Development and validation of a prediction model for incident hand osteoarthritis in the HUNT study.

OBJECTIVE: To develop and externally validate prediction models for incident hand osteoarthritis (OA) in a large population-based cohort of middle aged and older men and women. DESIGN: We included 17,153 men and 18,682 women from a population-based cohort, aged 35-70 years at baseline (1995-1997). Incident hand OA were obtained from diagnostic codes in the Norwegian National Patient Register (1995-2018). We studied whether a range of self-reported and clinically measured predictors could predict hand OA, using the Area Under the receiver-operating Curve (AUC) from logistic regression. External validation of an existing prediction model for male hand OA was tested on discrimination in a sample of men. Bootstrapping was used to avoid overfitting. RESULTS: The model for men showed modest discriminatory ability (AUC = 0.67, 95% CI 0.62-0.71). Adding a genetic risk score did not improve prediction. Similar discrimination was observed in the model for women (AUC = 0.62, 95% CI 0.59-0.64). Prediction was not improved by adding a genetic risk score or hormonal and reproductive factors. Applying external validation, similar results were observed among men in HUNT (The Nord-Trøndelag Health Study) as in the developmental sample (AUC = 0.62, 95% CI 0.57-0.65). CONCLUSION: We developed prediction models for incident hand OA in men and women. For women, the model included body mass index (BMI), heavy physical work, high physical activity and perceived poor health. The model showed moderate discrimination. For men, we have shown that a prediction model including BMI, education and information on sleep can predict incident hand OA in several populations with moderate discriminative ability.

The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT study.

BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.

Age of menarche is associated with knee joint replacement due to primary osteoarthritis (The HUNT Study and the Norwegian Arthroplasty Register).

OBJECTIVE: To investigate whether parity, age at menarche, menopausal status, age at menopause, use of oral contraceptives (OC) or use of hormone replacement therapy (HRT) were associated with total knee replacement (TKR) or total hip replacement (THR) due to primary osteoarthritis. METHOD: In a prospective cohort study of 30,289 women from the second and third surveys of the Nord-Trøndelag Health Study, data were linked to the Norwegian Arthroplasty Register (NAR) in order to identify TKR or THR due to primary osteoarthritis. Cox proportional hazards models were used to estimate the hazard ratios (HRs). RESULTS: We observed 430 TKRs and 675 THRs during a mean follow-up time of 8.3 years. Increasing age at menarche was inversely associated with the risk of TKR (P-trend < 0.001). Past users and users of systemic HRT were at higher risk of TKR compared to never users (HR 1.42 (95% confidence interval (CI) 1.06-1.90) and HR 1.40 (95% CI 1.03-1.90), respectively). No association was found between parity, age at menarche, menopausal status, age at menopause, oral contraceptive use or HRT use and THR. CONCLUSION: We found that increasing age at menarche reduced the risk of TKR. Past users and users of systemic HRT were at higher risk of TKR compared to never users. Parity did not increase the risk of THR or TKR.

The causal role of smoking on the risk of hip or knee replacement due to primary osteoarthritis: a Mendelian randomisation analysis of the HUNT study.

OBJECTIVE: Smoking has been associated with a reduced risk of hip and knee osteoarthritis (OA) and subsequent joint replacement. The aim of the present study was to assess whether the observed association is likely to be causal. METHOD: 55,745 participants of a population-based cohort were genotyped for the rs1051730 C > T single-nucleotide polymorphism (SNP), a proxy for smoking quantity among smokers. A Mendelian randomization analysis was performed using rs1051730 as an instrument to evaluate the causal role of smoking on the risk of hip or knee replacement (combined as total joint replacement (TJR)). Association between rs1051730 T alleles and TJR was estimated by hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were adjusted for age and sex. RESULTS: Smoking quantity (no. of cigarettes) was inversely associated with TJR (HR 0.97, 95% CI 0.97-0.98). In the Mendelian randomization analysis, rs1051730 T alleles were associated with reduced risk of TJR among current smokers (HR 0.84, 95% CI 0.76-0.98, per T allele), however we found no evidence of association among former (HR 0.97, 95% CI 0.88-1.07) and never smokers (HR 0.97, 95% CI 0.89-1.06). Neither adjusting for body mass index (BMI), cardiovascular disease (CVD) nor accounting for the competing risk of mortality substantially changed the results. CONCLUSION: This study suggests that smoking may be causally associated with the reduced risk of TJR. Our findings add support to the inverse association found in previous observational studies. More research is needed to further elucidate the underlying mechanisms of this causal association.

Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation.

