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Hypothyroidism is a common condition, and numerous studies have been published over the last decade to assess the potential risks associated with this disorder when inappropriately treated. The standard of care for treatment of hypothyroidism remains levothyroxine (LT4) at doses to achieve biochemical and clinical euthyroidism. However, about 15% of hypothyroid patients experience residual hypothyroid symptoms. Some population-based studies and international population-based surveys have confirmed dissatisfaction with LT4 treatment in some hypothyroid patients. It is well established that hypothyroid patients treated with LT4 exhibit higher serum thyroxine:triiodothyronine ratios and can have a persistent increase in cardiovascular risk factors. Moreover, variants in deiodinases and thyroid hormone transporter genes have been associated with subnormal T3 concentrations, persistent symptoms in LT4-treated patients, and improvement in response to the addition of liothyronine to LT4 therapy. The American (ATA) and European Thyroid Association (ETA) guidelines have recently evolved in their recognition of the potential limitations of LT4. This shift is reflected in prescribing patterns: Physicians’ use of combination therapy is prevalent and possibly increasing. Randomized clinical trials have recently been published and, while they have found no improvement in treating hypothyroid patients, a number of important limitations did not allow generalizability. Meta-analyses have reported a preference rate for combination therapy in 46.2% hypothyroid patients treated with LT4. To promote discussions about an optimal study design, the ATA, ETA, and British Thyroid Association have recently published a consensus document. Our study provides a useful counterpoint on the controversial benefits of treating hypothyroid patients with combination therapy.

Background and ObjectivesRecent studies suggest the utility of blood biomarkers in detecting changes in neurodegenerative disorders. The objective of our research was to test the hypothesis that the longitudinal changes in total tau (t-tau), neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) are associated with structural MRI and the development of clinical Alzheimer disease (AD) and cognitive decline.MethodsData came from a population-based sample with serum concentrations of t-tau, Nf-L, and GFAP and cognitive characteristics measured over 17 years. The inclusion criteria for this investigation were based on participants with blood samples, cognitive function testing, and clinical diagnosis for AD. The longitudinal changes in the serum biomarkers were examined using linear mixed models for log10-transformed concentrations.ResultsIn 1,327 participants (60% Black participants and 60% women, the concentration of t-tau increased annually by 4.8% (95% CI = 4.0–5.6) and Nf-L by 5.9% (95% CI = 5.4–6.4). The longitudinal change in GFAP was higher among Black participants than among White participants (4.4% vs 3.5% per year,p= 0.028). Baseline MRI characteristics were associated with the longitudinal changes in serum biomarkers of clinical AD. Specifically, a higher baseline third ventricular volume was associated with a higher rate of increase in the concentration of t-tau, and white matter hyperintensities predicted a higher rate of increase in Nf-L. The rate of change in concentrations of t-tau, Nf-L, and GFAP was significantly higher among those who developed clinical AD than in those with no cognitive impairment. For each standard deviation unit decline in global cognition, longitudinal change in t-tau increased by 81% (95% CI = 76–86), Nf-L by 113% (95% CI = 105–120), and GFAP by 66% (95% CI = 62–70).DiscussionBlood biomarkers showed significant longitudinal changes corresponding to cognitive decline, clinical AD, and structural MRI characteristics. Our findings show that longitudinal changes in serum biomarkers were associated with several cognitive endophenotypes.Classification of EvidenceThe study found Class II evidence that longitudinal changes in serum t-tau, Nf-L, and GFAP were associated with cognitive decline and the development of clinical AD in people older than 65 years.

Introduction The estimate of people with clinical Alzheimer's disease (AD) and mild cognitive impairment provides an understanding of the disease burden. Methods We estimated people with cognitive impairment using a quasibinomial regression model in 10,342 participants with cognitive test scores. Results The 2020 US Census-adjusted prevalence of clinical AD was 11.3% (95% confidence interval [CI] = 10.7-11.9): 10.0% among non-Hispanic Whites, 14.0% among Hispanics, and 18.6% among non-Hispanic Blacks. We estimate that in 2020, 6.07 (95% CI = 5.75-6.38) million people were living with clinical AD, which increases to 13.85 (95% CI = 12.98-14.74) million in 2060, 423% higher among Hispanics, 192% higher among Blacks, and 63% higher among Whites. However, there are predicted to be more significant increases in later years among those over 85 and women compared to men. Discussion The number of people with clinical AD will increase as the "baby boom" generation reaches older ages, exerting a strong upward influence on disease burden.

