Subjective expectation of reaching age 85: agreement with population statistics and association with behavioral and psychological factors.

BACKGROUND: It is not clearly known how well Danes estimate their chances of reaching the average life expectancy and whether identifiable population subgroups misestimate their life expectancy, and potentially also investments and savings in health and pensions. Therefore, in this study, we examined on the individual level whether subjective life expectancy is in line with the statistically calculated chance of reaching age 85, and further explored the psychological and behavioral factors associated with under or overestimation. METHODS: We opted for a cross-sectional survey design based on a sample of 5,379 Danish citizens aged 50-70 years, returning a web-based questionnaire with socio-demographic data supplemented from a national registry. Average participant estimates of their chance of reaching age 85 for each age range and sex group were compared with actuarial data. We then performed multiple linear regression analyses to examine factors associated with the subjective expectancy of reaching age 85 years. RESULTS: We found that 32% of females and 23% of males reported 100% certainty of reaching age 85, and average expected survival chance exceeded the statistically predicted survival chance for 23% of males and 16% for females in age-ranges 50-60 and 61-70. Our multivariable analysis found that health literacy, internal health locus of control, willingness to take health risks, self-rated health, and health and life satisfaction all showed a significant positive association with expectation of reaching age 85. Moreover, those on daily medications, ex- or current smokers, and heavy drinkers were significantly less optimistic about reaching age 85. CONCLUSIONS: Particularly for the population groups with inaccurate life expectancies, the significant associations with psychological and behavioral factors open a way for initiatives based on behavior change theories to reach a better agreement between subjective and statistical life expectancy.

Long-term weight loss in a 24-month primary care-anchored telehealth lifestyle coaching program: Randomized controlled trial.

Long-term weight loss can reduce the risk of type 2 diabetes for people living with obesity and reduce complications for patients diagnosed with type 2 diabetes. We investigated whether a telehealth lifestyle-coaching program (Liva) leads to long-term (24 months) weight loss compared to usual care. In a randomized controlled trial, n = 340 participants living with obesity with or without type 2 diabetes were enrolled and randomized via an automated computer algorithm to an intervention group (n = 200) or to a control group (n = 140). The telehealth lifestyle-coaching program comprised of an initial one-hour face-to-face motivational interview followed by asynchronous telehealth coaching. The behavioural change techniques used were enabled by individual live monitoring. The primary outcome was a change in body weight from baseline to 24 months. Data were assessed for n = 136 participants (40%), n = 81 from the intervention group and n = 55 from the control group, who completed the 24-month follow-up. After 24 months mean body weight and body mass index were reduced significantly for completers in both groups, but almost twice as much was registered for those in the intervention group which was not significant between groups -4.4 (CI -6.1; -2.8) kg versus -2.5 (CI -3.9; -1.1) kg, P = 0.101. Haemoglobin A1c was significantly reduced in the intervention group -3.1 (CI -5.0; -1.2) mmol/mol, but not in the control group -0.2 (CI -2.4; -2.0) mmol/mol without a significant between group difference (P = 0.223). Low completion was partly due to coronavirus disease 2019. Telehealth lifestyle coaching improve long-term weight loss (> 24 months) for obese people with and without type 2 diabetes compared to usual care.

Prolongation of disease-free life: When is the benefit sufficient to warrant the effort of taking a preventive medicine?

The prolongation of disease-free life (PODL) required by people to be willing to accept an offer of a preventive treatment is unknown. Quantifying the required benefits could guide information and discussions about preventive treatment. In this study, we investigated how large the benefit in prolongation of a disease-free life (PODL) should be for individuals aged 50-80 years to accept a preventive treatment offer. We used a cross-sectional survey design based on a representative sample of 6847 Danish citizens aged 50-80 years. Data were collected in 2019 through a web-based standardized questionnaire administered by Statistics Denmark, and socio-demographic data were added from a national registry. We analyzed the data with chi-square tests and stepwise multinomial logistic regression. The results indicate that the required minimum benefit from the preventive treatment varied widely between individuals (1-week PODL = 14.8%, ≥4 years PODL = 39.2%), and that the majority of individuals (51.1%) required a PODL of ≥2 years. The multivariable analysis indicate that education and income were independently and negatively associated with requested minimum benefit, while age and smoking were independently and positively associated with requested minimum benefit to accept the preventive treatment. Most individuals aged 50-80 years required larger health benefits than most preventive medications on average can offer. The data support the need for educating patients and health care professionals on how to use average benefits when discussing treatment benefits, especially for primary prevention.