Analysis of extracellular matrix degradation systems has led to the insight that in cancer invasion there is often crucial interplay between cancer cells and several types of surrounding non-neoplastic stromal cells. Likewise, in normal tissue remodeling processes, the synthesis of proteolytic components is often distributed between several cell types, and there are strong similarities between neoplastic and non-neoplastic processes in the same tissue. Thus, tissue remodeling events are excellent models for studies of extracellular proteolysis in cancer. This has become even clearer by recent analyses of genetically modified mice.

Mutational analysis of a ras catalytic domain.

We used linker insertion-deletion mutagenesis to study the catalytic domain of the Harvey murine sarcoma virus v-rasH transforming protein, which is closely related to the cellular rasH protein. The mutants displayed a wide range of in vitro biological activity, from those that induced focal transformation of NIH 3T3 cells with approximately the same efficiency as the wild-type v-rasH gene to those that failed to induce any detectable morphologic changes. Correlation of transforming activity with the location of the mutations enabled us to identify three nonoverlapping segments within the catalytic domain that were dispensable for transformation and six other segments that were required for transformation. Segments that were necessary for guanosine nucleotide (GDP) binding corresponded to three of the segments that were essential for transformation; two of the three segments share strong sequence homology with other purine nucleotide-binding proteins. Loss of GDP binding was associated with apparent instability of the protein. Lesions in two of the three other required regions significantly reduced GDP binding, while small lesions in the last required region did not impair GDP binding or membrane localization. We speculate that this latter region interacts with the putative cellular target of ras. The results suggest that transforming ras proteins require membrane localization, guanosine nucleotide binding, and an additional undefined function that may represent interaction with their target.

A transforming ras gene can provide an essential function ordinarily supplied by an endogenous ras gene.

Microinjection of monoclonal antibody Y13-259, which reacts with all known mammalian and yeast ras-encoded proteins, has previously been shown to prevent NIH 3T3 cells from entering the S phase (L. S. Mulcahy, M. R. Smith, and D. W. Stacey, Nature [London] 313:241-243, 1985). We have now found several transformation-competent mutant v-rasH genes whose protein products in transformed NIH 3T3 cells are not immunoprecipitated by this monoclonal antibody. These mutant proteins are, however, precipitated by a different anti-ras antibody. Each of these mutants lacks Met-72 of v-rasH. In contrast to the result for cells transformed by wild-type v-rasH, Y13-259 microinjection of NIH 3T3 cells transformed by these mutant ras genes did not prevent the cells from entering the S phase. These results imply that a transformation-competent ras gene can supply a normal essential function for NIH 3T3 cells. When the proteins encoded by the mutant ras genes were overproduced in Escherichia coli, several mutant proteins that lacked Met-72 failed to bind Y13-259 in a Western blot. However, a ras protein from a mutant lacking amino antibody, but a ras protein from a mutant lacking amino acids 72 to 84 did not. These results suggest that Y13-259 may bind to a higher ordered structure that has been restored in the mutant lacking amino acids 72 to 82.

Essential AP-1 and PEA3 binding elements in the human urokinase enhancer display cell type-specific activity.

We have characterized a transcriptional enhancer of the human urokinase-type plasminogen activator (uPA) gene in three transformed human cell lines: HeLa, HepG2 and HT1080. The enhancer is located approximately 2 kbp upstream of the mRNA cap site and is active in all three cell lines. By footprinting and gel retardation analysis we found that it contained two binding sites for transcription factor AP-1, encoded by the fos and jun proto-oncogene families. The most upstream of these sites was juxtaposed to a binding site for PEA3, a product of the ets/Spi proto-oncogene family. By transient transfection analysis of deletions, point mutations and subcloned fragments, we found these sites to be crucial for enhancer activity. However, the sites displayed differences in activity in the three different cell lines. The downstream AP-1 site was almost exclusively responsible for enhancer activity in HeLa cells, whereas the AP-1/PEA3 site played a major role in HT1080 and HepG2 cells. The implications of our findings for the known regulation of uPA expression by transforming oncogenes, adenovirus E1A protein and glucocorticoids are discussed.

Service delivery and community: social capital, service systems integration, and outcomes among homeless persons with severe mental illness.

OBJECTIVES: This study evaluated the influence of features of community social environment and service system integration on service use, housing, and clinical outcomes among homeless people with serious mental illness. STUDY SETTING: A one-year observational outcome study was conducted of homeless people with serious mental illness at 18 sites. DATA SOURCES: Measures of community social environment (e.g., social capital) were based on local surveys and voting records. Housing affordability was assessed with housing survey data. Service system integration was assessed through interviews with key informants at each site to document interorganizational transactions. Standardized clinical measures were used to assess clinical and housing outcomes in face-to-face interviews. RESEARCH DESIGN: Structural equation modeling was used to determine the relationship between (1) characteristics of the social environment (social capital, housing affordability); (2) the level of integration of the service system for persons who are homeless in each community; (3) access to and use of services by individual clients; and (4) successful exit from homelessness or clinical improvement. PRINCIPAL FINDINGS: Social capital was associated with greater service systems integration, which was associated in turn with greater access to assistance from a public housing agency and to a greater probability of exiting from homelessness at 12 months. Housing affordability also predicted exit from homelessness. Neither environmental factors nor systems integration predicted outcomes for psychiatric problems, substance abuse, employment, physical health, or income support. CONCLUSION: Community social capital and service system integration are related through a series of direct and indirect pathways with better housing outcomes but not with superior clinical outcomes for homeless people with mental illness. Implications for designing improved service systems are discussed.

