Hospital District of Helsinki and Uusimaa

Abstract Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored 1,2 . FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10 –11 ) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Abstract Objective: To examine whether long term consumption of a probiotic milk could reduce gastrointestinal and respiratory infections in children in day care centres. Design: Randomised, double blind, placebo controlled study over seven months. Setting: 18 day care centres in Helsinki, Finland. Participants: 571 healthy children aged 1-6 years: 282 (mean (SD) age 4.6 (1.5) years) in the intervention group and 289 (mean (SD) age 4.4 (1.5) years) in the control group. Intervention: Milk with or without Lactobacillus GG. Average daily consumption of milk in both groups was 260 ml. Main outcome measures: Number of days with respiratory and gastrointestinal symptoms, absences from day care because of illness, respiratory tract infections diagnosed by a doctor, and course of antibiotics. Results: Children in the Lactobacillus group had fewer days of absence from day care because of illness (4.9 (95% confidence interval 4.4 to 5.5) v 5.8 (5.3 to 6.4) days, 16% difference, P=0.03; age adjusted 5.1 (4.6 to 5.6) v 5.7 (5.2 to 6.3) days, 11% difference, P=0.09). There was also a relative reduction of 17% in the number of children suffering from respiratory infections with complications and lower respiratory tract infections (unadjusted absolute % reduction −8.6 (−17.2 to −0.1), P=0.05; age adjusted odds ratio 0.75 (0.52 to 1.09), P=0.13) and a 19% relative reduction in antibiotic treatments for respiratory infection (unadjusted absolute % reduction −9.6 (−18.2 to −1.0), P=0.03; adjusted odds ratio 0.72 (0.50 to 1.03), P=0.08) in the Lactobacillus group. Conclusions: Lactobacillus GG may reduce respiratory infections and their severity among children in day care. The effects of the probiotic Lactobacillus GG were modest but consistently in the same direction. What is already known on this topic Children attending day care centres are at high risk of respiratory and gastrointestinal infection The successful prevention of respiratory infections could be extremely useful for families and for society in general Short term use of probiotic bacteria has been shown to reduce the severity of rotavirus diarrhoea and the incidence of diarrhoea associated with the use of antibiotics What this study adds In a double blind, randomised, long term study milk containing Lactobacillus GG slightly reduced the incidence of respiratory infections and antibiotic treatment in children

BACKGROUND: The use of standardized mesh kits for repair of pelvic-organ prolapse has spread rapidly in recent years, but it is unclear whether this approach results in better outcomes than traditional colporrhaphy. METHODS: In this multicenter, parallel-group, randomized, controlled trial, we compared the use of a trocar-guided, transvaginal polypropylene-mesh repair kit with traditional colporrhaphy in women with prolapse of the anterior vaginal wall (cystocele). The primary outcome was a composite of the objective anatomical designation of stage 0 (no prolapse) or 1 (position of the anterior vaginal wall more than 1 cm above the hymen), according to the Pelvic Organ Prolapse Quantification system, and the subjective absence of symptoms of vaginal bulging 12 months after the surgery. RESULTS: Of 389 women who were randomly assigned to a study treatment, 200 underwent prolapse repair with the transvaginal mesh kit and 189 underwent traditional colporrhaphy. At 1 year, the primary outcome was significantly more common in the women treated with transvaginal mesh repair (60.8%) than in those who underwent colporrhaphy (34.5%) (absolute difference, 26.3 percentage points; 95% confidence interval, 15.6 to 37.0). The surgery lasted longer and the rates of intraoperative hemorrhage were higher in the mesh-repair group than in the colporrhaphy group (P<0.001 for both comparisons). Rates of bladder perforation were 3.5% in the mesh-repair group and 0.5% in the colporrhaphy group (P=0.07), and the respective rates of new stress urinary incontinence after surgery were 12.3% and 6.3% (P=0.05). Surgical reintervention to correct mesh exposure during follow-up occurred in 3.2% of 186 patients in the mesh-repair group. CONCLUSIONS: As compared with anterior colporrhaphy, use of a standardized, trocar-guided mesh kit for cystocele repair resulted in higher short-term rates of successful treatment but also in higher rates of surgical complications and postoperative adverse events. (Funded by the Karolinska Institutet and Ethicon; ClinicalTrials.gov number, NCT00566917.).

