving the positive predictive value and thus reducing the false-positive rate. However, variations of the DNA test are required for different populations. In this study we examined CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF patients attending the centres in Stockholm, Lund and Uppsala, comprising about 75% of the CF population in Sweden. The frequency of deltaF508 among CF alleles was 68.3%. There were two other mutations, 394delTT and 3659delC, found to be fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were comparatively rare. A simple and effective method of analysing the three mutations from Guthrie cards has been developed. Assuming Hardy-Weinberg equilibrium, 90% of our CF patients will be expected to carry at least one deltaF508 allele and 97.6% to carry at least one deltaF508, 394delTT or 3659delC copy. Including the latter two in a screening programme would thus substantially reduce the risk of a false-negative outcome.

Female patients with cystic fibrosis suffer from reproductive endocrinological disorders despite good clinical status.

Ten women with cystic fibrosis (CF) were evaluated with regard to hormonal profiles during a natural and a clomiphene citrate (CC) stimulated cycle. Five of the women were found to be anovulatory during a natural cycle. All women except one did respond with ovulation to CC stimulation indicating adequate ovarian response. Neither did they show increased follicle-stimulating hormone (FSH) concentrations on day 10 after CC treatment confirming normal ovarian reserve. Clinically the anovulatory women differed from the ovulating in two aspects: more profound essential fatty acid deficiency (EFAD) and higher peak/basal insulin response during an oral glucose tolerance test. The anovulatory women had significantly lower luteal oestradiol and progesterone but higher total testosterone concentrations when compared to healthy controls and the ovulatory CF women. The pathological insulin response and high testosterone concentrations resemble those seen in women with polycystic ovarian (PCO) syndrome. However, the CF patients in our study had normal ovaries, as deduced from ultrasound examination and normal luteinizing hormone (LH)/FSH ratio. It is suggested that EFAD as well as hypersecretion of insulin may be of importance for the observed ovarian dysfunction. Further studies are needed to evaluate the relation between ovulatory mechanisms and EFAD in CF women as well as studies to compare anovulatory CF women with women with PCO syndrome.

Time spent on waiting lists for medical care: an insurance approach.

In this paper, we develop a simple model of the benefits and costs of being on a waiting list. The model shows that complex factors are in operation, implying that a shorter waiting time need not necessarily be preferred to a longer waiting time. We also present an empirical study, where a sample of Swedes are offered the possibility of purchasing private insurance, thus reducing waiting time for surgery beyond the three-month guarantee offered by the public sector health care system. Respondents could choose between two insurance contracts. A 'spike' model, where the probability of a zero WTP is strictly positive, was developed and estimated to obtain demand functions for private insurance.

Cystic fibrosis through a female perspective: psychosocial issues and information concerning puberty and motherhood.

The purpose of the study was to investigate psychosocial issues concerning puberty and motherhood among CF adult females, to see how they had obtained and conceived information on these matters and how they would like information to be given. Fourteen adult CF females were interviewed. The majority of the women felt socially accepted and did not remember being ashamed over their delayed puberty. Thirteen of the women had been or were living in stable sexual relationships. However, the study revealed problems with destructive behaviour during puberty due to thoughts about premature death, secret worries over delayed puberty, poorly received information about puberty and fertility, avoidance of close relationships with the opposite sex during adolescence and concerns about being a mother with a chronic illness. Information about puberty and fertility should be given individually and in small discussion groups with teenage girls combined with thorough medical and psychological guidance concerning motherhood.

Polymorphic expression of multidrug resistance mRNA in lung parenchyma of nonpregnant and pregnant rats: a comparison to cystic fibrosis mRNA expression.

