Lori C. Guthrie

Time perspective and socioeconomic status: a link to socioeconomic disparities in health?

Time perspective is a measure of the degree to which ones thinking is motivated by considerations of the future, present, or past. Time perspective has been proposed as a potential mediator of socioeconomic disparities in health because it has been associated with health behaviors and is presumed to vary with socioeconomic status. In this cross-sectional community-based survey of respondents recruited from hair salons and barber shops in a suburb of Washington DC, we examined the association between time perspective and both education level and occupation. We asked participants (N=525) to complete a questionnaire that included three subscales (future, present-fatalistic, and present-hedonistic) of the Zimbardo Time Perspective Inventory. Participants with more formal education and those with professional occupations had higher scores on the future time perspective subscale, and lower scores on the present-fatalistic subscale, than participants with less formal education or a non-professional occupation. Present-fatalistic scores were also higher among participants whose parents had less formal education. Present-hedonistic scores were not associated with either education level or professional occupation. Time perspective scores were not independently associated with the likelihood of obesity, smoking, or exercise. In this community sample, future time perspective was associated with current socioeconomic status, and past-fatalistic time perspective was associated with both current and childhood socioeconomic status.

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Tumor localization and biochemical response to cure in tumor-induced osteomalacia

Tumor‐induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor‐23 (FGF23)‐secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with 111Indium‐octreotide with single photon emission computed tomography (octreo‐SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG‐PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo‐SPECT imaging, and 16 of 20 FDG‐PET/CT imaging. Eighteen of 19 (95%) were positive on octreo‐SPECT, and 14 of 16 (88%) on FDG‐PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo‐SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG‐PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease‐free at last follow‐up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C‐terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25‐dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo‐SPECT was more sensitive and specific, but in many cases FDG‐PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Clinically important changes in individual and composite measures of rheumatoid arthritis activity: thresholds applicable in clinical trials.

Objective Thresholds of minimal clinically important improvement (MCII) are needed to plan and interpret clinical trials. We estimated MCIIs for the rheumatoid arthritis (RA) activity measures of patient global assessment, pain score, Health Assessment Questionnaire Disability Index (HAQ), Disease Activity Score-28 (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Methods In this prospective longitudinal study, we studied 250 patients who had active RA. Disease activity measures were collected before and either 1 month (for patients treated with prednisone) or 4 months (for patients treated with disease modifying medications or biologics) after treatment escalation. Patient judgments of improvement in arthritis status were related to prospectively assessed changes in the measures. MCIIs were changes that had a specificity of 0.80 for improvement based on receiver operating characteristic curve analysis. We used bootstrapping to provide estimates with predictive validity. Results At baseline, the mean (±SD) DAS28-ESR (erythrocyte sedimentation rate) was 6.16±1.2 and mean SDAI was 38.6±14.8. Improvement in overall arthritis status was reported by 167 patients (66.8%). Patients were consistent in their ratings of improvement versus no change or worsening, with receiver operating characteristic curve areas ≥0.74. MCIIs with a specificity for improvement of 0.80 were: patient global assessment −18, pain score −20, HAQ −0.375, DAS28-ESR −1.2, DAS28-CRP (C-reactive protein) −1.0, SDAI −13, and CDAI −12. Conclusions MCIIs for individual core set measures were larger than previous estimates. Reporting the proportion of patients who meet these MCII thresholds can improve the interpretation of clinical trials in RA.

Comparison of the Construct Validity and Sensitivity to Change of the Visual Analog Scale and a Modified Rating Scale as Measures of Patient Global Assessment in Rheumatoid Arthritis

Objective. Patient global assessment (PGA) is commonly measured using a visual analog scale (VAS). The VAS asks patients to integrate many dimensions of rheumatoid arthritis (RA) activity, yet its scope is poorly defined and its endpoints are vague. We investigated whether a modified Rating Scale that used marker states and more defined endpoints would provide a more valid measure of PGA. Methods. In our prospective longitudinal study, 164 patients with active RA rated their global arthritis activity using the VAS and Rating Scale before and after treatment. To compare construct validity, we correlated each score with 2 reference measures of RA activity, the 28-joint count Disease Activity Score (DAS28) and the physician global assessment, and examined how each measure was associated with different aspects of RA activity, including pain, functioning, and depressive symptoms, in multivariate regression analyses. We also examined sensitivity to change. Results. Both measures were correlated with the DAS28 (r = 0.39 for VAS; r = 0.35 for Rating Scale) and physician global assessment (r = 0.41 for VAS; r = 0.26 for Rating Scale) at the baseline visit. Pain and depressive symptoms had the strongest association with the VAS, while functional limitations and depressive symptoms had the strongest association with the Rating Scale. Residual analysis showed no differences in heterogeneity of patients’ ratings. VAS was more sensitive to change than the Rating Scale (standardized response means of 0.55 and 0.45). Conclusion. As measures of PGA, the VAS and Rating Scale had comparable construct validity, but differed in which aspects of arthritis activity influenced scores. VAS was more sensitive to change.

