A prediction model for assessing residential radon concentration in Switzerland

Indoor radon is regularly measured in Switzerland. However, a nationwide model to predict residential radon levels has not been developed. The aim of this study was to develop a prediction model to assess indoor radon concentrations in Switzerland. The model was based on 44,631 measurements from the nationwide Swiss radon database collected between 1994 and 2004. Of these, 80% randomly selected measurements were used for model development and the remaining 20% for an independent model validation. A multivariable log-linear regression model was fitted and relevant predictors selected according to evidence from the literature, the adjusted R², the Akaike's information criterion (AIC), and the Bayesian information criterion (BIC). The prediction model was evaluated by calculating Spearman rank correlation between measured and predicted values. Additionally, the predicted values were categorised into three categories (50th, 50th-90th and 90th percentile) and compared with measured categories using a weighted Kappa statistic. The most relevant predictors for indoor radon levels were tectonic units and year of construction of the building, followed by soil texture, degree of urbanisation, floor of the building where the measurement was taken and housing type (P-values <0.001 for all). Mean predicted radon values (geometric mean) were 66 Bq/m³ (interquartile range 40-111 Bq/m³) in the lowest exposure category, 126 Bq/m³ (69-215 Bq/m³) in the medium category, and 219 Bq/m³ (108-427 Bq/m³) in the highest category. Spearman correlation between predictions and measurements was 0.45 (95%-CI: 0.44; 0.46) for the development dataset and 0.44 (95%-CI: 0.42; 0.46) for the validation dataset. Kappa coefficients were 0.31 for the development and 0.30 for the validation dataset, respectively. The model explained 20% overall variability (adjusted R²). In conclusion, this residential radon prediction model, based on a large number of measurements, was demonstrated to be robust through validation with an independent dataset. The model is appropriate for predicting radon level exposure of the Swiss population in epidemiological research. Nevertheless, some exposure misclassification and regression to the mean is unavoidable and should be taken into account in future applications of the model.

Modeling of red blood cell life-spans in hematologically normal populations

Despite the impact of red blood cell (RBC) Life-spans in some disease areas such as diabetes or anemia of chronic kidney disease, there is no consensus on how to quantitatively best describe the process. Several models have been proposed to explain the elimination process of RBCs: random destruction process, homogeneous life-span model, or a series of 4-transit compartment model. The aim of this work was to explore the different models that have been proposed in literature, and modifications to those. The impact of choosing the right model on future outcomes prediction--in the above mentioned areas--was also investigated. Both data from indirect (clinical data) and direct life-span measurement (biotin-labeled data) methods were analyzed using non-linear mixed effects models. Analysis showed that: (1) predictions from non-steady state data will depend on the RBC model chosen; (2) the transit compartment model, which considers variation in life-span in the RBC population, better describes RBC survival data than the random destruction or homogenous life-span models; and (3) the additional incorporation of random destruction patterns, although improving the description of the RBC survival data, does not appear to provide a marked improvement when describing clinical data.

Association between symptoms and quality of life in patients with schizophrenia: a pooled analysis of changes over time

Quality of life is an important outcome in the treatment of patients with schizophrenia. It has been suggested that patients' quality of life ratings (referred to as subjective quality of life, SQOL) might be too heavily influenced by symptomatology to be a valid independent outcome criterion. There has been only limited evidence on the association of symptom change and changes in SQOL over time. This study aimed to examine the association between changes in symptoms and in SQOL among patients with schizophrenia. A pooled data set was obtained from eight longitudinal studies that had used the Brief Psychiatric Rating Scale (BPRS) for measuring psychiatric symptoms and either the Lancashire Quality of Life Profile or the Manchester Short Assessment of Quality of Life for assessing SQOL. The sample comprised 886 patients with schizophrenia. After controlling for heterogeneity of findings across studies using linear mixed models, a reduction in psychiatric symptoms was associated with improvements in SQOL scores. In univariate analyses, changes in all BPRS subscales were associated with changes in SQOL scores. In a multivariate model, only associations between changes in the BPRS depression/anxiety and hostility subscales and changes in SQOL remained significant, with 5% and 0.5% of the variance in SQOL changes being attributable to changes in depression/anxiety and hostility respectively. All BPRS subscales together explained 8.5% of variance. The findings indicate that SQOL changes are influenced by symptom change, in particular in depression/anxiety. The level of influence is limited and may not compromise using SQOL as an independent outcome measure.

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

There is growing evidence that the great phenotypic variability in patients with cystic fibrosis (CF) not only depends on the genotype, but apart from a combination of environmental and stochastic factors predominantly also on modifier gene effects. It has been proposed that genes interacting with CF transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed the impact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CF disease outcome. SNPs that potentially alter gene function were genotyped in 95 well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysis was used to assess the relationship between sequence variants and the repeated measurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes. Twenty-five SNPs were used for statistical analysis, where we found strong associations for one SNP in PPP2R4 with the lung clearance index (P ≤ 0.01), the specific effective airway resistance (P ≤ 0.005) and the forced expiratory volume in 1 s (P ≤ 0.005). In addition, we identified one SNP in SNAP23 to be significantly associated with three lung function parameters as well as one SNP in PPP2R1A and three in KRT19 to show a significant influence on one lung function parameter each. Our findings indicate that direct interacters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residual function of p.Phe508del-CFTR while variants in KRT19 may modulate the amount of p.Phe508del-CFTR at the apical membrane and consequently modify CF disease.

