Cross-calibration of dual-energy X-ray densitometers for a large, multi-center genetic study of osteoporosis

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and an increased risk of fragility fractures. Bone mineral density (BMD) is the most important determinant of osteoporotic fracture risk, but the genes responsible for BMD regulation and fracture are incompletely defined. To enable multi-center studies to examine the genetic influences on BMD there is a requirement to standardize measurements across different manufacturers of bone densitometers, different versions of machines and different normative ranges. This paper describes a method developed to allow near-identical subjects with low age-adjusted BMD (based on Z-scores) to be recruited in 17 centers using 27 different densitometers. Cross-calibration was based on measurements using a European spine phantom circulated to all centers and measured ten times on each individual machine. From theses values an individual exponential curve, based on nominal versus observed BMD, was derived for each machine. As expected, there were large and significant variations in nominal BMD values, not only between scanners from different manufacturers but also between different versions of scanners from the same manufacturer. Hologic scanners tended to underestimate the nominal BMD, while Lunar scanners overestimated the value. Norland scanners gave mixed values over estimating BMD at the lower nominal value (0.5 g/cm²) while underestimating the value at the higher value (1.5 g/cm²). The validity of the exponential equations was tested using hip and spine measurements on 991 non-proband women from a familial osteoporosis study (FAMOS). After cross-calibration there was a considerable reduction in variation between machines. This observation, coupled with the absence of a similar reduction in variation attributable to a linear regression on age, demonstrated the validity of the cross-calibration approach. Use of the cross-calibration curves along with a standard normative range (in the case of this study, the Hologic normative range) allowed age-specific Z-scores to be used as an inclusion criterion in this genetic study, a method that will be useful for other trials where age-specific BMD inclusion criteria are required.     

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.     

Hemorrhagic and nonhemorrhagic brain lesions: evaluation with 0.35-T fast MR imaging

Two fast magnetic resonance (MR) imaging techniques, advanced Fourier and partial-flip imaging, were used at 0.35 T to examine 21 patients with suspected intracranial lesions; the results were quantitatively compared with a conventional spin-echo study. Both of the fast MR techniques yielded a fourfold reduction in imaging time per section. The advanced Fourier sequence showed contrast that was identical to the conventional spin-echo study with signal-to-noise ratios of 58% and 57% for the first and second echoes, respectively. The partial-flip sequence showed a contrast of 109% and 57% for lesions versus substantia alba, and 107% and 78% for substantia grisea versus substantia alba relative to the first and second echoes of the conventional spin-echo study. The partial-flip sequence was particularly sensitive to magnetic susceptibility; this produced artifacts that may undermine the usefulness of partial flip for routine screening in certain parts of the brain. However, this susceptibility significantly improved the detection of intracranial hemorrhage when compared with the spin-echo sequence, particularly when combined with phase mapping of the partial-flip study.     

Dietary selenium's protective effects against methylmercury toxicity

Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity. Mercury exposures that are uniformly neurotoxic and lethal among animals fed low dietary Se are far less serious among those with normal Se intakes and are without observable consequences in those fed Se-enriched diets. Although these effects have been known since 1967, they have only lately become well understood. Recent studies have shown that Se-enriched diets not only prevent MeHg toxicity, but can also rapidly reverse some of its most severe symptoms. It is now understood that MeHg is a highly specific, irreversible inhibitor of Se-dependent enzymes (selenoenzymes). Selenoenzymes are required to prevent and reverse oxidative damage throughout the body, particularly in the brain and neuroendocrine tissues. Inhibition of selenoenzyme activities in these vulnerable tissues appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity. Because Hg's binding affinities for Se are up to a million times higher than for sulfur, its second-best binding partner, MeHg inexorably sequesters Se, directly impairing selenoenzyme activities and their synthesis. This may explain why studies of maternal populations exposed to foods that contain Hg in molar excess of Se, such as shark or pilot whale meats, have found adverse child outcomes, but studies of populations exposed to MeHg by eating Se-rich ocean fish observe improved child IQs instead of harm. However, since the Se contents of freshwater fish are dependent on local soil Se status, fish with high MeHg from regions with poor Se availability may be cause for concern. Further studies of these relationships are needed to assist regulatory agencies in protecting and improving child health.     

Comparison of Methodologies for Calculating Quality Measures Based on Administrative Data versus Clinical Data from an Electronic Health Record System: Implications for Performance Measures

New reimbursement policies and pay-for-performance programs to reward providers for producing better outcomes are proliferating. Although electronic health record (EHR) systems could provide essential clinical data upon which to base quality measures, most metrics in use were derived from administrative claims data. We compared commonly used quality measures calculated from administrative data to those derived from clinical data in an EHR based on a random sample of 125 charts of Medicare patients with diabetes. Using standard definitions based on administrative data (which require two visits with an encounter diagnosis of diabetes during the measurement period), only 75% of diabetics determined by manually reviewing the EHR (the gold standard) were identified. In contrast, 97% of diabetics were identified using coded information in the EHR.The discrepancies in identified patients resulted in statistically significant differences in the quality measures for frequency of HbA1c testing, control of blood pressure, frequency of testing for urine protein, and frequency of eye exams for diabetic patients. New development of standardized quality measures should shift from claims-based measures to clinically based measures that can be derived from coded information in an EHR. Using data from EHRs will also leverage their clinical content without adding burden to the care process.