Association between health literacy, general psychological factors, and adherence to medical treatment among Danes aged 50-80 years.

BACKGROUND: Understanding behavioral factors associated with low health literacy (HL) is relevant for health care providers to better support their patients' health and adherence to preventive treatment. In this study, we aim to study associations between low HL and socio-demographic characteristics, medication-related perceptions and experience, as well as general psychological factors among patients aged 50-80 years. METHODS: We used a cross-sectional survey design based on a representative group of 6,871 Danish citizens aged 50-80 years returning a web-based questionnaire with socio-demographic data added from a national registry. Chi-square tests were conducted to analyze associations between low HL and daily use of medication and self-rated health. Chi-square tests and binary logistic regression were conducted for analyzing data from respondents using prescribed medicines daily (N = 4,091). RESULTS: Respondents with low HL were more often on daily medications (19 % [777/4,091] vs. 16 % [436/2,775]; P < 0.001) and were more likely to have poorer self-rated health (P < 0.001). Among patients on daily medications, low HL was significantly higher among men and those with lower educational attainment and lower family income. Low HL was independently and positively associated with perceptions that taking prescribed medicines daily is difficult and time-consuming, with forgetting to take prescribed medicines, and with lower satisfaction with life and poor self-assessed health. CONCLUSIONS: Our study provides information that patients aged 50-80 years with low HL are challenged on their adherence to treatment plans which is not only related to traditional sociodemographic factors but also on perceptions related to taking medication per se.

Evolution of the ß-lactam-resistant Streptococcus pneumoniae PMEN3 clone over a 30 year period in Barcelona, Spain.

Objectives: To analyse the epidemiology and genetic evolution of PMEN3 (Spain9V-156), a penicillin-non-susceptible clone of Streptococcus pneumoniae, causing invasive pneumococcal disease (IPD) in Barcelona during 1987-2016. Methods: WGS was performed on 46 representative isolates and the data were used to design additional molecular typing methods including partial MLST, PCR-RFLP and detection of surface-exposed proteins and prophages, to assign the remaining isolates to lineages. The isolates were also subjected to antimicrobial susceptibility testing. Results: Two hundred and twenty-seven adult cases of IPD caused by PMEN3 were identified. PMEN3 caused mainly pneumonia (84%) and the 30 day mortality rate was 23.1%. Evidence of recombination events was found, mostly in three regions, namely the capsular operon (associated with capsular switching) and adjacent regions containing pbp2x and pbp1a, the murM gene and the pbp2b-ddl region. Some of these genetic changes generated successful new variant serotype lineages, including one of serotype 11A that is not included in the current PCV13 vaccine. Other genetic changes led to increased MICs of ß-lactams. Notably, most isolates also harboured prophages coding for PblB-like proteins. Despite these adaptations, the ability of this clone to cause IPD remained unchanged over time, highlighting the importance of its core genetic background. Conclusions: Our study demonstrated successful adaptation of PMEN3 to persist over time despite the introduction of broader antibiotics and conjugate vaccines. In addition to enhancing understanding of the molecular evolution of PMEN3, these findings highlight the need for the development of non-serotype-based vaccines to fight pneumococcal infection.

Dermal uptake and percutaneous penetration of organophosphate esters in a human skin ex vivo model.

