Number of musculoskeletal pain sites leads to increased long-term healthcare contacts and healthcare related costs - a Danish population-based cohort study.

BACKGROUND: People with musculoskeletal pain seek more healthcare than the general population, however little is known about the long-term effect on healthcare use. The aim of this study was to examine the consequences of number of musculoskeletal pain sites on long-term care-seeking and healthcare-related costs and explore how health anxiety influences this relationship. METHODS: We conducted a Danish population-based longitudinal cohort study of 4883 participants combining self-reported survey data from 2008 with ten-year follow-up data from national health registers. Using a causal inference framework, we examined associations between number of pain sites (range 0-7)/level of health anxiety (high/low level) and face-to-face healthcare contacts/healthcare-related costs. Data were analyzed using negative binomial regression with generalized estimating equations. Regression models were adjusted for sex, age, duration of pain, level of education, comorbidity, personality traits, risk of depression, marital status, physical job exposure, and previous healthcare utilization. RESULTS: For each additional pain site general healthcare contacts (Incidence Rate Ratio (IRR): 1.04 (95% CI: 1.03-1.05)), healthcare-related costs (IRR: 1.06 (95% CI: 1.03-1.08) and musculoskeletal healthcare contacts (IRR: 1.11 (95% CI:1.09-1.14) increased. Those with high levels of health anxiety at baseline had a slightly higher number of general healthcare contacts (IRR 1.06 (1.01-1.11), independent of number of pain sites. However, level of anxiety did not influence the effect of number of pain sites on any healthcare use or cost outcomes. CONCLUSIONS: We found evidence for a causal association between increasing number of pain sites and greater healthcare use and cost, and high levels of health anxiety did not increase the strength of this association. This suggests that number of pain sites could be a potential target for biopsychosocial interventions in order to reduce the need for future care-seeking.

Immersion challenge with low and highly virulent infectious salmon anaemia virus reveals different pathogenesis in Atlantic salmon, Salmo salar L.

The salmonid orthomyxovirus infectious salmon anaemia virus (ISAV) causes disease of varying severity in farmed Atlantic salmon, Salmo salar L. Field observations suggest that host factors, the environment and differences between ISAV strains attribute to the large variation in disease progression. Variation in host mortality and dissemination of ISAV isolates with high and low virulence (based on a previously published injection challenge) were investigated using immersion challenge. Virus dissemination was determined using real-time PCR and immunohistochemistry in several organs, including blood. Surprisingly, the low virulent virus (LVI) replicated and produced nucleoprotein at earlier time points post-infection compared to the virus of high virulence (HVI). This was particularly noticeable in the gills as indicated by different viral load profiles. However, the HVI reached a higher maximum viral load in all tested organs and full blood. This was associated with a higher mortality of 100% as compared to 20% in the LVI group by day 23 post-infection. Immersion challenge represented a more natural infection method and suggested that specific entry routes into the fish may be of key importance between ISAV strains. The results suggest that a difference in virulence is important for variations in virus dissemination and pathogenesis (disease development).

Effect of strength training in addition to general exercise in the rehabilitation of patients with non-specific neck pain. A randomized clinical trial.

BACKGROUND: The optimal type of exercise protocol in the physical rehabilitation of non-specific neck pain has not yet been established. Furthermore, the role of fear-avoidance belief in the maintenance of pain and disability has been highlighted. Research indicates that exercise may be a means to reduce fear-avoidance belief, but evidence is scarce. AIM: To compare the effect of two different exercise programs on pain, strength and fear-avoidance belief. DESIGN: Randomized clinical trial. SETTING: A specialized outpatient hospital clinic in Denmark. POPULATION: Twenty-three men and 60 women on sick leave due to non-specific neck pain. METHODS: Participants were randomized to either general physical activity (GPA group) or GPA and additional strength training of the neck and shoulder (SST group). The primary outcome was pain intensity. Secondary outcomes were muscle strength of the neck and shoulder and fear-avoidance belief. RESULTS: Pain was significantly reduced within groups with a median of -1 (IQR: -3 to 0, P<0.001) in the SST group and -1 (IQR: -4 to 1, P=0.046) in the GPA group. The difference between groups was not significant. Changes in strength did not differ between groups. Both groups experienced significant increases in neck flexion strength of 14.7 N (IQR: -1 to 28.4, P=0. 001) in the SST group and 6.9 N (IQR: -4.9 to18.6, P=0.014) in the GPA group. Furthermore, the SST group achieved an increase of 18.6 N (IQR: -2.6 to 69.7, P=0.005) in neck extension. Fear-avoidance beliefs improved with 6 (IQR: 3 to 12, P<0.001) in the SST group, while the GPA group improved with 3 (IQR: 0 to 8, P=0.004). This between-group difference was significant (P=0.046). CONCLUSION AND REHABILITATION IMPACT: This study indicates that in rehabilitation of subjects severely disabled by non-specific neck pain, there is no additional improvement on pain or muscle strength when neck exercises are given as a home-based program with a minimum of supervision. However, strength training of the painful muscles seems to be effective in decreasing fear-avoidance beliefs.

NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features.

Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q-/-7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.

Genetics of therapy-related myelodysplasia and acute myeloid leukemia.

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS-BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q-/-5 and 7q-/-7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia.

Alternative genetic pathways were previously outlined in the pathogenesis of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) based on cytogenetic characteristics. Some of the chromosome aberrations, the recurrent balanced translocations or inversions, directly result in chimeric rearrangement of genes for hematopoietic transcription factors (class II mutations) which disturb cellular differentiation. Other genetic abnormalities in t-MDS and t-AML comprise activating point mutations or internal tandem duplications of genes involved in signal transduction as tyrosine kinase receptors or genes more downstream in the RAS-BRAF pathway (class I mutations). The alternative genetic pathways of t-MDS and t-AML can now be further characterized by a different clustering of six individual class I mutations and mutations of AML1 and p53 in the various pathways. In addition, there is a significant association between class I and class II mutations possibly indicating cooperation in leukemogenesis, and between mutations of AML1 and RAS related to subsequent progression from t-MDS to t-AML. Therapy-related and de novo myelodysplasia and acute myeloid leukemia seem to share genetic pathways, and surprisingly gene mutations were in general not more frequent in patients with t-MDS or t-AML as compared to similar cases of de novo MDS and AML studied previously.

Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia.

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.

Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML.

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.

Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia.

The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.

Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities.

New insights into causative factors for the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), with associations to specific cytogenetic and genetic abnormalities have been obtained primarily from studies of patients with the therapy-related subsets of the two diseases. Current knowledge now makes it possible to distinguish between at least seven major genetic subgroups of MDS and AML, and has directed research towards more specific causative factors also for de novo MDS and AML.

Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy.

Eighty-two unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) were investigated for internal tandem duplications of the FLT3 gene (FLT3/ITD), for internal tandem duplications of the MLL gene (MLL/ITD) and for mutations of the WT1 gene. FLT3/ITD were observed in three patients, another two patients presented MLL/ITD whereas mutations of the WT1 gene were not observed. All FLT3/ITD included the tyrosine-rich stretch between codons 589 and 599, and both MLL/ITD presented break points within Alu-repeats, as previously observed in de novo AML. The ITD were not related to any specific type of previous therapy, but three out of the five cases were observed among only six patients with overt t-AML and a normal karyotype (P = 0.0043). Interestingly, one of the patients with FLT3/ITD presented overt t-AML of subtype M1 with a normal karyotype after treatment with an alkylating agent. Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present. Thus FLT3/ITD may in this case represent a primary event in leukemogenesis, whereas the t(15;17) may represent a secondary event most likely induced by subsequent therapy. In conclusion, FLT3/ITD and MLL/ITD are mainly observed in uncharacteristic cases of t-AML with a normal karyotype and unrelated to previous therapy for which reason they could represent sporadic cases of de novoAML.

Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992.

