Assessment of the clinical and cost-effectiveness evidence in the reimbursement decisions of new cancer drugs.

BACKGROUND: This study aimed to describe the clinical and cost-effectiveness evidence supporting reimbursement decisions of new cancer drugs and analyze the influence of trial characteristics and the cost per quality-adjusted life years (QALYs) on the likelihood of reimbursement in Sweden. PATIENTS AND METHODS: Data were extracted from all appraisal dossiers for new cancer drugs seeking reimbursement in Sweden and claiming added therapeutical value between the years 2010 and 2020. The data were analyzed using descriptive statistics, and logistic regression models were also used with the cost per QALY, study design, comparator, and evidence on final outcomes in the clinical trials as predictors of reimbursement. RESULTS: All 60 included appraisals were based on trial evidence that assessed at least one final outcome (overall survival [OS] or quality of life [QoL]), although rarely as a primary outcome. Of the appraisals with a final decision (n = 58), 79% were approved for reimbursement. Among the reimbursed drugs, only half had trial evidence demonstrating improved OS or QoL. Only one drug had trial evidence supporting improvements in both OS and QoL. The average cost per QALY for reimbursed cancer drugs was estimated to be 748 560 SEK (€73 583). A higher cost per QALY was found to decrease the likelihood of reimbursement by 9.4% for every 100 000 SEK (€9830) higher cost per QALY (P = 0.03). For cost-effectiveness models without direct evidence of improvements in final outcomes, a larger QALY gain was observed compared with those with evidence mainly relying on intermediate and surrogate outcomes. CONCLUSIONS: There are substantial uncertainties in the clinical and cost-effectiveness evidence underlying reimbursement decisions of new cancer drugs. Decision makers should be cautious of the limited evidence on patient-centered outcomes and the implications of allocating resources to expensive treatments with uncertain value for money.

Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway.

Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.

Caries increment and prediction from 12 to 18 years of age: a follow-up study.

AIM: This was to determine the increment of caries from 12 to 18 years of age and to explore the possibility of predicting caries increment in this period based on the caries experience at age 12 years. STUDY DESIGN: Prospective longitudinal survey. METHODS: A sample of 12-year-old children (n =159) were examined in 1993 and 70% of them re-examined at 18 years of age. Bitewing radiographs were taken and a diagnostic system using five caries grades (D(1) to D D(5)) was used at both ages. Children at risk were defined as those who developed manifest caries lesions (D(3-5)FS) on approximal surfaces during the follow-up period. Possible predictors were analysed by calculation of sensitivity, specificity, efficiency of the test, proportion that tested positive and actual proportion of the population at risk. RESULTS: The mean caries increment (D(1-5)MFS) from 12 to 18 years of age was 4.2 (SD +/- 9.1). The percentage of caries-free adolescents at 12 and 18 years of age was 10% and 1% respectively; 25% had either a reversal or no increment in caries experience while the D(1-5)MFS increased in 65% of the adolescents. Of the increment of manifest lesions (D(3-5)FS), 18% were located in incisors/canines, 40% in premolars, 26% in first molars and 16% in second molars. Premolars had the largest proportion of the approximal surfaces with manifest caries increment. The best predictors of children at risk of approximal caries increment (D(3-5)FS) were caries experience (D(1-5)FS) on the approximal surfaces of premolars and second molars at the age of 12 years. The individuals that developed four or more manifest lesions on approximal surfaces between 12 and 18 years were the easiest to predict (sensitivity + specificity = 175%). CONCLUSIONS: There was a considerable increment of manifest caries lesions from 12 to 18 years of age in all tooth groups. The best predictors for increment of manifest caries on approximal surfaces during the age period were approximal caries in premolars and second molars at the age of 12 years.

Health-related quality of life in narcolepsy.

OBJECTIVES: To describe health-related quality of life in Norwegian patients with narcolepsy compared with data from the general population. PATIENTS AND METHODS: Seventy-seven patients with narcolepsy with cataplexy were included in the final analysis. Health-related quality of life was assessed by SF-36 questionnaire. RESULTS: Men and women with narcolepsy had lower scores in all SF-36 domains, except vitality. Most profoundly affected were bodily pain (men: p = 0.0001, women: p = 0.0001), social function (men: p = 0.0001, women: p = 0.0001) and general health (men p = 0.04, women: p = 0.0001). CONCLUSIONS: Narcolepsy has a clear negative effect on quality of life which is not sufficiently counteracted by medical treatment. We suggest that earlier diagnosis and treatment after onset of symptoms may be important in reducing the negative effects on quality of life. Special attention should be paid to the patients social functioning and general well-being.