The influence of a continuous rate infusion of dexmedetomidine on the nociceptive withdrawal reflex and temporal summation during isoflurane anaesthesia in dogs

Objective To examine the influence of a low dose dexmedetomidine infusion on the nociceptive withdrawal reflex and temporal summation in dogs during isoflurane anaesthesia. Study design Prospective experimental blinded cross-over study. Animals Eight healthy mixed breed dogs, body weight Mean +/- SD 26.5 +/- 8.4 kg and age 25 +/- 16 months. Methods Anaesthesia was induced with propofol and maintained with isoflurane (Fe'ISO 1.3%) delivered in oxygen and air. After stabilization, baseline recordings (time 0) were obtained, then a dexmedetomidine bolus (1 mug kg(-1) IV) followed by a continuous rate infusion (1 mug kg(-1) hour(-1) ) or saline placebo were administered. At times 10, 30 and 60 minutes after the initial bolus, electrical stimulations of increasing intensity were applied over the lateral plantar digital nerve, and administered both as single and as repeated stimuli. The resulting reflex responses were recorded using electromyography. Data were analysed using a multivariable linear regression model and a Kruskal Wallis test for single stimulation data, and repeated measures anova and paired t-test for repeated stimulation data. Results The AUC for the stimulus-response curves after single stimulation were similar for both treatments at time 0. At times 10, 30 and 60 the AUCs for the stimulus-response curves were significantly lower with dexmedetomidine treatment than with placebo. Temporal summation was evident in both treatments at times 0, 10, 30 and 60 starting from a stimulation intensity of 10 mA. The magnitude of temporal summation was smaller in dexmedetomidine than in placebo treated dogs at time 10, 30 and 60, but not at time 0. Conclusions During isoflurane anaesthesia, low dose dexmedetomidine suppresses the nociceptive reflex responses after single and repeated electrical stimulation. Clinical relevance This experimental study confirms previous reports on its peri-operative efficacy under clinical conditions, and further indicates that dexmedetomidine might reduce the risk of post-operative chronic pain development.

CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

BACKGROUND In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Higher emotional distress in female partners of cancer patients: prevalence and patient-partner interdependencies in a 3-year cohort

OBJECTIVE: Assessment and treatment of psychological distress in cancer patients was recognized as a major challenge. The role of spouses, caregivers, and significant others became of salient importance not only because of their supportive functions but also in respect to their own burden. The purpose of this study was to assess the amount of distress in a mixed sample of cancer patients and their partners and to explore the dyadic interdependence. METHODS: An initial sample of 154 dyads was recruited, and distress questionnaires (Hospital Anxiety and Depression Scale, Symptom Checklist 9-Item Short Version and 12-Item Short Form Health Survey) were assessed over four time points. Linear mixed models and actor-partner interdependence models were applied. RESULTS: A significant proportion of patients and their partners (up to 40%) reported high levels of anxiety, depression, psychological distress, and low quality of life over the course of the investigation. Mixed model analyses revealed that higher risks for clinical relevant anxiety and depression in couples exist for female patients and especially for female partners. Although psychological strain decreased over time, the risk for elevated distress in female partners remained. Modeling patient-partner interdependence over time stratified by patients' gender revealed specific effects: a moderate correlation between distress in patients and partners, and a transmission of distress from male patients to their female partners. CONCLUSIONS: Our findings provide empirical support for gender-specific transmission of distress in dyads coping with cancer. This should be considered as an important starting point for planning systemic psycho-oncological interventions and conceptualizing further research.

Days spent in acute care hospitals at the end of life of cancer patients in four Swiss cantons: a retrospective database study (SAKK 89/09).

Number of days spent in acute hospitals (DAH) at the end of life is regarded as an important care quality indicator for cancer patients. We analysed DAH during 90 days prior to death in patients from four Swiss cantons. Claims data from an insurance provider with about 20% market share and patient record review identified 2086 patients as dying of cancer. We calculated total DAH per patient. Multivariable generalised linear modelling served to evaluate potential explanatory variables. Mean DAH was 26 days. In the multivariable model, using complementary and alternative medicine (DAH = 33.9; +8.8 days compared to non-users) and canton of residence (for patient receiving anti-cancer therapy, Zürich DAH = 22.8 versus Basel DAH = 31.4; for other patients, Valais DAH = 22.7 versus Ticino DAH = 33.7) had the strongest influence. Age at death and days spent in other institutions were additional significant predictors. DAH during the last 90 days of life of cancer patients from four Swiss cantons is high compared to most other countries. Several factors influence DAH. Resulting differences are likely to have financial impact, as DAH is a major cost driver for end-of-life care. Whether they are supply- or demand-driven and whether patients would prefer fewer days in hospital remains to be established.