A resident-based reimbursement system for intermediate care facilities for the mentally retarded.

In this article, the authors present a resident-based reimbursement system for intermediate care facilities for the mentally retarded (ICFs-MR), which represent a large and growing proportion of the medicaid budget. The statistical relationship between resident disability level and the expected cost of caring for the individual is estimated, allowing for the prediction of expected resource use across the population of ICF-MR residents. The system incorporates an indirect cost rate, a base direct care rate (constant across all providers), and an individual-specific direct care rate, based on the expected cost of care.

Service system performance and integration: a baseline profile of the ACCESS demonstration sites. Access to Community Care and Effective Services and Supports.

OBJECTIVE: Networks of agencies at the 18 demonstration sites in the Access to Community Care and Effective Services and Supports (ACCESS) program for homeless persons with serious mental illness were surveyed to profile baseline levels of systems performance and integration as part of a longitudinal evaluation of systems change and client outcomes. METHODS: Interviews were conducted with a representative from each of 875 agencies in the 18 service networks. Information was obtained about the perceived performance of the service system and the extent of systems integration as measured by client referrals, funds exchanges, and information sharing between agencies. Measures consisted of two multi-item scales assessing the accessibility and coordination of services for the target population in each community and four indexes of interagency relationships. RESULTS: Services at baseline for homeless mentally ill persons at the program sites were rated as relatively inaccessible, and the coordination of services between agencies was rated as even more problematic. Interagency ties were largely based on client referrals and information exchanges, with very few instances of funding transfers in the form of contracts or grants. On average, at baseline agencies that had received an ACCESS grant were better connected to their local service network than were other agencies. CONCLUSIONS: Consistent with the premise of the ACCESS demonstration, services for persons who are homeless and mentally ill in urban America are fragmented and not very accessible. The longitudinal design of the evaluation will allow for an assessment of efforts to improve services and systems integration and of the effects of these improvements on client outcomes.

The EEOC charge priority policy and claimants with psychiatric disabilities.

OBJECTIVE: In June 1995 the U.S. Equal Employment Opportunity Commission (EEOC) instituted a new charge priority policy. Under the new policy, charges are classified as one of three priority levels during or immediately after intake. Only charges assigned a high priority receive a full investigation. This paper examines the effect of the charge priority policy on individuals with psychiatric disabilities who filed Americans With Disabilities Act (ADA) charges with the EEOC. METHODS: Using data extracted from the EEOC's charge data system, the authors analyzed all 66,298 ADA claims prioritized and closed between June 1995 and March 1998. The z test for difference in proportions and the generalized estimating equations procedure were used. The primary outcome measure was the priority assignment received by ADA claimants. RESULTS: Charges that received a high priority assignment were more likely to result in benefits for claimants. Charges filed by claimants with psychiatric disabilities were significantly less likely to be assigned a high priority than charges filed by other claimants. Claimants with psychiatric disabilities were also significantly less likely to benefit from their claims. CONCLUSIONS: The strong relationship between being assigned high priority and receiving benefits as a result of filing a charge demonstrates the importance of accurate priority categorization. The finding that people with psychiatric disabilities are less likely than others to benefit from their claims is cause for concern, particularly given the fact that the accuracy of the charge prioritization system has not been validated.

Outcomes of employment discrimination charges filed under the Americans With Disabilities Act.

OBJECTIVE: The outcomes of employment discrimination charges filed under the Americans With Disabilities Act (ADA) by individuals with psychiatric disabilities and those with other disabilities were compared. METHODS: Data obtained from the Equal Employment Opportunity Commission (EEOC) consisted of all ADA employment claims closed as of March 31, 1998. Charges were categorized by whether they were investigated by the EEOC or by a Fair Employment Practice Agency (FEPA). RESULTS: Of the 175,226 charges filed, 83.2 percent were closed by March 31, 1998. Of these, 15.7 percent brought some kind of benefit to charging parties, although only 1.7 percent resulted in new hires or reinstatements. Of charges investigated by FEPAs, 23.3 percent led to some benefit, compared with 11.5 percent of charges investigated by the EEOC. Of charges investigated by the EEOC, the median actual monetary benefit was $5,646, compared with $2,400 for charges investigated by FEPAs. A total of 13.6 percent of charges filed by individuals with psychiatric disabilities resulted in benefits, compared with a benefit rate of 16 percent for persons with other disabilities. The median actual monetary benefit received by persons with psychiatric disabilities was $5,000, compared with $3,500 for those with nonpsychiatric disabilities. Individuals whose charges were investigated in the first three years of ADA implementation were more likely to receive benefits than individuals whose charges were investigated more recently. CONCLUSIONS: Most employment discrimination charges filed under the ADA do not result in benefits or a finding of reasonable cause. Outcomes for people with psychiatric disabilities do not differ substantially from those for people with other disabilities.