Multidrug resistance (MDR1b) and cystic fibrosis transmembrane conductance regulator (CFTR) proteins are members of the "ATP-binding cassette" superfamily of transporters. They are associated with chloride channel activities and ATP secretion and have complementary patterns of expression in several organs. In the rat uterus, CFTR expression is replaced by MDR1b expression during pregnancy. We have studied whether expression of MDR1b and CFTR also vary in the lung during pregnancy. No variations in MDR1b or CFTR mRNA levels during pregnancy were detected. However, there was an unusual degree of variation in MDR1b mRNA expression in lung parenchyma between animals in both the control group and the pregnant group. If present among humans, polymorphic expression of MDR1 in lung parenchyma may explain part of the differences in lung symptomatology observed in the CF patients carrying the same mutation.

The cost-effectiveness of a cardiovascular risk reduction program in general practice.

An economic evaluation was conducted alongside a randomised controlled trial of two lifestyle interventions and a routine care (control) group to assess the cost-effectiveness of a general practice-based lifestyle change program for patients with risk factors for cardiovascular disease. Routine care was the base case comparator because it represents 'current therapy' for cardiovascular disease (CVD). A 'no care' control group was not considered a clinically acceptable alternative to lifestyle interventions. The interventions consisted of an education guide and video for GPs to assess individual patient risk factors and plan a program for risk factor behavior change. Each patient received a risk factor assessment, education materials, a series of videos to watch on lifestyle behaviors and some patients received a self-help booklet. Eighty-two general practitioners were randomised from 75 general practices in Sydney's Western Metropolitan Region to (i) routine care (n = 25), (ii) video group (n = 29) or (iii) video + self help group (n = 28). GPs enrolled patients into the trial who met selection criteria for being at risk of CVD. There were 255 patients in the routine care (control) group, 270 in the video (intervention) group and 232 in the video + self help (intervention) group enrolled in the trial. Outcome measures included patient risk factor status: blood pressure, body mass index, cholesterol and smoking status at entry to trial and after 1 year. Changes in risk factors were used to estimate quality adjusted life years (QALYs) gained. One hundred and thirty patients in the routine care group, 199 in the video group and 155 in the video + self help group remained in the trial at the 12-month review and had complete data. The cost per QALY for males ranged from $AUD152,000 to 204,000. Further analysis suggests that a program targeted at 'high risk' males would cost approximately $30,000 per QALY. The lifestyle interventions had no significant effect on cardiovascular risk factors when compared to routine patient care. There remains insufficient evidence that lifestyle programs conducted in general practices are effective. Resources for general practice-based lifestyle programs may be better spent on high risk patients who are contemplating changes in risk factor behaviours.

Patients' willingness to pay for autologous blood donation.

Most cost-effectiveness analyses of autologous blood donation show very small health benefits for a substantial increase in resource utilization. However, these analyses do not consider the psychological benefits of peace of mind to patients participating in the program. In order to quantitate these benefits, we employed contingent valuation methodology to measure the willingness of patients undergoing elective surgery, to pay for autologous blood donation. The internal consistency of patient responses was investigated through correlations of willingness-to-pay values with risk perceptions and patient characteristics. Two hundred and thirty-five patients completed the self-administered questionnaire which included demographic, willingness-to-pay and risk perception questions. Median population willingness to pay for autologous blood donation was approximately $900 per patient. In multivariate analysis, willingness to pay varied significantly with dread of allogenic transfusion, perceived risk of requiring a blood transfusion and income. Patients who participate in autologous blood donation programs value the procedure highly and state they are willing to pay significant amounts out of pocket to assure themselves of available autologous blood. Willingness to pay correlated significantly with factors expected to influence value decisions.

Delayed puberty in girls with cystic fibrosis despite good clinical status.