<b>Objective</b>&nbsp;To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs). <b>Design</b>&nbsp;Systematic review followed by a one stage bayesian individual patient data meta-analysis. <b>Data sources</b>&nbsp;Studies from Canadian and European healthcare databases. <b>Review methods</b>&nbsp;Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. <b>Exposure and outcomes</b>&nbsp;Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction. <b>Results</b>&nbsp;A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio &gt;1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations. <b>Conclusions</b>&nbsp;All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

BACKGROUND: Self-assessment assists nurses to maintain and improve their practice by identifying their strengths and areas that may need to be further developed. Professional competence profiles encourage them to take an active part in the learning process of continuing education. Although competence recognition offers a way to motivate practising nurses to produce quality care, few measuring tools are available for this purpose. AIM: This paper describes the development and testing of the Nurse Competence Scale, an instrument with which the level of nurse competence can be assessed in different hospital work environments. METHODS: The categories of the Nurse Competence Scale were derived from Benner's From Novice to Expert competency framework. A seven-step approach, including literature review and six expert groups, was used to identify and validate the indicators of nurse competence. After a pilot test, psychometric testing of the Nurse Competence Scale (content, construct and concurrent validity, and internal consistency) was undertaken with 498 nurses. The 73-item scale consists of seven categories, with responses on a visual analogy scale format. The frequency of using competencies was additionally tested with a four-point scale. RESULTS: Self-assessed overall scores indicated a high level of competence across categories. The Nurse Competence Scale data were normally distributed. The higher the frequency of using competencies, the higher was the self-assessed level of competence. Age and length of work experience had a positive but not very strong correlation with level of competence. According to the item analysis, the categories of the Nurse Competence Scale showed good internal consistency. CONCLUSION: The results provide strong evidence of the reliability and validity of the Nurse Competence Scale.

The combination of transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) provides us the possibility to non-invasively probe the brain's excitability, time-resolved connectivity and instantaneous state. Early attempts to combine TMS and EEG suffered from the huge electromagnetic artifacts seen in EEG as a result of the electric field induced by the stimulus pulses. To deal with this problem, TMS-compatible EEG systems have been developed. However, even with amplifiers that are either immune to or recover quickly from the pulse, great challenges remain. Artifacts may arise from the movement of electrodes, from muscles activated by the pulse, from eye movements, from electrode polarization, or from brain responses evoked by the coil click. With careful precautions, many of these problems can be avoided. The remaining artifacts can be usually reduced by filtering, but control experiments are often needed to make sure that the measured signals actually originate in the brain. Several studies have shown the power of TMS-EEG by giving us valuable information about the excitability or connectivity of the brain.

OBJECTIVE: To assess whether gestational diabetes mellitus (GDM) can be prevented by a moderate lifestyle intervention in pregnant women who are at high risk for the disease. RESEARCH DESIGN AND METHODS: Two hundred ninety-three women with a history of GDM and/or a prepregnancy BMI of ≥30 kg/m(2) were enrolled in the study at <20 weeks of gestation and were randomly allocated to the intervention group (n = 155) or the control group (n = 138). Each subject in the intervention group received individualized counseling on diet, physical activity, and weight control from trained study nurses, and had one group meeting with a dietitian. The control group received standard antenatal care. The diagnosis of GDM was based on a 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation. RESULTS: A total of 269 women were included in the analyses. The incidence of GDM was 13.9% in the intervention group and 21.6% in the control group ([95% CI 0.40-0.98%]; P = 0.044, after adjustment for age, prepregnancy BMI, previous GDM status, and the number of weeks of gestation). Gestational weight gain was lower in the intervention group (-0.58 kg [95% CI -1.12 to -0.04 kg]; adjusted P = 0.037). Women in the intervention group increased their leisure time physical activity more and improved their dietary quality compared with women in the control group. CONCLUSIONS: A moderate individualized lifestyle intervention reduced the incidence of GDM by 39% in high-risk pregnant women. These findings may have major health consequences for both the mother and the child.

ABSTRACT Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency &lt; 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF&lt;10%) of which 62 were over two-fold enriched in Finland. We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia. These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

Lactobacilli supposedly have low pathogenicity; they are seldom detected in blood culture. Lactobacillus rhamnosus GG, which originates indigenously in the human intestine, became available for use as a probiotic in 1990 in Finland. We evaluated the possible effects of the increased probiotic use of L. rhamnosus GG on the occurrence of bacteremia due to lactobacilli. Lactobacilli were isolated in 0.02% of all blood cultures and 0.2% of all blood cultures with positive results in Helsinki University Central Hospital and in Finland as a whole, and no trends were seen that suggested an increase in Lactobacillus bacteremia. The average incidence was 0.3 cases/100,000 inhabitants/year in 1995-2000 in Finland. Identification to the species level was done for 66 cases of Lactobacillus bacteremia, and 48 isolates were confirmed to be Lactobacillus strains. Twenty-six of these strains were L. rhamnosus, and 11 isolates were identical to L. rhamnosus GG. The results indicate that increased probiotic use of L. rhamnosus GG has not led to an increase in Lactobacillus bacteremia.