Psychometric properties and the prevalence, intensity and causes of oral impacts on daily performance (OIDP) in a population of older Tanzanians.

BACKGROUND: The objective was to study whether a Kiswahili version of the OIDP (Oral Impacts on Daily Performance) inventory was valid and reliable for use in a population of older adults in urban and rural areas of Tanzania; and to assess the area specific prevalence, intensity and perceived causes of OIDP. METHOD: A cross-sectional survey was conducted in Pwani region and in Dar es Salaam in 2004/2005. A two-stage stratified cluster sample design was utilized. Information became available for 511 urban and 520 rural subjects (mean age 62.9 years) who were interviewed and participated in a full mouth clinical examination in their own homes. RESULTS: The Kiswahili version of the weighted OIDP inventory preserved the overall concept of the original English version. Cronbach's alpha was 0.83 and 0.90 in urban and rural areas, respectively, and the OIDP inventory varied systematically in the expected direction with self-reported oral health measures. The respective prevalence of oral impacts was 51.2% and 62.1% in urban and rural areas. Problems with eating was the performance reported most frequently (42.5% in urban, 55.1% in rural) followed by cleaning teeth (18.2% in urban, 30.6% in rural). More than half of the urban and rural residents with impacts had very little, little and moderate impact intensity. The most frequently reported causes of impacts were toothache and loose teeth. CONCLUSION: The Kiswahili OIDP inventory had acceptable psychometric properties among non-institutionalized adults 50 years and above in Tanzania. The impacts affecting their performances were relatively common but not very severe.

The relationship between caries in the primary dentition at 5 years of age and permanent dentition at 10 years of age - a longitudinal study.

OBJECTIVES: To explore a possible relationship between the caries experience and pattern in the primary dentition at 5 years of age and the permanent dentition at 10 years of age. Further, to examine the possibility of predicting children in a caries-risk group at 5 years verified at 10 years of age. MATERIALS AND METHODS: A sample of 186 children (90 males) were clinically examined as 5-year-olds and re-examined as 10-year-olds by calibrated dentists. A five-graded diagnostic system including enamel caries was used. Bitewing radiographs were taken. A true risk group of children at 10 years were defined as those with at least one dentin or filled lesion on the mesial surface of 6-year molars, and/or on incisors, and/or total DMFS (decayed, missing, and filled surfaces) more than 1 SD above the mean. The prediction was measured in terms of OR (odds ratio), sensitivity/specificity, and receiver operating characteristic curves. RESULTS: Statistically significant correlations (r=0.5) were found between the caries experience in the two dentitions as well as between the primary second molars at baseline and the permanent teeth at 10 years. 'Primary second molars' and 'all primary molars' were the most powerful predictors for allocation into the risk group (24% of the sample). The highest achieved sum of sensitivity and specificity, 148%, was attained at a cut-off point above two carious surfaces in enamel and/or dentin in primary second molars. CONCLUSIONS: Statistically significant relationship in disease between the dentitions was found. More than two surfaces with caries experience in primary second molars are suggested as a clinically useful predictor at 5 years of age for being at high risk at age 10.

Caries in primary teeth at 5 and 10 years of age: a longitudinal study.

AIM: This was to explore the caries development in the primary dentition in children aged 5 and later when they were 10, with an emphasis on the caries increment according to type of teeth and surfaces. METHODS: The study was a prospective, longitudinal survey where the children were examined in 1993 when they were 5 years of age (n=217) and re-examined in 1998 when they were 10 (n=186). Caries was examined clinically and with radiographs by calibrated dentists based on a caries diagnostic grading system from 0 to 5. Primary incisors were excluded from the registrations at 10 years of age, while teeth exfoliating during the period were included, based on notes from the dental records. RESULTS: Intra- and inter-examiner reliability ranged from kappa 0.62 to 0.90. Dmfs at 5 years was 5.4 (incisors included) and 7.4 at 10 years (incisors excluded, other exfoliated teeth included). The mean caries increment during the age period showed no significant difference between children with and without caries at 5 years of age. Molar-approximal lesions dominated the increment, and when such lesions were diagnosed at 5 years of age, there was an increased risk for more severe caries (dentine lesions) during the period. CONCLUSION: The caries increment in the primary dentition is considerable for the majority of children during the age period 5-10 years. Even if a risk assessment based on the prevalence of approximal caries at 5 years of age may be useful for deciding individual recall intervals, the results of this study seem to suggest frequent check-ups are needed for the whole population.

Development and implementation of the Norwegian monitoring programme for agricultural landscapes.