BACKGROUND: Previous studies have shown that puberty is delayed among patients with cystic fibrosis (CF). Malnutrition has been considered the main etiologic factor. Today with improved medical therapy and nutritional support, most CF patients obtain an almost normal nutritional status. OBJECTIVES: To investigate whether pubertal development among female CF patients at the Stockholm CF Center was normal and, if not, what other parameters besides nutrition might influence this. METHODS: Seventeen patients were studied retrospectively regarding age at peak height velocity and menarche. Menarcheal age (MA) was compared with normal population data and related to clinical and nutritional status, genotype, oral glucose tolerance test (OGTT), and essential fatty acid levels. RESULTS: The mean age at peak height velocity (12.9 +/- 0.8 years) and at menarche (14.9 +/- 1.4 years) was significantly higher in the CF patients compared with normal controls (11.9 +/- 1.0 years and 13.0 +/- 1.0 years, respectively). No correlation was found between menarchal age and nutritional or clinical parameters. The patients with pathological OGTT without overt diabetes were significantly older at menarche (15.8 +/- 1.7 years) compared with the patients with normal OGTT (14.3 +/- 0.9 years). The patients who were homozygous for the most common mutation, deltaF508, were significantly older at menarche (15.2 +/- 1.9 years) than those who were not (14.7 +/- 0.9 years). CONCLUSIONS: Pubertal delay still existed among the CF patients despite good clinical status. The patients homozygous for deltaF508 and those with pathological OGTT showed the most delayed puberty.

Cystic fibrosis mRNA expression in rat brain: cerebral cortex and medial preoptic area.

Cystic fibrosis transmembrane conductance regulator (CFTR) mRNA expression has been found in the medial preoptic area using in situ hybridization, addressing the possibility of CFTR regulation of sexual maturation and reproductive behaviour. CFTR mRNA has also been found in the cortical deep pyramidal layer V implying possible involvement of CFTR in 'motor' function and output control over bodily movements and secretion. CFTR production in the brain regions observed in this study implicate involvement of CFTR in cerebral control over motor/visceral and endocrine systems.

The relationship between cost-effectiveness analysis and cost-benefit analysis.

This paper examines the relationship between cost-effectiveness analysis and cost-benefit analysis. Provided that a cost-effectiveness analysis includes all the relevant societal costs, it is shown that a cost-effectiveness analysis can be interpreted as a cost-benefit analysis where the willingness to pay per effectiveness unit is assumed to be constant and the same for everyone. To relax this assumption the willingness to pay per effectiveness unit can be allowed to vary depending on for instance the size of the health effects and the target population. It is argued that cost-effectiveness analysis is best viewed as a subset of cost-benefit analysis, where the aim of the analysis is to estimate the cost function of producing health effects. It is also concluded that to interpret and use cost-effectiveness analysis as a tool to maximize the health effects for one specified real-world budget, will be inconsistent with a societal perspective and is likely to lead to major problems of suboptimization.

The cost-effectiveness of a cardiovascular multiple-risk-factor intervention programme in treated hypertensive men.

OBJECTIVES: The aim of this study was to carry out a cost-effectiveness analysis of a multifactorial intervention programme in treated hypertensive patients. DESIGN: A cost-effectiveness analysis based on 3 years of follow-up in an open, randomized, parallel-group study with allocation either to a comprehensive, multiple-risk factor modification programme or to conventional treatment. SETTING: An outpatient clinic of a city hospital. SUBJECTS: Inclusion criteria were: male sex, age 50-72 (mean 66.4) years, treated hypertension and at least one of the following: serum cholesterol > or = 6.5 mmol L-1, and/or smoking and/or diabetes mellitus. A total of 508 patients were included in the study. INTERVENTIONS: Advice given to individuals, and group meetings based on nutritional advice and behavioural treatment principles. If necessary, drug therapy could be instituted to achieve the treatment goals in the intervention group: serum total cholesterol of < 6.0 mmol L-1, no smoking, HbAlc < 6.0% and diastolic blood pressure < 90 mmHg in both groups. MAIN OUTCOME MEASURE: Incremental cost per life-year gained of the intervention programme. RESULTS: The cost per life-year gained was SEK 4000 in an estimation based on the observed risk reduction and ranged between SEK 62,000 and SEK 163,000 in three estimations based on the risk factor changes. CONCLUSIONS: The analysis indicates that the intervention programme is cost-effective in the studied patient population.