BACKGROUND AND METHODS: In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989. RESULTS: At the time of the most recent follow-up, 79 months after the start of the study, 47 patients were alive and 43 were dead. The rate of complete remission after bone marrow transplantation was 43 percent for all patients and 58 percent for the patients who had engraftment. The actuarial survival at 76 months was 40 percent. The median duration of relapse-free survival among patients who were in complete remission after bone marrow transplantation was 48 months. The stage of the disease at diagnosis and the number of treatment regimens tried before bone marrow transplantation were predictive of the likelihood of complete remission after engraftment. There were trends toward longer survival among patients who were responsive to treatment before bone marrow transplantation, patients with Stage I disease at diagnosis, and patients who had received only first-line treatment before transplantation, as compared with those who were not responsive, those with Stage II or III disease at diagnosis, and those who had received three or more lines of treatment, but the differences in these factors were not statistically significant. Two post-transplantation factors predicted better long-term survival: complete remission after engraftment and grade I graft-versus-host disease, rather than grade II, III, or IV. CONCLUSIONS: Allogeneic bone marrow transplantation with the use of HLA-matched sibling donors appears to be a promising method of treatment for some patients with multiple myeloma.

BACKGROUND: Concurrent head-to-head comparisons of healthcare interventions regarding cost-utility are rare. The concept of favorable cost-effectiveness of total hip or knee arthroplasty is thus inadequately verified. PATIENTS AND METHODS: In a trial involving several thousand patients from 10 medical specialties, 223 patients who were enrolled for hip or knee replacement surgery were asked to fill in the 15D health-related quality of life (HRQoL) survey before and after operation. RESULTS: Mean (SD) HRQoL score (on a 0-1 scale) increased in primary hip replacement patients (n = 96) from 0.81 (0.084) preoperatively to 0.86 (0.12) at 12 months (p < 0.001). In revision hip replacement (n = 24) the corresponding scores were 0.81 (0.086) and 0.82 (0.097) respectively (p = 0.4), and in knee replacement (n = 103) the scores were 0.81 (0.093) and 0.84 (0.11) respectively (p < 0.001). Of 15 health dimensions, there were statistically significant improvements in moving, usual activities, discomfort and symptoms, distress, and vitality in both primary replacement groups. Mean cost per quality-adjusted life year (QALY) gained during a 1-year period was euro 6,710 for primary hip replacement, euro 52,274 for revision hip replacement, and euro 13,995 for primary knee replacement. INTERPRETATION: Hip and knee replacement both improve HRQoL. The cost per QALY gained from knee replacement is twice that gained from hip replacement.

In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains.As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors.Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.

BACKGROUND: The role of plate fixation in the management of fresh displaced midclavicular fractures is unsettled. The objective of this study was to evaluate the drawbacks and pitfalls of this treatment method. METHODS: We analyzed the complications encountered in 103 consecutive adult patients with severely displaced fresh fractures of the middle third of the clavicle who were treated by open reduction and internal fixation using AO/ASIF plates. These 103 patients accounted for 9.5% of the 1,081 patients with fresh midclavicular fractures seen between 1989 and 1995. The mean age of the 103 patients was 33.4 years (range, 19-62 years). RESULTS: Seventy-nine patients had an uneventful recovery, whereas 24 (23%) suffered one or several complications. The major complications included deep infection, plate breakage, nonunion, and refracture after plate removal. The most common of the minor complications was plate loosening resulting in malunion. The infection rate was 7.8%. A total of 14 reoperations were performed because of the complications. Permanent nonunion ensued in two patients. A severely comminuted fracture (relative risk of failure, 5.15) as well as a state of alcohol intoxication on admission (relative risk of failure, 3.12) were identified as markers of increased complication risk. CONCLUSIONS: Patient noncompliance with the postoperative regimen could be suspected to have been a major cause of the failures. The high complication rate supports a reserved attitude toward plate fixation of fresh midclavicular fractures. The method should be reserved for patients who have trustworthy personal motives for quick pain relief and functional recovery.