Organophosphate esters (OPEs) are used as flame retardants, plasticizers, and as hydraulic fluids. They are present in indoor environments in high concentrations compared with other flame retardants, and human exposure is ubiquitous. In this study we provide data for estimating dermal uptake for eight OPEs and ranking in OPEs risk assessment. Dermal uptake and percutaneous penetration of the OPEs were studied in a Franz diffusion cell system using human skin dosed with a mixture of OPEs in an ethanol:toluene (4:1) solution. Large variation in penetration profiles was observed between the OPEs. The chlorinated OPEs tris(2-chloroisopropyl) phosphate (TCIPP), and in particular tris(2-chloroethyl) phosphate (TCEP), penetrated the skin quite rapidly while tris(1,3-dichlor-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) tended to build up in the skin tissue and only smaller amounts permeated through the skin. For tris(isobutyl) phosphate (TIBP), tris(n-butyl) phosphate (TNBP), and tris(methylphenyl) phosphate (TMPP) the mass balance was not stable over time indicating possible degradation during the experimental period of 72 h. The rates at which OPEs permeated through the skin decreased in the order TCEP > TCIPP ≥ TBOEP > TIBP ≥ TNBP > TDCIPP > TPHP > TMPP. Generally, the permeation coefficient, kp, decreased with increasing log Kow, whereas lag time and skin deposition increased with log Kow. The present data indicate that dermal uptake is a non-negligible human exposure pathway for the majority of the studied OPEs.

ALFAXALONE ANESTHESIA IN THE BENGALESE FINCH ( LONCHURA DOMESTICA).

The objective of this study was to evaluate the use of alfaxalone in a small passerine species. A dose-response trial was conducted whereby 10, 30, and 50 mg/kg alfaxalone was administered subcutaneously (SC) to 10 Bengalese finches ( Lonchura domestica) in a randomized complete crossover study design. Subsequently, a similar protocol was used to compare 30 mg/kg alfaxalone alone or combined with either 0.7 mg/kg midazolam or 1 mg/kg butorphanol SC. Induction and recovery times were recorded and depth of anesthesia monitored at 5-min intervals throughout each procedure. Functional oxygen saturation and pulse rates were measured with a pulse oximeter at 15 min after administration of the anesthetic agent(s). Dose-dependent decreases in induction time and prolongation of anesthetic duration were seen with increasing alfaxalone dosage. Alfaxalone combined with midazolam resulted in faster inductions, and the addition of both midazolam and butorphanol resulted in longer durations of anesthesia than alfaxalone alone. The addition of midazolam significantly decreased the pulse rate at 15 min compared with alfaxalone alone. Alfaxalone was found to be an effective agent for inducing anesthesia when administered subcutaneously, and no complications were observed. Increasing the dose, and combining with a benzodiazepine or opioid increased the duration of anesthesia with minimal or no effects on respiratory or pulse rates, within the dose range investigated.

Genomic analysis of 495 vancomycin-resistant Enterococcus faecium reveals broad dissemination of a vanA plasmid in more than 19 clones from Copenhagen, Denmark.

OBJECTIVES: From 2012 to 2014, there has been a huge increase in vancomycin-resistant (vanA) Enterococcus faecium (VREfm) in Copenhagen, Denmark, with 602 patients infected or colonized with VREfm in 2014 compared with just 22 in 2012. The objective of this study was to describe the genetic epidemiology of VREfm to assess the contribution of clonal spread and horizontal transfer of the vanA transposon (Tn1546) and plasmid in the dissemination of VREfm in hospitals. METHODS: VREfm from Copenhagen, Denmark (2012-14) were whole-genome sequenced. The clonal structure was determined and the structure of Tn1546-like transposons was characterized. One VREfm isolate belonging to the largest clonal group was sequenced using long-read technology to close a 37 kb vanA plasmid. RESULTS: Phylogeny revealed a polyclonal structure where 495 VREfm isolates were divided into 13 main groups and 7 small groups. The majority of the isolates were located in three groups (n = 44, 100 and 218) and clonal spread of VREfm between wards and hospitals was identified. Five Tn1546-like transposon types were identified. A dominant truncated transposon (type 4, 92%) was spread across all but one VREfm group. The closed vanA plasmid was highly covered by reads from isolates containing the type 4 transposon. CONCLUSIONS: This study suggests that it was the dissemination of the type 4 Tn1546-like transposon and plasmid via horizontal transfer to multiple populations of E. faecium, followed by clonal spread of new VREfm clones, that contributed to the increase in and diversity of VREfm in Danish hospitals.

