Biomimetic Reductive Cleavage of Keto Aryl Ether Bonds by Small-Molecule Thiols.

The nucleophilic and reductive properties of thiolates and thiols make them ideal candidates as redox mediators via the thiol/disulfide couple. One mechanism for biological lignin depolymerization entails reduction of keto aryl ether bonds by an SN 2 mechanism with the thiol redox mediator glutathione. In this study, mimicking this chemistry in a simple protein- and metal-free process, several small organic thiols are surveyed for their ability to cleave aryl keto ethers that model the ß-O-4 linkages found in partially oxidized lignin. In polar aprotic solvents, ß-mercaptoethanol and dithiothreitol yielded up to 100 % formation of phenol and acetophenone products from 2-phenoxyacetophenone, but not from its reduced alcohol congener. The effects of reaction conditions and of substituents on the aryl rings and the keto ether linkage are assessed. These results, together with activation barriers computed by quantum chemical simulations and direct observation of the expected intermediate thioether, point to an SN 2 mechanism. This study confirms that small organic thiols can reductively break down lignin-relevant keto aryl ether linkages.

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: dose-response analysis of thyroid follicular adenomas detected during first screening in Ukraine (1998-2000).

The Chornobyl (Chernobyl) accident in 1986 exposed many individuals to radioactive iodines, chiefly (131)I, the effects of which on benign thyroid diseases are largely unknown. To investigate the risk of follicular adenoma in relation to radiation dose after Chornobyl, the authors analyzed the baseline data from a prospective screening cohort study of those exposed as children or adolescents. A stratified random sample was selected from all individuals who were younger than 18 years, had thyroid radioactivity measurements taken within 2 months after the accident, and resided in the three heavily contaminated areas in Ukraine. This analysis is based on the 23 cases diagnosed in 12,504 subjects for whom personal history of thyroid diseases was known. The dose-response relation was linear with an excess relative risk of 2.07 per gray (95% confidence interval: 0.28, 10.31). The risk was significantly higher in women compared with men, with no clear modifying effects of age at exposure. In conclusion, persons exposed to radioactive iodines as children and adolescents have an increased risk of follicular adenoma, though it is smaller than the risk of thyroid cancer in the same cohort. Compared with results from other studies, this estimate is somewhat smaller, but confidence intervals overlap, suggesting compatibility.

Differences in sonographic conspicuity according to papillary thyroid cancer subtype: results of the Ukrainian-American cohort study after the Chornobyl accident.

OBJECTIVE: Over time, the histology of papillary thyroid cancers detected in a repeatedly screened population exposed to radiation at Chornobyl (Chernobyl) has shifted from a more aggressive subtype toward less aggressive subtypes. This change may reflect biologic behavior but could also be influenced by the detectability of different subtypes. The study objective was to identify whether there is any relationship between the conspicuity of sonographically detected papillary cancers and histologic subtype. MATERIALS AND METHODS: Sonographic images of 84 papillary cancers occurring in young people exposed to radiation at Chornobyl were each given a conspicuity score using a subjective 1-5 scale by four independent expert readers blinded to histologic subtype. The effects of tumor subtype, tumor encapsulation, reader, machine type, and nodule size on sonographic conspicuity were determined using analysis of variance and Spearman correlations. RESULTS: Cancer subtype was related to sonographic conspicuity (p < 0.01). The relatively aggressive solid subtype of papillary carcinoma was more conspicuous than the papillary, follicular, and mixed subtypes (p < 0.05). The other subtypes did not differ significantly from each other in conspicuity. Conspicuity was not significantly related to nodule size, degree of encapsulation, age and sex of the subject, or machine type. Although the mean conspicuity score for each reader differed significantly, reliability of conspicuity judgments across readers was fair. CONCLUSION: In subjects exposed to radiation from the Chornobyl accident, the solid subtype of papillary carcinoma appears to be more conspicuous on sonography than the other subtypes. Therefore, the change in subtype observed over time in this repeatedly screened population may be influenced by differences in nodule conspicuity.

Factors associated with elevated serum concentrations of anti-TPO antibodies in subjects with and without diffuse goitre. Results from the Ukrainian-American Cohort Study of thyroid cancer and other thyroid diseases following the Chornobyl accident.