OBJECTIVE: To study the long-term effects of radiotherapy on cognitive function in adult patients operated on for low-grade glioma. METHODS: A cohort of 160 patients who underwent surgery for low-grade gliomas of cerebral hemisphere between 1980 and 1992 in a single institution serving a defined population was studied. At a mean follow-up time of 7 years, 28 of the 101 patients who had postoperative irradiation (and no second surgery or chemotherapy) were still alive and eligible for MRI and neuropsychological study. Twenty-three of 59 patients who did not have radiotherapy, second surgery, or chemotherapy were alive and eligible at a mean of 10 years. RESULTS: The group that had postoperative irradiation performed significantly worse than the group that did not in cognitive tests. This difference was not accounted for by histologic diagnosis; location, extent of removal, or progression of the tumor; or any patient factor. Leukoencephalopathy was more severe in the group that had postoperative irradiation than in the group without radiotherapy, and correlated to poor memory performances only in the postoperative radiotherapy group. Average Karnofsky performance scale score was significantly lower in the group that had postoperative irradiation than in the group that did not. CONCLUSION: In adults with low-grade glioma, postoperative radiotherapy poses a significant risk of long-term leukoencephalopathy and cognitive impairment.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is increasingly used in presurgical brain mapping. Preoperative nTMS results correlate well with direct cortical stimulation (DCS) data in the identification of the primary motor cortex. Repetitive nTMS can also be used for mapping of speech-sensitive cortical areas. OBJECTIVE: The current cohort study compares the safety and effectiveness of preoperative nTMS with DCS mapping during awake surgery for the identification of language areas in patients with left-sided cerebral lesions. METHODS: Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system. RESULTS: Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca's area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively. CONCLUSION: Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology.

Navigated transcranial magnetic stimulation combined with electroencephalography (nTMS-EEG), allows noninvasive studies of cortical excitability and connectivity in humans. We investigated the reproducibility of nTMS-EEG in seven healthy subjects by repeating left motor and prefrontal cortical stimulation with a 1-week interval. TMS was applied at three intensities: 90, 100, and 110% of subjects' motor threshold (MT). The TMS-compatible neuronavigation system guaranteed precise repositioning of the stimulation coil. The responses were recorded by a 60-channel whole head TMS-compatible EEG amplifier. A high overall reproducibility (r > 0.80) was evident in nTMS-EEG responses over both hemispheres for both motor and prefrontal cortical stimulation. The results suggest that nTMS-EEG is a reliable tool for studies investigating cortical excitability changes in the test-retest designs.

OBJECTIVES: The objectives of this study were to identify, in a systematic literature review, published studies having used quality-adjusted life years (QALYs) based on actual measurements of patients' health-related quality of life (HRQoL) and to determine which HRQoL instruments have been used to calculate QALYs. Furthermore, the aims were to characterize studies with regard to medical specialty, intervention studied, results obtained, quality, country of origin, QALY gain observed, and interpretation of results regarding cost-effectiveness. METHODS: Systematic searches of the literature were made using the MEDLINE, Embase, CINAHL, SCI, and Cochrane Library electronic databases. Initial screening of identified articles was based on abstracts read independently by two of the authors; full-text articles were again evaluated by two authors, who made the final decision on which articles should be included. RESULTS: The search identified 3,882 articles; 624 were obtained for closer review. Of the reviewed full-text articles, seventy reported QALYs based on actual before-after measurements using a valid HRQoL instrument. The most frequently used instrument was EuroQol HRQoL instrument (EQ-5D, 47.5 percent). Other instruments used were Health Utilities Index (HUI, 8.8 percent), the Rosser-Kind Index (6.3 percent), Quality of Well-Being (QWB, 6.3 percent), Short Form-6D (SF-6D, 5.0 percent), and 15D (2.5 percent). The rest (23.8 percent) used a direct valuation method: Time Trade-Off (10.0 percent), Standard Gamble (5.0 percent), visual analogue scale (5.0 percent), or rating scale (3.8 percent). The most frequently studied medical specialties were orthopedics (15.5 percent), pulmonary diseases (12.7 percent), and cardiology (9.9 percent). Ninety percent of the studies came from four countries: United Kingdom, United States, Canada, the Netherlands. Approximately half of the papers were methodologically high quality randomized trials. Forty-nine percent of the studied interventions were viewed by the authors of the original studies as being cost-effective; only 13 percent of interventions were deemed not to be cost-effective. CONCLUSIONS: Although QALYs gained are considered an important measure of effectiveness of health care, the number of studies in which QALYs are based on actual measurements of patients' HRQoL is still fairly limited.

PURPOSE: Colonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago. MATERIALS AND METHODS: Cancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type. RESULTS: Compliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased. CONCLUSION: Long-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.