Novel Pathways for Ameliorating the Fitness Cost of Gentamicin Resistant Small Colony Variants.

Small colony variants (SCVs) of the human pathogen Staphylococcus aureus are associated with persistent infections. Phenotypically, SCVs are characterized by slow growth and they can arise upon interruption of the electron transport chain that consequently reduce membrane potential and thereby limit uptake of aminoglycosides (e.g., gentamicin). In this study, we have examined the pathways by which the fitness cost of SCVs can be ameliorated. Five gentamicin resistant SCVs derived from S. aureus JE2 were independently selected on agar plates supplemented with gentamicin. The SCVs carried mutations in the menaquinone and hemin biosynthesis pathways, which caused a significant reduction in exponential growth rates relative to wild type (WT; 0.59-0.72) and reduced membrane potentials. Fifty independent lineages of the low-fitness, resistant mutants were serially passaged for up to 500 generations with or without sub-lethal concentrations of gentamicin. Amelioration of the fitness cost followed three evolutionary trajectories and was dependent on the initial mutation type (point mutation vs. deletion) and the passage condition (absence or presence of gentamicin). For SCVs evolved in the absence of gentamicin, 12 out of 15 lineages derived from SCVs with point mutations acquired intra-codonic suppressor mutations restoring membrane potential, growth rate, gentamicin susceptibility and colony size to WT levels. For the SCVs carrying deletions, all lineages enhanced fitness independent of membrane potential restoration without alterations in gentamicin resistance levels. By whole genome sequencing, we identified compensatory mutations in genes related to the σB stress response (7 out of 10 lineages). Inactivation of rpoF that encode for the alternative sigma factor SigB (σB) partially restored fitness of SCVs. For all lineages passaged in the presence of gentamicin, fitness compensation via membrane potential restoration was suppressed, however, selected for secondary mutations in fusA and SAUSA300_0749. This study is the first to describe fitness compensatory events in SCVs with deletion mutations and adaptation of SCVs to continued exposure to gentamicin.

Bacterial viruses enable their host to acquire antibiotic resistance genes from neighbouring cells.

Prophages are quiescent viruses located in the chromosomes of bacteria. In the human pathogen, Staphylococcus aureus, prophages are omnipresent and are believed to be responsible for the spread of some antibiotic resistance genes. Here we demonstrate that release of phages from a subpopulation of S. aureus cells enables the intact, prophage-containing population to acquire beneficial genes from competing, phage-susceptible strains present in the same environment. Phage infection kills competitor cells and bits of their DNA are occasionally captured in viral transducing particles. Return of such particles to the prophage-containing population can drive the transfer of genes encoding potentially useful traits such as antibiotic resistance. This process, which can be viewed as 'auto-transduction', allows S. aureus to efficiently acquire antibiotic resistance both in vitro and in an in vivo virulence model (wax moth larvae) and enables it to proliferate under strong antibiotic selection pressure. Our results may help to explain the rapid exchange of antibiotic resistance genes observed in S. aureus.

Dermal uptake and percutaneous penetration of ten flame retardants in a human skin ex vivo model.

The dermal uptake and percutaneous penetration of ten organic flame retardants was measured using an ex vivo human skin model. The studied compounds were DBDPE, BTBPE, TBP-DBPE, EH-TBB, BEH-TEBP, α, ß and γ-HBCDD as well as syn- and anti-DDC-CO. Little or none of the applied flame retardants was recovered in either type of the receptor fluids used (physiological and worst-case). However, significant fractions were recovered in the skin depot, particularly in the upper skin layers. The primary effect of the worst-case receptor fluid was deeper penetration into the skin. The recovered mass was used to calculate lower- and upper-bound permeability coefficients kp. Despite large structural variation between the studied compounds, a clear, significant decreasing trend of kp was observed with increasing log Kow. The results indicate that the dermis may provide a significant barrier for these highly lipophilic compounds. However, based on our results, dermal uptake should be considered in exposure assessments, though it may proceed in a time-lagged manner compared to less hydrophobic compounds.