Little is known about the association of serum neurofilament light chain (NfL) concentrations and physical activity with the rate of cognitive decline in older adults.To examine the association of physical activity and NfL concentrations with cognitive decline in older adults over time.This cohort study used data from the Chicago Health and Aging Project (CHAP), a population-based cohort study that recruited participants through door-to-door census in 4 Chicago-area communities and collected data between 1993 and 2012 in cycles of 3 years. Participants in CHAP who had 2 or more cognitive function assessments and at least 1 blood sample collected for NfL measurement were selected for inclusion in the current study. Data were analyzed from January to December 2021.Self-reported physical activity (minutes per week) and serum NfL concentration (pg/mL).Associations of baseline physical activity and NfL concentrations with changes in global cognitive function over time as evaluated using the East Boston Memory Test for episodic memory, the Symbol Digit Modalities Test for perceptual speed, and the Mini-Mental State Examination. Mixed-effects regression analyses were conducted to examine associations at baseline and longitudinally.The study sample included 1158 participants (695 [60%] African American; 728 [63%] female), with a mean (SD) age of 77.4 (6.0) years and a mean educational level of 12.6 (3.5) years. Among participants with high NfL concentrations (25 pg/mL), those who engaged in medium physical activity (150 minutes per week) had a 12% slower rate of global cognitive decline (SD units, or β, -0.065; 95% CI, -0.099 to -0.032) and participants who engaged in high physical activity (≥150 minutes per week) had a 36% slower rate of decline (β, -0.048; 95% CI, -0.080 to -0.016) than did participants with low physical activity (no reported participation) (β, -0.075; 95% CI, -0.108 to -0.041). For participants with low NfL concentrations (≤25 pg/mL), those who took part in medium physical activity had 43% slower global cognitive decline (β, -0.025; 95% CI, -0.043 to -0.007) and individuals who participated in high physical activity had 30% slower decline (β, -0.031; 95% CI, -0.048 to -0.014) than did those who participated in low physical activity (β, -0.046; 95% CI, -0.066 to -0.025).The findings suggest that physical activity is associated with diminished cognitive decline among older adults with increased serum NfL concentrations. The results support the potential use of blood biomarkers in measuring the benefits of health behaviors, such as physical activity, and early intervention for older adults at risk for cognitive decline.

OBJECTIVE: The longitudinal association of blood biomarkers of total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) with common sporadic AD and cognitive decline are not established. METHODS: Using a single molecule array technology, ultrasensitive immunoassays for serum concentrations of total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) were measured in a population sample of 1,327 participants (60% African Americans and women) who had a clinical evaluation for AD, completed in-home cognitive assessments, and undergone 1.5T structural MRI. RESULTS: Higher concentrations of serum biomarkers were associated with the development of clinical AD, especially, the time-specific associations were notable: t-tau 8–16 years, and Nf-L and GFAP 4–8 years prior to clinical AD. Serum biomarkers were associated with faster cognitive decline over 16 years: baseline t-tau above 0.40 pg/mL had 30% faster decline, Nf-L above 25.5 pg/mL had 110% faster decline, and GFAP above 232 pg/mL had 130% faster decline compared to those in the lowest quartile. Participants with baseline GFAP above 232 pg/mL showed 160% faster decline in hippocampal volume compared to those below 160 pg/mL. Additionally, higher baseline t-tau was associated with faster increase in third ventricular volume, and baseline Nf-L and GFAP were associated with faster decline in cortical thickness. INTERPRETATION: Serum t-tau, Nf-L, and GFAP predict the development of sporadic AD and cognitive decline, and changes in structural brain characteristics, suggesting their usefulness not only as screening and predictive biomarkers, but also in capturing the pathogenesis of Alzheimer’s dementia.

