Severe maternal hypothyroidism corrected prior to the third trimester is associated with normal cognitive outcome in the offspring.

BACKGROUND: Concern about potential harmful effects of early maternal hypothyroidism (MH) on fetal brain development has led to calls for universal screening early in, or even before, pregnancy. However, evidence in humans that adverse effects are irreversible if thyroid hormone replacement is initiated after the first trimester is limited. Severe MH due to thyrotropin (TSH) receptor blocking antibodies (Abs) is associated with profound cognitive delay in the offspring if MH is untreated or inadequately treated; here, we sought to determine the outcome if treatment is given in early pregnancy. METHODS: We identified three women who had TSH receptor blocking Ab-induced MH during pregnancy and were treated with L-thyroxine (L-T4), starting at 27 weeks, 5 weeks, and the first month of gestation. The corresponding pretreatment serum TSH levels in the two women in whom data were available were 68 and 65 mU/L, falling to 6 mU/L at 25 and 24 weeks of gestation, respectively. The third woman with MH required 0.5 mg of L-T4 to normalize her thyroid hormone levels by 4 months of gestation. Their infants were also treated with L-T4 after neonatal screening that identified congenital hypothyroidism (CH). Neuropsychological tests to assess intelligence, language, memory, and visual-motor performance were administered to these three infants at 5.4 years of age (range 5.1-6.1) and to three sibling controls at 6.8 years (range 9.1-3.0). RESULTS: Children born after MH had average or above average results on all parameters. Comparative scores of the neuropsychological tests in sibling pairs for full-scale intelligence quotient (IQ) and performance IQ were variable; some scores were higher and some were lower in CH children. CONCLUSIONS: Although the findings do not exclude a subtle impact of MH during early gestation on intellectual function, the normal cognitive outcome despite overt MH should provide data with which to counsel mothers who have overt hypothyroidism early in pregnancy. Aggressive thyroid hormone replacement as soon as possible is important, but early termination of the pregnancy because of fear that the baby will have significant cognitive delay is not warranted.

Target-directed synthesis of antibacterial drug candidate GSK966587.

An efficient enantioselective total synthesis of the potent antibiotic GSK966587 was accomplished. Highlights of the synthesis include two innovative Heck reactions, a highly selective zincate base directed ortho-metalation, Sharpless asymmetric epoxidation, and a fully convergent final step fragment coupling.

Liver metastases in candidates for hepatic resection: comparison of helical CT and gadolinium- and SPIO-enhanced MR imaging.

PURPOSE: To prospectively compare accuracy of dynamic contrast material-enhanced thin-section multi-detector row helical computed tomography (CT), high-spatial-resolution three-dimensional (3D) dynamic gadolinium-enhanced magnetic resonance (MR) imaging, and superparamagnetic iron oxide (SPIO)-enhanced MR imaging with optimized gradient-echo (GRE) sequence for depiction of hepatic lesions; surgery and histologic analysis were the reference standard. MATERIALS AND METHODS: Local ethics committee approval was granted, and written informed consent was obtained. Fifty-eight patients (45 men, 13 women; age range, 47-82 years) with hepatic metastases were imaged with multi-detector row CT (3.2-mm section thickness), 3D dynamic gadolinium-enhanced MR imaging (2.5-mm effective section thickness), and SPIO-enhanced MR by using an optimized T2-weighted GRE sequence. Images were reviewed independently by two blinded observers who identified and localized lesions with a four-point confidence scale. Accuracy of each technique was measured with alternative free-response receiver operating characteristic analysis. Results were correlated with findings at surgery with intraoperative ultrasonography or histopathologic examination. Statistical differences among techniques for each observer were measured. RESULTS: Accuracy values for each observer for all metastases (n = 215) and 1.0-cm or smaller metastases (n = 80), respectively, follow: For CT, those for reader 1 were 0.82 and 0.65; for reader 2, 0.81 and 0.68. For gadolinium-enhanced MR imaging, those for reader 1 were 0.92 and 0.79; for reader 2, 0.90 and 0.76. For SPIO-enhanced MR imaging, those for reader 1 were 0.92 and 0.83; for reader 2, 0.92 and 0.81. For all metastases for both observers, there was no significant difference between MR techniques, but both were significantly more accurate than CT (P < .01). For metastases 1.0 cm or smaller and one observer, there was no significant difference between MR techniques, but both were more accurate than CT (P < .01); for the other observer, SPIO-enhanced MR imaging was more accurate than gadolinium-enhanced MR imaging (P < .05) and CT (P < .02), but there was no significant difference between gadolinium-enhanced MR imaging and CT (P = .2). CONCLUSION: Accuracy for gadolinium-enhanced MR imaging and SPIO-enhanced MR imaging was similar. Both techniques were significantly more accurate than CT.

Validity: on meaningful interpretation of assessment data.

CONTEXT: All assessments in medical education require evidence of validity to be interpreted meaningfully. In contemporary usage, all validity is construct validity, which requires multiple sources of evidence; construct validity is the whole of validity, but has multiple facets. Five sources--content, response process, internal structure, relationship to other variables and consequences--are noted by the Standards for Educational and Psychological Testing as fruitful areas to seek validity evidence. PURPOSE: The purpose of this article is to discuss construct validity in the context of medical education and to summarize, through example, some typical sources of validity evidence for a written and a performance examination. SUMMARY: Assessments are not valid or invalid; rather, the scores or outcomes of assessments have more or less evidence to support (or refute) a specific interpretation (such as passing or failing a course). Validity is approached as hypothesis and uses theory, logic and the scientific method to collect and assemble data to support or fail to support the proposed score interpretations, at a given point in time. Data and logic are assembled into arguments--pro and con--for some specific interpretation of assessment data. Examples of types of validity evidence, data and information from each source are discussed in the context of a high-stakes written and performance examination in medical education. CONCLUSION: All assessments require evidence of the reasonableness of the proposed interpretation, as test data in education have little or no intrinsic meaning. The constructs purported to be measured by our assessments are important to students, faculty, administrators, patients and society and require solid scientific evidence of their meaning.

Total Synthesis of Bistratamide D.

The total synthesis of the macrocyclic hexapeptide bistratamide D is reported. The synthetic strategy involved assembly of enantiomerically pure oxazole, thiazole, and oxazoline segments derived from amino acids. Macrocyclization of the hexapeptidic aminooxazoline-oxazole-thiazole carboxylic acid fragment was accomplished by activation with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).