Progression of age-related geographic atrophy: role of the fellow eye

PURPOSE. To evaluate the role of fellow eye status in determining progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS. A total of 300 eyes with GA of 193 patients from the prospective, longitudinal, natural history FAM Study were classified into three groups according to the AMD manifestation in the fellow eye at baseline examination: (1) bilateral GA, (2) early/intermediate AMD, and (3) exudative AMD. GA areas were quantified based on fundus autofluorescence images using a semiautomated image-processing method, and progression rates (PR) were estimated using two-level, linear, mixed-effects models. RESULTS. Crude GA-PR in the bilateral GA group (mean, 1.64 mm(2)/y; 95% CI, 1.478-1.803) was significantly higher than in the fellow eye early/intermediate group (0.74 mm(2)/y, 0.146-1.342). Although there was a significant difference in baseline GA size (P = 0.0013, t-test), and there was a significant increase in GA-PR by 0.11 mm(2)/y (0.05-0.17) per 1 disc area (DA; 2.54 mm(2)), an additional mean change of -0.79 (-1.43 to -0.15) was given to the PR beside the effect of baseline GA size. However, this difference was only significant when GA size was ?1 DA at baseline with a GA-PR of 1.70 mm(2)/y (1.54-1.85) in the bilateral and 0.95 mm(2)/y (0.37-1.54) in the early/intermediate group. There was no significant difference in PR compared with that in the fellow eye exudative group. CONCLUSIONS. The results indicate that the AMD manifestation of the fellow eye at baseline serves as an indicator for disease progression in eyes with GA ? 1 DA. Predictive characteristics not only contribute to the understanding of pathophysiological mechanisms, but also are useful for the design of future interventional trials in GA patients.

Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings

Background Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART. Method Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART. Results 3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12. Conclusion In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.

Mapping genetic variants associated with beta-adrenergic responses in inbred mice

β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

Genuine cross-correlations: Which surrogate based measure reproduces analytical results best?

The analysis of short segments of noise-contaminated, multivariate real world data constitutes a challenge. In this paper we compare several techniques of analysis, which are supposed to correctly extract the amount of genuine cross-correlations from a multivariate data set. In order to test for the quality of their performance we derive time series from a linear test model, which allows the analytical derivation of genuine correlations. We compare the numerical estimates of the four measures with the analytical results for different correlation pattern. In the bivariate case all but one measure performs similarly well. However, in the multivariate case measures based on the eigenvalues of the equal-time cross-correlation matrix do not extract exclusively information about the amount of genuine correlations, but they rather reflect the spatial organization of the correlation pattern. This may lead to failures when interpreting the numerical results as illustrated by an application to three electroencephalographic recordings of three patients suffering from pharmacoresistent epilepsy.

Factors influencing subjective quality of life in patients with schizophrenia and other mental disorders: a pooled analysis

Subjective quality of life (SQOL) is an important outcome in the treatment of patients with schizophrenia. However, there is only limited evidence on factors influencing SQOL, and little is known about whether the same factors influence SQOL in patients with schizophrenia and other mental disorders. This study aimed to identify the factors associated with SQOL and test whether these factors are equally important in schizophrenia and other disorders. For this we used a pooled data set obtained from 16 studies that had used either the Lancashire Quality of Life Profile or the Manchester Short Assessment of Quality of Life for assessing SQOL. The sample comprised 3936 patients with schizophrenia, mood disorders, and neurotic disorders. After controlling for confounding factors, within-subject clustering, and heterogeneity of findings across studies in linear mixed models, patients with schizophrenia had more favourable SQOL scores than those with mood and neurotic disorders. In all diagnostic groups, older patients, those in employment, and those with lower symptom scores had higher SQOL scores. Whilst the strength of the association between age and SQOL did not differ across diagnostic groups, symptom levels were more strongly associated with SQOL in neurotic than in mood disorders and schizophrenia. The association of employment and SQOL was stronger in mood and neurotic disorders than in schizophrenia. The findings may inform the use and interpretation of SQOL data for patients with schizophrenia.

Can a website-delivered computer-tailored physical activity intervention be acceptable, usable, and effective for older people?

Despite the numerous health benefits, population physical activity levels are low and declining with age. A continued increase of Internet access allows for website-delivered interventions to be implemented across age-groups, though older people have typically not been considered for this type of intervention. Therefore, the purpose of this study was to evaluate a website-delivered computer-tailored physical activity intervention, with a specific focus on differences in tailored advice acceptability, website usability, and physical activity change between three age-groups. To mimic "real-life" conditions, the intervention, which provided personalized physical activity feedback delivered via the Internet, was implemented and evaluated without any personal contact for the entire duration of the study. Data were collected online at baseline, 1-week, and 1-month follow-up and analyzed for three age-groups (≤44, 45-59, and ≥60 years) using linear mixed models. Overall, 803 adults received the intervention and 288 completed all measures. The oldest age-group increased physical activity more than the other two groups, spent the most time on the website, though had significantly lower perceived Internet self-confidence scores when compared with the youngest age-group. No differences were found in terms of website usability and tailored advice acceptability. These results suggest that website-delivered physical activity interventions can be suitable and effective for older aged adults.