A highly increased risk of myelodysplasia (MDS) and acute myeloid leukaemia (AML) is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors. More recently, single cases of acute lymphoblastic leukaemia (ALL), often presenting balanced translocations involving chromosome band 11q23, have been observed. We present two such cases with t(4;11)(q21;q23), one of whom had previously received only single-agent chemotherapy with 4-epi-doxorubicin. A review of the literature since 1992 including these two patients reveals a total of 23 cases of ALL or lymphoblastic lymphoma after chemotherapy presenting balanced translocations to 11q23. All 23 patients had previously received at least one topoisomerase II inhibitor, and in two patients 4-epi-doxorubicin had been administered as single-agent chemotherapy for breast cancer. The latency period to development of t-ALL was 24 months or less in 20 out of 22 cases. The MLL gene was found to be rearranged in 14 out of 14 cases, and in three out of six cases the breakpoint was at the telomeric part of the gene, as observed in most cases of AML following therapy with topoisomerase II inhibitors. These results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors in the future should be included with cases of MDS or AML in calculations of risk of leukaemia.

Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents.

Gene amplification is a rare phenomenon in acute leukemia, but recently amplification of specific chromosome bands containing genes rearranged in leukemia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 with 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of MLL were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together on the same chromosome arm representing amplification, 7 patients had single, extra duplicated copies of MLL, whereas both amplification and duplication were observed in the same cell in 1 patient. Comparative genomic hybridization demonstrated gain of varying, often large parts of 11q in five patients. The MLL gene was shown to be unrearranged in all 12 patients. Seven out of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients. Duplication or amplification of MLL was significantly associated with a complex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existence of a specific genetic pathway in t-MDS and t-AML with many previously unidentified chromosome aberrations demonstrated to represent extra copies of parts of 11q, including the unrearranged MLL gene.

Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis.

PURPOSE: To study mutations and loss of heterozygosity (LOH) of p53 in therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML). PATIENTS AND METHODS: Fifty-two unselected patients with t-MDS and 25 patients with t-AML were studied by polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) at the DNA level and by reverse transcriptase (RT)-PCR-SSCP at the mRNA level, and cases with aberrant SSCP patterns were sequenced. RESULTS: Somatically acquired mutations of p53 were observed in 21 of 77 cases of t-MDS or t-AML, and 19 of these 21 patients had received alkylating agents. Single-base substitutions at A:T pairs were more common in t-MDS and t-AML, whereas single-base substitutions at G:C pairs are most common in MDS and AML de novo and in solid tumors. Six patients demonstrated a cytogenetic loss of 17p13, and these six and an additional nine patients with p53 mutations demonstrated LOH of p53 at the DNA or mRNA level. This suggests a cytogenetic loss of the normal p53 allele in these nine cases combined with duplication of the homologous chromosome 17 carrying the mutated p53 allele. Mutations of p53 were significantly associated with deletion or loss of 5q (P <.0001) and a complex karyotype (P =.0001), but surprisingly were not associated with deletion or loss of 7q (P =.73), and were infrequent in patients with balanced chromosome translocations (P =.03). Mutations of p53 were more common in older patients (P =.036) and were associated with an extremely poor prognosis (P =.014), apparently restricted to the 15 cases with LOH of p53 ( P =.046). CONCLUSION: Mutations with loss of function of p53 are significantly associated with deletion or loss of 5q in t-MDS and t-AML after previous treatment with alkylating agents and are associated with genetic instability.

Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation.

Therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) after high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT) for malignant diseases have become an important problem. The actuarial risk has varied, but has often been high if compared to the risk after conventional therapy. Prior chemotherapy with large cumulative doses of alkylating agents is the most important risk factor. In addition, patient age and previous radiotherapy, particularly the use of total body irradiation (TBI) in the preparative regimen for ASCT, have been identified as risk factors. In 3 studies, patients transplanted with CD34(+ )cells from peripheral blood after chemotherapy priming showed a higher risk of t-MDS or t-AML than patients transplanted with cells isolated from the bone marrow without priming. To what extent this higher risk relates to the prior therapy with a different contamination with preleukemic, hematopoietic precursors of the CD34(+) cells obtained by the 2 methods, or is a direct result of chemotherapy priming, or of an increasing awareness of these complications, remains to be determined. The latent period from ASCT to t-MDS and t-AML has often been short, 12 months or less in 27% of the patients. Bone marrow pathology of early cases of t-MDS after ASCT has often been neither diagnostic nor prognostic, but most patients presented chromosome aberrations, primarily deletions or loss of the long arms of chromosomes 5 and 7. The prognosis was in general poor, although 17% with indolent t-MDS survived more than 18 months from diagnosis, and most of these presented a normal karyotype or a single chromosome aberration.

Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis.

OBJECTIVES: To determine the effect of repeated doses of aerosolized recombinant human deoxyribonuclease (rhDNase) on the development of anti-rhDNase antibodies, acute allergic reactions, and pulmonary function in patients with cystic fibrosis. DESIGN: A multicenter, open-label study in which 184 patients received 10 mg aerosolized rhDNase twice a day for 14 days followed by a 14-day washout period for a total of 6 treatment cycles. Serial determinations of anti-rhDNase antibodies and pulmonary functions were performed. RESULTS: Detectable anti-rhDNase antibodies developed in 16 (8.7%) patients. These patients had no changes in their symptoms from the time they entered the trial. Antibodies detected were all of the IgG isotype. Increases in both forced expired volume in 1 second and forced vital capacity were noted from the beginning to the end of each cycle of treatment returning to baseline during the off-treatment period of each cycle. Seropositivity to rhDNase was not associated with allergic reactions and had no relationship on improvement in pulmonary function. CONCLUSIONS: Development of anti-rhDNase antibodies occurred in a small number of patients and was not associated with side effects. Intermittent administration of rhDNase for 24 weeks to patients with cystic fibrosis was well tolerated and was not associated with anaphylaxis in any patient. Pulmonary function improved significantly during the 14-day cycles while rhDNase was administered and returned to baseline when rhDNase was discontinued.

Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.

We tested the hypothesis that recombinant human deoxyribonuclease 1 (rhDNase) reduces airflow obstruction and improves mucociliary clearance in patients with cystic fibrosis (CF), and that improvements seen in FEV1 and FVC after rhDNase treatment are independent of chest physical therapy (CPT). CF patients inhaled placebo (10 patients) or 2.5 mg rhDNAse aerosol (10 patients) twice a day for six consecutive days. Compared with baseline, there were no statistically significant differences between the two study groups by Day 6 for indices of airflow obstruction obtained from gamma-camera images of the right lung following inhalation of 99mTc aerosol, or for mucociliary clearance or the rate of clearance of the radioaerosol, quantified over a 6-h period. By Day 6, FEV1 and FVC were significantly higher in the rhDNase-treated group than in the placebo group, increasing by an average of 9.4 +/- 3.5% and 12.7 +/- 2.6%, respectively, as compared with a decrease of 1.8 +/- 1.7% and an increase of 0.4 +/- 1.1%, respectively (p < 0.05). There was no significant change in the FEV1/FVC ratio on Day 6 (0.68 +/- 0.05) compared with baseline (0.70 +/- 0.05) in the rhDNase group. On Day 6, FEV1 and FVC decreased after CPT in both study groups, but the decreases were not significant. Our results indicate that aerosolized rhDNase improves FEV1 and FVC independent of CPT. We were unable to demonstrate that rhDNase reduces airflow obstruction or improves mucociliary clearance.

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.

BACKGROUND: Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS: We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS: One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS: In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

Computer-assisted data collection in multicenter epidemiologic research. The Atherosclerosis Risk in Communities Study.

The Atherosclerosis Risk in Communities (ARIC) Study uses a computer-assisted data collection (CADC) system in which staff at four Field Centers directly record into microcomputers much of the data obtained from the 16,000 study participants during 4 hours of interviews and exams. A pilot study was conducted to evaluate the feasibility of training Field Center staff in the use of a CADC system and to assess study participants' reaction to such a system. When asked to compare CADC to a paper-based system, all five of the pilot study staff members preferred the CADC system. The 16 pilot study participants either had no preference (63%) or preferred CADC (37%). With respect to data quality, no systematic differences between the two methods of data collection were evident in the pilot study. The CADC system required approximately 10% longer for data collection, keying, and editing than the paper-based system took for collection alone. Immediate data entry in a CADC system may improve data quality by eliminating a transcription step and by allowing prompt detection of suspicious values while the participant is still available to provide confirmation or correction. CADC simplifies data collection by automating complex branching questions and can enhance data completeness. The ARIC CADC system is based on commercially available software customized by the study's Coordinating Center. The microcomputer-based CADC system described in this report may serve as the prototype for future epidemiologic studies that collect standardized data on large numbers of participants at a small number of sites.