Characterization of rural mental health service systems.

This paper explores two mental health systems in rural North Carolina that provide services to people with severe mental disorders. Recent findings show rural people with mental disorders receive less mental health care than their urban counterparts. This study asks whether rural service systems differ from urban systems in the way that their services are coordinated and structured. A popular conception is that public mental health systems in the United States are uncoordinated with many services provided outside the mental health sector. Rural service providers are seen as even more dependent on nonspecialized mental health providers than their urban counterparts. While many rural service barriers are attributed to the rural environment, little is known about rural service systems and how their organization might contribute to or negate barriers to care. Social network methods were used in this study to compare two rural with four urban systems of care. Findings confirm that mental health systems fit the de facto hypothesis, but that rural systems differ in ways not anticipated by the hypothesis. Rather than being more dependent on nonmental health agencies, rural mental health agencies are more interdependent.

Rural mental health leaders' perceptions of stigma and community issues.

This paper provides a description of the attitudes of rural leaders toward mental health issues using data collected in two rural counties (one in Virginia and one in North Carolina). Study participants (N = 63) are individuals identified as leaders making a significant positive contribution to mental health issues in each county. While the counties were matched on a number of demographic characteristics, the counties had one difference believed important: one had a county mental health center located within the county boundary while the other had no in-county mental health center. The study found that rural leaders believed that other community members held attitudes toward mentally ill persons that were more discriminatory than their own. In addition, rural leaders expressed that mental health was a more important concern to them than it was to the community as a whole. Finally, the importance placed on issues of importance to the community and the resulting issue of priority of relevance varied in response to the occupation of respondents. The study presents an approach to understanding how occupational structures affect community issue priorities among rural leaders.

New patterns of community care: coordinated services for dually diagnosed adults in North Carolina.

North Carolina has developed coordinated care systems for people dually diagnosed with both a mental retardation and a different major mental illness. In response to a class action lawsuit, the state has become a leader in treatment of this form of dual diagnosis. Systems of care for this "Thomas S class" operate in each of 41 area programs for mental health, developmental disabilities, and substance abuse. Networks of care among leaders in mental health and developmental disability promote the coordination of health, housing, social, and vocational services. A survey of 100 area program leaders finds extensive cooperation and a variety of services provided and contracted for, both within and beyond each area program, particularly among developmental disability specialists. Cooperation among leaders is associated with service variety and inter-organizational linkages. The extent of relationships among provider organizations is associated with better access to care. Best practice includes a single portal of entry and inter-agency councils.

A novel and personalized rehabilitation program for obese kidney transplant recipients.

INTRODUCTION: Physical rehabilitation programs for kidney transplant recipients are not routinely personalized to patients' physical and emotional health, which could result in a potentially limited health impact, shorter-term participation, and an overall low success rate. MATERIALS AND METHODS: We conducted an internal review board-approved randomized prospective study involving a 12-month supervised multidisciplinary rehabilitation program (GH method) initiated after kidney transplantation in obese recipients (body mass index >30). The new method incorporates 3 major components: physical exercise, behavioral interventions, and nutritional guidance. We compared 9 patients who underwent supervised rehabilitation with 8 patients who underwent standard care. Patients were followed up after the start of the intervention, and multiple assessments were performed. RESULTS: The adherence to training and follow-up was 100% in the intervention group, compared with 25% at 12 months in the control group. There was a trend for a higher glomerular filtration rate in the intervention group compared with the control group (55.5 ± 18.6 mL/min/1.73 m(2) vs 38.8 ± 18.9 mL/min/1.73 m(2), P = .06). The quality of life (SF-36) mean score improved more in the intervention group compared with the control group (583 ± 13 vs 436 ± 22, P = .008). There was a significantly higher employment rate in the intervention group, 77.7% at 12 months compared with 12.5% in the control group (P = .02). CONCLUSIONS: Our preliminary results suggest that this comprehensive approach to physical rehabilitation can improve adherence, kidney function, quality of life, and employment rate for obese patients after kidney transplantation.