OBJECTIVES: To examine factors associated with the prevalence of elevated anti-thyroid peroxidase antibodies (ATPO) among iodine-deficient adolescents and young adults and test whether associations vary according to the presence of diffuse goitre. DESIGN: Subjects were members of the Ukrainian-American Cohort Study exposed to the Chornobyl accident whose (131)I thyroid dose estimates were below 0.2 Gy. MEASUREMENTS: The odds ratios (ORs) for ATPO above 60 U/ml were estimated using logistic regression models for a number of factors in the total population (N = 5133), and separately for thyroid disease-free subjects (N = 3875), those with diffuse goitre (N = 921), and diffuse goitre without autoimmune thyroiditis (AIT; N = 883). RESULTS: Elevated ATPO was found in 9.9% of the total population and ORs were significantly higher in females, older individuals, those examined in earlier calendar years, residents of Kyiv and Chernihiv oblasts, subjects with a family history of thyroid disease, higher thyroid ultrasound volume, suppressed or elevated TSH, blood collection in March to May, very low thyroglobulin (Tg), and shorter serum storage time. When thyroid disease-free subjects and those with diffuse goitre were compared, there were few differences in antibody prevalence, and after excluding individuals with AIT, the only difference was an increased prevalence of elevated ATPO at low urinary iodine in those with goitre alone. CONCLUSIONS: Although a number of factors are associated with the prevalence of elevated ATPO in our study group, with the exception of urinary iodine these factors are independent of goitre, and differences between thyroid disease-free subjects and those with diffuse goitre are largely due to AIT.

Outcomes of patients with differentiated thyroid carcinoma following initial therapy.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

Pay for Performance in Medicaid: Evidence from Three Natural Experiments.

OBJECTIVE: To examine the impact of pay for performance in Medicaid on the quality and utilization of care. DATA SOURCES: Medicaid claims and encounter data in three intervention states (Pennsylvania, Minnesota, and Alabama) and three comparison states. STUDY DESIGN: Difference-in-difference analysis with propensity score-matched comparison group. Primary outcomes of interest were Healthcare Effectiveness Data and Information Set (HEDIS)-like process measures of quality, utilization by service category, and ambulatory care-sensitive admissions and emergency department visits. PRINCIPAL FINDINGS: In Pennsylvania, there was a statistically significant reduction of 88 ambulatory visits per 1,000 enrollee months compared with Florida. In Minnesota, there was a significant decrease of 7.2 hospital admissions per thousand enrollee months compared with Wisconsin. In Alabama, where incentives were not paid out until the end of a 2-year waiver period, there was a decline of 1.6 hospital admissions per thousand member months, and an increase of 59 ambulatory visits per 1,000 enrollees compared with Georgia. No significant quality improvements in intervention relative to control states. CONCLUSIONS: Our findings are mixed, with no measurable quality improvements across the three states, but reductions in hospital admissions in two programs. As states move to value-based payment for patient-centered medical homes and Accountable Care Organizations, lessons learned from these pioneering states should inform program design.

MEDICARE PAYMENTS AND SYSTEM-LEVEL HEALTH-CARE USE: The Spillover Effects of Medicare Managed Care.

The rapid growth of Medicare managed care over the past decade has the potential to increase the efficiency of health-care delivery. Improvements in care management for some may improve efficiency system-wide, with implications for optimal payment policy in public insurance programs. These system-level effects may depend on local health-care market structure and vary based on patient characteristics. We use exogenous variation in the Medicare payment schedule to isolate the effects of market-level managed care enrollment on the quantity and quality of care delivered. We find that in areas with greater enrollment of Medicare beneficiaries in managed care, the non-managed care beneficiaries have fewer days in the hospital but more outpatient visits, consistent with a substitution of less expensive outpatient care for more expensive inpatient care, particularly at high levels of managed care. We find no evidence that care is of lower quality. Optimal payment policies for Medicare managed care enrollees that account for system-level spillovers may thus be higher than those that do not.

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: objectives, design and methods.