Associations between patients' adherence and GPs' attitudes towards risk, statin therapy and management of non-adherence--a survey and register-based study.

BACKGROUND: Previous studies suggest that doctors' personal lifestyle, risk taking personality and beliefs about risk reducing therapies may affect their clinical decision-making. Whether such factors are further associated with patients' adherence with medication is largely unknown. OBJECTIVE: To estimate associations between GPs' attitudes towards risk, statin therapy and management of non-adherence and their patients' adherence, and to identify subgroups of GPs with poor patient adherence. METHODS: All Danish GPs were invited to participate in an online survey. We asked whether they regarded statin treatment as important, how they managed non-adherence and whether non-adherence annoyed them. The Jackson Personality Inventory-revised was used to measure risk attitude. The GPs' responses were linked to register data on their patients' redeemed statin prescriptions. Mixed effect logistic regression was used to estimate associations between patient adherence and GPs' attitudes. Adherence was estimated by the proportion of days covered in a 1-year period using an 80% cut-off. RESULTS: We received responses from 1398 GPs (42.2%) who initiated statin therapy in 12 192 patients during the study period. In total 6590 (54.1%) of these patients were adherent. Patients who had GPs rarely assessing their treatment adherence were less likely to be adherent than those who had GPs assessing their patients' treatment adherence now and then, odds ratio (OR) 0.86 [confidence interval (CI) 0.77-0.96]. No other associations were found between patients' adherence and GPs' attitudes. CONCLUSIONS: Our findings suggest that GPs' attitudes to risk, statin therapy or management of non-adherence are not significantly associated with their patients' adherence.

Aquatic Bird Bornavirus 1 in Wild Geese, Denmark.

To investigate aquatic bird bornavirus 1 in Europe, we examined 333 brains from hunter-killed geese in Denmark in 2014. Seven samples were positive by reverse transcription PCR and were 98.2%-99.8% identical; they were also 97.4%-98.1% identical to reference strains of aquatic bird bornavirus 1 from geese in North America.

Multiple hospital outbreaks of vanA Enterococcus faecium in Denmark, 2012-13, investigated by WGS, MLST and PFGE.

OBJECTIVES: In Denmark, the incidence of vancomycin-resistant Enterococcus faecium (VREfm) has increased since 2012. The aim of this study was to investigate the epidemiology and clonal relatedness of VREfm isolates in Danish hospitals in 2012-13 using WGS. The second aim was to evaluate if WGS-based typing could replace PFGE for typing of VREfm. METHODS: A population-based study was conducted including all VREfm isolates submitted for national surveillance from January 2012 to April 2013. All isolates were investigated by WGS, MLST and PFGE. RESULTS: One-hundred and thirty-two isolates were included. The majority of the isolates were from clinical samples (77%). Gastroenterology/abdominal surgery (29%) and ICUs (29%) were the predominant departments with VREfm. Genomics revealed a polyclonal structure of the VREfm outbreak. Seven subgroups of 3-44 genetically closely related isolates (separated by <17 SNPs) were identified using WGS. Direct or indirect transmission of VREfm between patients and intra- and inter-regional spreading clones was observed. We identified 10 STs. PFGE identified four major clusters (13-43 isolates) and seven minor clusters (two to three isolates). The results from the typing methods were highly concordant. However, WGS-based typing had the highest discriminatory power. CONCLUSIONS: This study emphasizes the importance of infection control measures to limit transmission of VREfm between patients. However, the diversity of the VREfm isolates points to the fact that other important factors may also affect the VREfm increase in Denmark. Finally, WGS is suitable for typing of VREfm and has replaced PFGE for typing of VREfm in Denmark.

Feasibility of smartphone diaries and personal dosimeters to quantitatively study exposure to ultraviolet radiation in a small national sample.