In-111 DTPA-octreotide scintigraphy for disease detection in metastatic thyroid cancer: comparison with F-18 FDG positron emission tomography and extensive conventional radiographic imaging.

Purpose The utility of In-111 DTPA octreotide scintigraphy (SRS) for disease detection in patients with metastatic thyroid carcinoma (TCA) remains controversial. The authors compared the sensitivity of In-111–based SRS, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and extensive conventional radiographic imaging (CRI) in this type of cancer. Methods SRS, FDG PET, and CRI were performed concurrently in 21 patients (age, 56.4 ± 12.9 years) who had aggressive TCA. Concordance rates % of lesion positivity among pairs of different techniques (A and B) were calculated as the ratio of the number of lesions positive with both techniques divided by the sum of the total number of lesions positive with technique A + total number of lesions positive with technique B, which was then multiplied by 200. Results The combined use of CRI, FDG PET, and SRS resulted in the detection of 105 lesions, presumed to be due to metastatic deposits. Sensitivities for SRS and FDG-PET imaging were 49.5% and 67.6%, respectively. The lesion detection concordance rates were as follows: CRI versus FDG PET, 80.8%; CRI versus SRS, 74.2%; and FDG-PET versus SRS, 58.6%. Importantly, SRS detected five unexpected lesions, which were negative by both CRI and FDG-PET imaging. In two representative patients, a positive correlation (Spearman’s rank = 0.71;P = 0.0576) existed between the percentage of lesional In-111 DTPA octreotide uptake and the standard uptake value in eight concordant lesions. Conclusion Although SRS has only moderate sensitivity for disease detection in metastatic TCA, sometimes it can reveal lesions that otherwise would be undetectable by either CRI or FDG-PET imaging.

Time perspective and medication adherence among individuals with hypertension or diabetes mellitus

OBJECTIVE The study determined if time perspective was associated with medication adherence among people with hypertension and diabetes. METHODS Using the Health Beliefs Model, we used path analysis to test direct and indirect effects of time perspective and health beliefs on adherence among 178 people who participated in a community-based survey near Washington, D.C. We measured three time perspectives (future, present fatalistic, and present hedonistic) with the Zimbardo Time Perspective Inventory and medication adherence by self-report. RESULTS The total model demonstrated a good fit (RMSEA=0.17, 90% CI [0.10, 0.28], p=0.003; comparative fit index=0.91). Future time perspective and age showed direct effects on increased medication adherence; an increase by a single unit in future time perspective was associated with a 0.32 standard deviation increase in reported adherence. There were no significant indirect effects of time perspective with reported medication adherence through health beliefs. CONCLUSION The findings provide the first evidence that time perspective plays an under-recognized role as a psychological motivator in medication adherence. PRACTICE IMPLICATIONS Patient counseling for medication adherence may be enhanced if clinicians incorporate consideration of the patients time perspective.

Time perspective and smoking, obesity, and exercise in a community sample.

OBJECTIVE To examine associations between time perspective and smoking, body mass index, and exercise. METHODS In this community-based survey, adults reported smoking and exercise habits and weight and height and completed the Zimbardo Time Perspective Inventory. RESULTS Subjects (N=265) who were more future oriented reported more frequent exercise, but were more likely to smoke. Fatalistic and hedonistic present orientations were not associated with smoking, obesity, or exercise. CONCLUSIONS Time perspective is not consistently associated with common health behaviors in adults.

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Familial tumoral calcinosis (FTC)/hyperostosis‐hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor‐23 (FGF23), N‐acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25‐dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C‐terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C‐reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia‐inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin‐1 (IL‐1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well‐being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL‐1 antagonists suggests that anti‐inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

Domain-specific transition questions demonstrated higher validity than global transition questions as anchors for clinically important improvement

OBJECTIVES Estimates of minimal clinically important differences in health measures may be affected by the anchor used. We examined if domain-specific transition questions had higher construct validity than global health transition questions as anchors for measures in a given domain. STUDY DESIGN AND SETTING In a prospective study of 249 patients with rheumatoid arthritis, we examined changes in pain, physical function, joint swelling, stiffness, fatigue, and depression with treatment. We related these changes to a domain-specific transition question, global arthritis transition question, and the Short Form-36 (SF-36) health transition item. RESULTS Changes in all six clinical measures were more highly correlated with the domain-specific transition questions than with the global arthritis question and SF-36 transition question. Discrimination between patients who improved or not was also better using domain-specific questions. Estimates of minimal clinically important improvement (MCII) differed with the anchor when these were based on mean changes. MCII estimates from receiver operating characteristic curve analysis were not influenced by the choice of anchor when anchors had high agreement. CONCLUSION Domain-specific transition questions had higher construct validity as anchors for determining clinically important differences in health measures focused on a single domain than either global disease or general health transition questions.