The thyroid gland in children is one of the organs that is most sensitive to external exposure to X and gamma rays. However, data on the risk of thyroid cancer in children after exposure to radioactive iodines are sparse. The Chornobyl accident in Ukraine in 1986 led to the exposure of large populations to radioactive iodines, particularly (131)I. This paper describes an ongoing cohort study being conducted in Belarus and Ukraine that includes 25,161 subjects under the age of 18 years in 1986 who are being screened for thyroid diseases every 2 years. Individual thyroid doses are being estimated for all study subjects based on measurement of the radioactivity of the thyroid gland made in 1986 together with a radioecological model and interview data. Approximately 100 histologically confirmed thyroid cancers were detected as a consequence of the first round of screening. The data will enable fitting appropriate dose-response models, which are important in both radiation epidemiology and public health for prediction of risks from exposure to radioactive iodines from medical sources and any future nuclear accidents. Plans are to continue to follow-up the cohort for at least three screening cycles, which will lead to more precise estimates of risk.

The spillover effects of Medicare managed care: Medicare Advantage and hospital utilization.

More than a quarter of Medicare beneficiaries are enrolled in Medicare Advantage, which was created in large part to improve the efficiency of health care delivery by promoting competition among private managed care plans. This paper explores the spillover effects of the Medicare Advantage program on the traditional Medicare program and other patients, taking advantage of changes in Medicare Advantage payment policy to isolate exogenous increases in Medicare Advantage enrollment and trace out the effects of greater managed care penetration on hospital utilization and spending throughout the health care system. We find that when more seniors enroll in Medicare managed care, hospital costs decline for all seniors and for commercially insured younger populations. Greater managed care penetration is not associated with fewer hospitalizations, but is associated with lower costs and shorter stays per hospitalization. These spillovers are substantial - offsetting more than 10% of increased payments to Medicare Advantage plans.

Subclinical hypothyroidism after radioiodine exposure: Ukrainian-American cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident (1998-2000).

BACKGROUND: Hypothyroidism is the most common thyroid abnormality in patients treated with high doses of iodine-131 (131I). Data on risk of hypothyroidism from low to moderate 131I thyroid doses are limited and inconsistent. OBJECTIVE: This study was conducted to quantify the risk of hypothyroidism prevalence in relation to 131I doses received because of the Chornobyl accident. METHODS: This is a cross-sectional (1998-2000) screening study of thyroid diseases in a cohort of 11,853 individuals < 18 years of age at the time of the accident, with individual thyroid radioactivity measurements taken within 2 months of the accident. We measured thyroid-stimulating hormone (TSH), free thyroxine, and antibodies to thyroid peroxidase (ATPO) in serum. RESULTS: Mean age at examination of the analysis cohort was 21.6 years (range, 12.2-32.5 years), with 49% females. Mean 131I thyroid dose was 0.79 Gy (range, 0-40.7 Gy). There were 719 cases with hypothyroidism (TSH > 4 mIU/L), including 14 with overt hypothyroidism. We found a significant, small association between (131)I thyroid doses and prevalent hypothyroidism, with the excess odds ratio (EOR) per gray of 0.10 (95% confidence interval, 0.03-0.21). EOR per gray was higher in individuals with ATPO < or = 60 U/mL compared with individuals with ATPO > 60 U/mL (p < 0.001). CONCLUSIONS: This is the first study to find a significant relationship between prevalence of hypothyroidism and individual (131)I thyroid doses due to environmental exposure. The radiation increase in hypothyroidism was small (10% per Gy) and limited largely to subclinical hypothyroidism. Prospective data are needed to evaluate the dynamics of radiation-related hypothyroidism and clarify the role of antithyroid antibodies.

Recurrence after treatment of micropapillary thyroid cancer.

BACKGROUND: Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine. METHODS: The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocal micropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years. RESULTS: Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p = 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine. CONCLUSIONS: Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer.

Modeling motor connectivity using TMS/PET and structural equation modeling.

Structural equation modeling (SEM) was applied to positron emission tomographic (PET) images acquired during transcranial magnetic stimulation (TMS) of the primary motor cortex (M1(hand)). TMS was applied across a range of intensities, and responses both at the stimulation site and remotely connected brain regions covaried with stimulus intensity. Regions of interest (ROIs) were identified through an activation likelihood estimation (ALE) meta-analysis of TMS studies. That these ROIs represented the network engaged by motor planning and execution was confirmed by an ALE meta-analysis of finger movement studies. Rather than postulate connections in the form of an a priori model (confirmatory approach), effective connectivity models were developed using a model-generating strategy based on improving tentatively specified models. This strategy exploited the experimentally imposed causal relations: (1) that response variations were caused by stimulation variations, (2) that stimulation was unidirectionally applied to the M1(hand) region, and (3) that remote effects must be caused, either directly or indirectly, by the M1(hand) excitation. The path model thus derived exhibited an exceptional level of goodness (chi(2)=22.150, df=38, P=0.981, TLI=1.0). The regions and connections derived were in good agreement with the known anatomy of the human and primate motor system. The model-generating SEM strategy thus proved highly effective and successfully identified a complex set of causal relationships of motor connectivity.