BACKGROUND: In 2007, a national skin cancer prevention campaign was launched to reduce the UV exposure of the Danish population. To improve campaign evaluation a questionnaire validation using UV-dosimeters was initiated. AIM: To show the feasibility of dosimeters for national representative studies and of smartphones as a data collection tool. MATERIALS AND METHODS: Participants were sent a dosimeter which they wore for 7 days, received a short diary questionnaire by text message each day and subsequently a longer questionnaire. Correlation between responses from questionnaire, smartphone diaries and dosimeters were examined. RESULTS: This study shows a 99.5% return rate (n = 205) of the dosimeters by ordinary mail and high response-rates for a smartphone questionnaire dairy. Correlation coefficients for outdoor-time reported through smartphones and dosimeters as average by week 0.62 (0.39-0.77), P < 0.001 (n = 40). Correlation coefficient for outdoor time estimated by questionnaire and dosimeters were 0.42 (0.11-0.64), P = 0.008. The subjective perception of the weather was the only covariate significantly influencing questionnaire estimates of actual outdoor exposure. We showed that dosimeter studies are feasible in national settings and that smartphones are a useful tool for monitoring and collecting UV behavior data. CONCLUSION: We found diary data reported on a daily basis through smartphones more strongly associated with actual outdoor time than questionnaire data. Our results demonstrate tools and possible considerations for executing a UV behavior questionnaire validation.

Bringing Feedback in From the Outback via a Generic and Preference-Sensitive Instrument for Course Quality Assessment.

BACKGROUND: Much effort and many resources have been put into developing ways of eliciting valid and informative student feedback on courses in medical, nursing, and other health professional schools. Whatever their motivation, items, and setting, the response rates have usually been disappointingly low, and there seems to be an acceptance that the results are potentially biased. OBJECTIVE: The objective of the study was to look at an innovative approach to course assessment by students in the health professions. This approach was designed to make it an integral part of their educational experience, rather than a marginal, terminal, and optional add-on as "feedback". It becomes a weighted, but ungraded, part of the course assignment requirements. METHODS: A ten-item, two-part Internet instrument, MyCourseQuality (MCQ-10D), was developed following a purposive review of previous instruments. Shorthand labels for the criteria are: Content, Organization, Perspective, Presentations, Materials, Relevance, Workload, Support, Interactivity, and Assessment. The assessment is unique in being dually personalized. In part 1, at the beginning of the course, the student enters their importance weights for the ten criteria. In part 2, at its completion, they rate the course on the same criteria. Their ratings and weightings are combined in a simple expected-value calculation to produce their dually personalized and decomposable MCQ score. Satisfactory (technical) completion of both parts contributes 10% of the marks available in the course. Providers are required to make the relevant characteristics of the course fully transparent at enrollment, and the course is to be rated as offered. A separate item appended to the survey allows students to suggest changes to what is offered. Students also complete (anonymously) the standard feedback form in the setting concerned. RESULTS: Piloting in a medical school and health professional school will establish the organizational feasibility and acceptability of the approach (a version of which has been employed in one medical school previously), as well as its impact on provider behavior and intentions, and on student engagement and responsiveness. The priorities for future improvements in terms of the specified criteria are identified at both individual and group level. The group results from MCQ will be compared with those from the standard feedback questionnaire, which will also be completed anonymously by the same students (or some percentage of them). CONCLUSIONS: We present a protocol for the piloting of a student-centered, dually personalized course quality instrument that forms part of the assignment requirements and is therefore an integral part of the course. If, and how, such an essentially formative Student-Reported Outcome or Experience Measure can be used summatively, at unit or program level, remains to be determined, and is not our concern here.

Insights into alpha-hemolysin (Hla) evolution and expression among Staphylococcus aureus clones with hospital and community origin.

