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.

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.

Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer.

Urokinase plasminogen activator (uPA) regulates a proteolytic cascade that facilitates cancer invasion through degradation of the extracellular matrix, and high levels of uPA in human breast cancer tissue correlate with poor prognosis. We previously found that, in ductal breast cancer, uPA mRNA is highly expressed by myofibroblasts surrounding invasively growing cancer cells. However, the localization of uPA protein has not been settled in the published literature. Because uPA is a secreted molecule, it could conceivably be localized differently from its mRNA. We have studied the localization of uPA immunoreactivity in detail. Twenty-five cases of invasive ductal carcinoma were analyzed with three different uPA antibody preparations, all of which gave an essentially identical stromal staining pattern. Using double immunofluorescence, we identified uPA immunoreactivity in myofibroblasts and macrophages in all cases examined. Additionally, in approximately half of the tumors, we saw uPA staining of endothelial cells. In 3 of the 25 cases, a small subpopulation of the cancer cells was uPA-positive. We conclude that uPA immunoreactivity is almost exclusively associated with stromal cells, which thus play a major role in generation of proteolytic activity in ductal breast cancer.

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 precise and efficient stereological method for determining murine lung metastasis volumes.

We have developed a computer-assisted stereological method based on unbiased principles for estimating metastasis volumes in mouse lungs. We evaluated this method using the transplantable Lewis lung carcinoma. Twenty-one days after subcutaneous inoculation of 10(6) Lewis lung cells into C57BL/6J mice, the mice had primary tumors with an average volume of 2300 mm(3). After perfusion fixation, the lungs were removed, embedded in OCT compound, snap-frozen, and processed for stereology. The metastasis volumes were estimated by application of the Cavalieri principle after evaluation of single sections from several evenly distributed tissue levels. The metastasis volume in a group of nine mice varied between 0.01 and 14.4 mm(3), with an average of 6.1 mm(3). The coefficient of variation was 0.9. The coefficient of error of the volume estimation was determined in five cases and varied from 0.08 to 0.23. Thus, the variation on the metastasis volumes that is achieved by this method contributes very little, 2.5%, to the total variance within the group of mice. In conclusion, we have developed an efficient and unbiased method to determine the metastasis burden in mouse lungs.

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.

Successful systems integration strategies: the access program for persons who are homeless and mentally ill.

In 1993, the Access to Community Care and Effective Services and Supports (ACCESS) federal demonstration program was initiated. Using a quasi-experimental design, the 5-year demonstration program sought to assess the impact of integrated systems of care on outcomes for homeless persons with mental illness. The authors report on which integration strategies were chosen and how their implementation is quantified. Data collected primarily through annual site visits revealed that only two strategies were used by all nine systems. The systems integration strategies employed remained relatively stable over the 5 years. Successful implementation appears to be related to the strategies selected.

Synthesis and posttranslational regulation of pyruvate formate-lyase in Lactococcus lactis.

The enzyme pyruvate formate-lyase (PFL) from Lactococcus lactis was produced in Escherichia coli and purified to obtain anti-PFL antibodies that were shown to be specific for L. lactis PFL. It was demonstrated that activated L. lactis PFL was sensitive to oxygen, as in E. coli, resulting in the cleavage of the PFL polypeptide. The PFL protein level and its in vivo activity and regulation were shown by Western blotting, enzyme-linked immunosorbent assay, and metabolite measurement to be dependent on the growth conditions. The PFL level during anaerobic growth on the slowly fermentable sugar galactose was higher than that on glucose. This shows that variation in the PFL protein level may play an important role in the regulation of metabolic shift from homolactic to mixed-acid product formation, observed during growth on glucose and galactose, respectively. During anaerobic growth in defined medium, complete activation of PFL was observed. Strikingly, although no formate was produced during aerobic growth of L. lactis, PFL protein was indeed detected under these conditions, in which the enzyme is dispensable due to the irreversible inactivation of PFL by oxygen. In contrast, no oxygenolytic cleavage was detected during aerobic growth in complex medium. This observation may be the result of either an effective PFL deactivase activity or the lack of PFL activation. In E. coli, the PFL deactivase activity resides in the multifunctional alcohol dehydrogenase ADHE. It was shown that in L. lactis, ADHE does not participate in the protection of PFL against oxygen under the conditions analyzed. Our results provide evidence for major differences in the mechanisms of posttranslational regulation of PFL activity in E. coli and L. lactis.

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.

TPW22, a lactococcal temperate phage with a site-specific integrase closely related to Streptococcus thermophilus phage integrases.

The temperate phage TPW22, induced from Lactococcus lactis subsp. cremoris W22, and the evolutionarily interesting integrase of this phage were characterized. Phage TPW22 was propagated lytically on L. lactis subsp. cremoris 3107, which could also be lysogenized by site-specific integration. The attachment site (attP), 5'-TAAGGCGACGGTCG-3', of phage TPW22 was present on a 7.5-kb EcoRI fragment, a 3.4-kb EcoRI-HindIII fragment of which was sequenced. Sequence information revealed the presence of an integrase gene (int). The deduced amino acid sequence showed 42 and 28% identity with integrases of streptococcal and lactococcal phages, respectively. The identities with these integrase-encoding genes were 52 and 45%, respectively, at the nucleotide level. This could indicate horizontal gene transfer. A stable integration vector containing attP and int was constructed, and integration in L. lactis subsp. cremoris MG1363 was obtained. The existence of an exchangeable lactococcal phage integration module was suggested. The proposed module covers the phage attachment site, the integrase gene, and surrounding factor-independent terminator structures. The phages phiLC3, TP901-1, and TPW22 all have different versions of this module. Phylogenetically, the TPW22 Int links the phiLC3 lactococcal integrase with known Streptococcus thermophilus integrases.

Case management models for persons who are homeless and mentally ill: the ACCESS demonstration project. Access to Community Care and Effective Services and Supports.

Persons who are homeless and mentally ill present unique challenges to service providers and human service systems. In vivo case management approaches such as assertive community treatment (ACT) have shown promise in engaging this population. This paper explores case management models employed within the ACCESS program, a five year, 18-site demonstration program enriching services for homeless persons with serious mental illness. We describe the implementation of case management with ACCESS programs and determine the extent of variation across sites using a measure of fidelity to ACT. While programs reported using four models, much similarity was found among programs on multiple dimensions.

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.

Different paths to justice: the ADA, employment, and administrative enforcement by the EEOC and FEPAs.

Under Title I of the ADA, individuals who believe they have been subjected to disability-based employment discrimination may file an administrative charge. This article looks at who files charges; over what issues, and with what outcomes in both Equal Employment Opportunity Commission (EEOC) field offices, and state and local fair employment practice agencies (FEPAs). The data for the article are computerized records of all ADA charges filed through March 31, 1998. The data indicate that individuals who rely on a FEPA to investigate their charge have a greater likelihood of obtaining a beneficial outcome than individuals who rely on the EEOC, but proportionately more individuals receiving a beneficial outcome are likely to receive monetary benefits from the EEOC than from a FEPA. Further, those who receive beneficial outcomes will probably receive greater monetary benefits from charges investigated by the EEOC than from those investigated by a FEPA.

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.