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: pathology analysis of thyroid cancer cases in Ukraine detected during the first screening (1998-2000).

BACKGROUND: The Ukrainian American Cohort Study evaluated the risk of thyroid disorders in a group of individuals who were younger than age 18 years at the time of the Chornobyl (Chernobyl) accident. In this article, the authors describe the pathology of thyroid carcinomas detected in the first screening. METHODS: From 1998 to 2000, 13,243 individuals completed the first cycle of screening examinations. Eighty patients underwent surgery between 1998 and 2004. Intraoperative and postoperative pathologic studies were performed at the Institute of Endocrinology and Metabolism, Kyiv. RESULTS: Pathologic analysis revealed 45 thyroid carcinomas, including 43 papillary thyroid carcinomas (PTCs) (95.6%) and 2 follicular thyroid carcinomas (FTCs) (4.4%). TNM classification (5th edition) of the PTCs included 8 T1 tumors (18.6%), 16 T2 tumors (37.2%), and 19 T4 tumors (44.2%). Fifteen PTCs (34.9%) were N1a,N1b, and 3 PTCs (7.0%) were M1. Among the PTCs, 8 exhibited the classical papillary histologic pattern (18.6%), 14 exhibited a follicular histologic pattern (32.6%), 5 exhibited a solid histologic pattern (11.6%), and 16 exhibited a mixed histologic pattern (37.2%). Both FTCs had a microfollicular-solid structure. Eleven of 20 cohort members who underwent surgery before the first screening had PTCs. Regional metastases (63.6%) and distant metastases (18.2%) were more common in this group. CONCLUSIONS: Multifocal growth, lymphatic and blood vessel invasion, extrathyroid spread, and regional and distant metastases were more frequent in less differentiated PTCs (>30% solid structure). Small carcinomas (

Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American Thyroid Association.

The fetus is totally dependent in early pregnancy on maternal thyroxine for normal brain development. Adequate maternal dietary intake of iodine during pregnancy is essential for maternal thyroxine production and later for thyroid function in the fetus. If iodine insufficiency leads to inadequate production of thyroid hormones and hypothyroidism during pregnancy, then irreversible fetal brain damage can result. In the United States, the median urinary iodine (UI) was 168 microg/L in 2001-2002, well within the range of normal established by the World Health Organization (WHO), but whereas the UI of pregnant women (173 microg/L; 95% CI 75-229 microg/L) was within the range recommended by WHO (150-249 microg/L), the lower 95% CI was less than 150 microg/L. Therefore, until additional physiologic data are available to make a better judgment, the American Thyroid Association recommends that women receive 150 microg iodine supplements daily during pregnancy and lactation and that all prenatal vitamin/mineral preparations contain 150 microg of iodine.

A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: thyroid cancer in Ukraine detected during first screening.

BACKGROUND: The Chornobyl accident in 1986 exposed thousands of people to radioactive iodine isotopes, particularly (131)I; this exposure was followed by a large increase in thyroid cancer among those exposed as children and adolescents, particularly in Belarus, the Russian Federation, and Ukraine. Here we report the results of the first cohort study of thyroid cancer among those exposed as children and adolescents following the Chornobyl accident. METHODS: A cohort of 32 385 individuals younger than 18 years of age and resident in the most heavily contaminated areas in Ukraine at the time of the accident was invited to be screened for any thyroid pathology by ultrasound and palpation between 1998 and 2000; 13 127 individuals (44%) were actually screened. Individual estimates of radiation dose to the thyroid were available for all screenees based on radioactivity measurements made shortly after the accident and on interview data. The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model. RESULTS: Forty-five pathologically confirmed cases of thyroid cancer were found during the 1998-2000 screening. Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate (P<.001), yielding an estimated excess relative risk of 5.25 per Gy (95% confidence interval [CI] = 1.70 to 27.5). Greater age at exposure was associated with decreased risk of radiation-related thyroid cancer, although this interaction effect was not statistically significant. CONCLUSION: Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population.