BACKGROUND: Alpha-hemolysin (Hla) is a major virulence factor in the pathogenesis of Staphylococcus aureus infection, being active against a wide range of host cells. Although hla is ubiquitous in S. aureus, its genetic diversity and variation in expression in different genetic backgrounds is not known. We evaluated nucleotide sequence variation and gene expression profiles of hla among representatives of hospital (HA) and community-associated (CA) S. aureus clones. METHODS: 51 methicillin-resistant S. aureus and 22 methicillin-susceptible S. aureus were characterized by PFGE, spa typing, MLST and SCCmec typing. The internal regions of hla and the hla promoter were sequenced and gene expression was assessed by RT-PCR. RESULTS: Alpha-hemolysin encoding- and promoter sequences were diverse, with 12 and 23 different alleles, respectively. Based on phylogenetic analysis, we suggest that hla may have evolved together with the S. aureus genetic background, except for ST22, ST121, ST59 and ST93. Conversely, the promoter region showed lack of co-evolution with the genetic backgrounds. Four non-synonymous amino acid changes were identified close to important regions of hla activity. Amino acid changes in the RNAIII binding site were not associated to hla expression. Although expression rates of hla were in general strain-specific, we observed CA clones showed significantly higher hla expression (p = 0.003) when compared with HA clones. CONCLUSION: We propose that the hla gene has evolved together with the genetic background. Overall, CA genetic backgrounds showed higher levels of hla expression than HA, and a high strain-to-strain variation of gene expression was detected in closely related strains.

Percutaneous penetration--methodological considerations.

Studies on percutaneous penetration are needed to assess the hazards after unintended occupational skin exposures to industrial products as well as the efficacy after intended consumer exposure to topically applied medicinal or cosmetic products. During recent decades, a number of methods have been developed to replace methods involving experimental animals. The results obtained from these methods are decided not only by the chemical or product tested, but to a significant degree also by the experimental set-up and decisions made by the investigator during the planning phase. The present MiniReview discusses some of the existing and well-known experimental in vitro and in vivo methods for studies of percutaneous penetration together with some more recent and promising methods. After this, some considerations and recommendations about advantages and limitations of the different methods and their relevance for the prediction of percutaneous penetration are given. Which method to prefer will depend on the product to be tested and the question asked. Regulatory guidelines exist for studies on percutaneous penetration, but researchers as well as regulatory bodies need to pay specific attention to the vehicles and solvents used in donor and sampling fluids so that it reflects in-use conditions as closely as possible. Based on available experimental data, mathematical models have been developed to aid predictions of skin penetration. The authors question the general use of the present mathematical models in hazard assessment, as they seem to ignore outliers among chemicals as well as the heterogeneity of skin barrier properties and skin conditions within the exposed populations.

A competing risk approach for the European Heart SCORE model based on cause-specific and all-cause mortality.

BACKGROUND: The European Heart SCORE model constitutes the basis for national guidelines for primary prevention and treatment of cardiovascular disease (CVD) in several European countries. The model estimates individuals' 10-year CVD mortality risks from age, sex, smoking status, systolic blood pressure, and total cholesterol level. The SCORE model, however, is not mathematically consistent and does not estimate all-cause mortality. Our aim is to modify the SCORE model to allow consistent estimation of both CVD-specific and all-cause mortality. METHODS: Using a competing risk approach, we first re-estimated the cause-specific risk of dying from cardiovascular disease, and secondly we incorporated non-CVD mortality. Finally, non-CVD mortality was allowed to also depend on smoking status, and not only age and sex. From the models, we estimated CVD-specific and all-cause 10-year mortality risk, and the expected residual lifetime together with corresponding expected effects of statin treatment. RESULTS: The modified model provided CVD-specific 10-year mortality risks similar to those of the European Heart SCORE model. Incorporation of non-CVD mortality increased 10-year mortality risks, in particular for older individuals. When non-CVD mortality was assumed unaffected by smoking status, the absolute risk reduction due to statin treatment ranged from 0.0% to 3.5%, whereas the gain in expected residual lifetime ranged from 3 to 11 months. Statin effectiveness increased for non-smokers and declined for smokers, when smoking was allowed to influence non-CVD mortality. CONCLUSION: The modified model provides mathematically consistent estimates of mortality risk and expected residual lifetime together with expected benefits from statin treatment.