This paper describes the development and implementation of the Norwegian monitoring programme for agricultural landscapes--the '3Q programme'. The main objective of the scheme is to indicate development trends in the agricultural landscape, and their consequences for spatial structure, biodiversity, cultural heritage and accessibility. The monitoring programme aims to give policy feedback and provide data to fulfill international reporting requirements. This paper describes the background to the programme and reasons behind the choice of methods. Results are presented to show the accuracy of the methods employed and the range of indicator values recorded in the programme. Strengths and limitations of the monitoring programme are discussed, and potential future improvements and developments are outlined. Although there remains a potential for methodological improvement, we stress the importance of establishing a baseline to enable the detection of development trends in a rapidly changing environment.

Relationship between caries prevalence at 5 years of age and dental anxiety at 10.

AIM: The aim of this study was to explore a possible relationship between the individual prevalence of caries in 5-year-old children and dental anxiety in the same children when they became 10 years of age. MATERIALS AND METHODS: A group of 217 children was examined clinically and radiographically for caries at 5 years of age when initial, as well as manifest caries lesions, were recorded. A total of 180 children were available for follow-up at 10 years of age, and dental anxiety was measured by the use of the psychometric questionnaire CFSS-DS. RESULTS: The mean dmfs at 5 years of age was 5.4 (SD+/-7.3) and the mean CFSS-DS at 10 years of age 22.5 (SD+/-6.8). The correlation coefficient between dmfs and CFSS-DS was 0.255 (p < 0.001). Children with high dental anxiety (CFSS-DS sum score higher than one SD above the mean) (N = 22) had a mean dmfs of 10.7, while those with lower dental anxiety had dmfs of 4.7 (p < 0.001). The majority (68%) of the children with high dental anxiety had more than five carious lesions at 5 years of age. CONCLUSION: Children with many carious lesions at the age of 5 years are at high risk for being dentally anxious at 10 years of age. Classical conditioning, including procedural pain and other negative experiences during dental treatment as the unconditioned stimuli, is the most likely reason for this.

Tunnel restorations placed in routine practice and observed for 24 to 54 months.

OBJECTIVE: The purpose of this study was to evaluate the feasibility and performance of tunnel restorations placed in routine public dental service. METHOD AND MATERIALS: A total of 420 small approximal lesions received tunnel restorations 12 general practitioners. Three hundred two restorations in 179 patients were available for evaluation after a minimum period of 24 months. The restorations were evaluated by modified US Public Health Service criteria. RESULTS: After service periods up to 54 months, 57% of the restorations were found to be clinically and radiographically acceptable. The remainder had already been replaced or were assessed as unacceptable. High levels of carious activity and internal-type preparations resulted in the poorest prognosis. The success rates varied considerably among the operators, but these differences did not reach statistical significance. CONCLUSION: The indications for use of the tunnel restoration technique for the treatment of primary approximal lesions seem to be limited at present. Partial tunnel restorations may have a somewhat better prognosis than the internal tunnels, but high carious activity has a detrimental effect. Tunnel restorations may be considered for particularly cooperative patients with a low caries rate as a semipermanent treatment for small lesions.

Response to methylphenidate in boys with attention-deficit hyperactivity disorder.

The response to methylphenidate was examined in 36 boys, aged 7-11 y, with attention-deficit hyperactivity disorder (ADHD) in a double-blind, placebo-controlled, crossover design. Hyperactivity and conduct problems were significantly reduced during methylphenidate treatment. Stimulant medication was associated with improvements on tests of sustained attention, working memory and motor steadiness. When individual changes were studied, it was found that 83% showed a significant improvement in their hyperactivity at home or at school, and for 60% their levels of hyperactive behaviour were within the normal range. High levels of hyperactivity at school and relatively low age were significant predictors of normalization of hyperactivity in at least one setting. However, these predictors could only classify correctly 71% of the children. In clinical practice a trial with stimulants is indicated in ADHD children who show symptoms that are sufficiently severe to cause impairment at home and at school.

A 3-year clinical study of tunnel restorations.

Tunnel restorations (n = 161) performed by 4 dentists were evaluated after a mean of 35 months in situ. Demineralized enamel was to be spared during preparation. The preparations were filled with a cermet glass ionomer (polyalkenoate) cement. Evaluation was carried out using clinical and radiographical criteria. During the observation period, approximately 16% of the restorations were replaced due to caries in dentin and 14% due to marginal ridge fracture. Cavitation in the approximal surface and/or increased radiolucency of the approximal enamel were observed in 34% of the remaining tunnel-restored teeth. A significantly higher frequency of failures were registered when treating patients with a high caries activity, where the initial lesion was large, and where the restoration did not reach the approximal surface.

Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients.

OBJECTIVES: To determine the probability of drug continuation in a large cohort of methotrexate treated rheumatoid arthritis (RA) patients, the reasons for discontinuation of methotrexate, the overall survival of the members of this cohort, and the causes of death in these patients. METHODS: Yearly follow up was conducted in methotrexate treated RA patients who formed a cohort between 1981 and 1986 at a tertiary care centre. The probability of drug continuation and the patients' survival were calculated using standard statistical procedures; standardised mortality ratios were calculated using death certificate data and USA general population and mortality tables. RESULTS: The probability of methotrexate continuation at 10 years from the time the first members entered the cohort was 30%. Toxicity (and its severity) was the most frequent cause of discontinuing methotrexate. The cumulative probability of survival was 85% for women and 45% for men. A greater than expected number of deaths from infections was observed, but the number of deaths from cancer and cardiovascular diseases were within the range expected. CONCLUSIONS: Toxicity remains the most common cause for methotrexate discontinuation. Survival was comparable to that of other RA cohorts. Methotrexate may be implicated as an associated factor in the deaths from infections.

Cavity design and dimensions of tunnel preparations versus composite resin Class-II preparations.

Fourteen pairs of extracted contralateral premolars with small, artificial, standardized, approximal 'caries lesions' were placed in 14 plaster jaws. Fourteen dentists made a mesial tunnel preparation and a distal composite resin preparation on one tooth and vice versa on the contralateral tooth. Less tooth substance was removed in the tunnel preparations than in the class-II preparations, but this difference was not statistically significant when the resin class-II preparations were made without occlusal retention. Twenty-five per cent of the tunnel preparations had residual 'caries', as opposed to 7% in the class-II composite preparations. Tunnel preparations with larger occlusal openings had less residual 'caries'. The morphology of the class-II resin preparations varied considerably, indicating a lack of precise descriptions in the dental literature.

Marginal ridge strength of teeth with tunnel preparations.

The aim of this study was to investigate how the cavity design of tunnel preparations influences the strength of the marginal ridge and to assess the ability of a restoration to support it. Extracted upper premolars were divided into eight experimental groups and one control group of intact teeth. The size and the position of the tunnel preparation in relation to the marginal ridge differed in four of the groups, the preparations remaining unfilled, while teeth in four corresponding groups were filled. The teeth were subjected to incremental dynamic forces until fracture of the marginal ridge occurred at which point a 'maximum energy-index' was calculated. The relationship between this index and the experimental variables was analysed by the Cox proportional hazards model. The results for both filled and unfilled teeth indicated that the distance from the preparation to the marginal ridge is more influential on weakening the ridge than is the buccopalatinal size of the opening. A conservative tunnel restoration situated 2 mm from the marginal ridge, does not significantly weaken an otherwise intact tooth.

Estimation of the difference in crown vigour for 2280 coniferous trees in Norway from 1989 to 1994, adjusted for the effects of ageing.

The considerable deposition of airborne pollutants over Norway has caused concern about the effect on the country's conifer forests. Monitoring of the forest vitality is carried out as an annual assessment of the crown vigour of a representative sample of conifer trees. Crown vigour is a subjective and imprecise indicator, but reasonably precise when change is concerned. A method is described where the expected decline in vitality due to ageing is removed. The remaining, age-adjusted change in crown vigour is then assessed under the prevalent hypothesis of ongoing forest decline. The uncertainties involved with the method are discussed in the conclusion.

[Tourette syndrome in children. An analysis of everyday problems--neurology or emotional conflicts?]. / Tourettes syndrom hos barn. En analyse av hverdagsproblemer--neurologi eller emosjonelle konflikter?

Over a three year period, 109 children aged 5-17 were diagnosed as having Tourette syndrome. They were all evaluated by a team composed of persons with backgrounds in special education, physiotherapy or neuropsychology, and a paediatrician with experience in child neurology. All the children satisfied the criteria of several motor tics and at least one vocal tic lasting more than one year. Besides the tics the most common symptoms were attention deficit disorder and motor hyperactivity. These symptoms were present in 79 children (73%). 42 children (39%) met the criteria for minimal brain dysfunction. Problems relating to attention, activity, perception, motor control and language are generally considered to be part of a neurological dysfunction. We also investigated the children's emotional profile by looking into factors such as aggression, fluctuations of mood, peer relationships and impulsiveness. More than half of the children experienced serious problems in these areas. We believe that emotional problems of this nature are an integral part of their neurological dysfunction and that they can seldom be attributed to psychological factors in their families or to other events related to everyday life.