Key Points Question Is physical activity associated with slower cognitive decline in people with higher total tau concentrations? Findings In this population-based cohort study comprising 1159 participants, medium physical activity was associated with a 58% slower rate of cognitive decline, and high physical activity was associated with a 41% slower rate of cognitive decline compared with little physical activity among those with high total tau concentrations. For participants with low total tau concentrations, medium physical activity was associated with a 2% slower rate of cognitive decline, and high physical activity was associated with a 27% slower rate of cognitive decline compared with little physical activity. Meaning This study suggests that measurement of blood biomarkers may offer an opportunity for early intervention of physical activity to reduce the rate of cognitive decline., Importance Tau is a brain protein located in neurons and develops abnormally in individuals with Alzheimer disease. New technology is convenient for measuring blood total tau concentrations and provides a unique and increased opportunity for early intervention to slow cognitive decline. Objective To evaluate the association of physical activity and total tau concentrations with cognitive decline at baseline and over time. Design, Setting, and Participants The Chicago Health and Aging Project is a population-based cohort study conducted in 4 Chicago communities. Data collection occurred in 3-year cycles between 1993 and 2012. Participants completed in-home interviews. Clinical evaluations, which included blood samples, were performed with a stratified random sample of 1159 participants. Statistical analyses were conducted from October 30, 2020, to May 25, 2021. Exposures Physical activity and total serum tau concentrations. Data on physical activity were obtained through self-report items, and a sum of minutes per week was calculated. Little physical activity was defined as no participation in a minimum of 4 of the items on the physical activity measure. Medium activity was defined as participating in less than 150 minutes of physical activity per week, and high activity was defined as participating in 150 minutes or more of physical activity per week. Main Outcomes and Measures The main outcome for this study is global cognitive function, measured through a battery of cognitive tests. The study hypothesis was developed after data were collected. Results Of the 1159 participants in the study, 728 were women (63%), and 696 were African American (60%); the mean (SD) age was 77.4 (6.0) years, and the mean (SD) educational level was 12.6 (3.5) years. Participants with high total tau concentrations with medium physical activity had a 58% slower rate of cognitive decline (estimate, –0.028 standard deviation unit [SDU] per year [95% CI, –0.057 to 0.002 SDU per year]; difference, 0.038 SDU per year [95% CI, 0.011-0.065 SDU per year]), and those with high physical activity had a 41% slower rate of cognitive decline (estimate, –0.038 SDU per year [95% CI, –0.068 to –0.009 SDU per year]; difference, 0.027 SDU per year [95% CI, –0.002 to 0.056 SDU per year]), compared with those with little physical activity. Among participants with low total tau concentrations, medium physical activity was associated with a 2% slower rate of cognitive decline (estimate, –0.050 SDU per year [95% CI, –0.069 to –0.031 SDU per year]; difference, 0.001 SDU per year [95% CI, –0.019 to 0.021 SDU per year]), and high physical activity was associated with a 27% slower rate of cognitive decline (estimate, –0.037 SDU per year [95% CI, –0.055 to –0.019 SDU per year]; difference, 0.014 SDU per year [95% CI, –0.007 to 0.034 SDU per year]), compared with little physical activity. Individual tests of cognitive function showed similar results. Conclusions and Relevance This study suggests that, among participants with both high and low total tau concentrations, physical activity was associated with slower cognitive decline. Results support the potential utility of blood biomarkers in measuring the benefits associated with health behaviors and may contribute to specifying target populations or informing interventions for trials that focus on improving physical activity behavior. Future work should examine the association of total tau concentrations with other health behaviors and physical activity types., This cohort study uses data from the Chicago Health and Aging Project to evaluate the association of physical activity and total tau concentrations with cognitive decline at baseline and over time

OBJECTIVES To examine the effects of age and race on the association of apolipoprotein E (APOE) genotypes with cognitive decline in a population sample. DESIGN Longitudinal study of 18 years' duration. SETTING Biracial urban US population sample. PARTICIPANTS There were a total of 5807 participants, 60% African American (AA) and 40% European American (EA). MEASUREMENTS A composite cognitive function based on individual tests of episodic memory, perceptual speed, and the Mini-Mental State Examination. RESULTS The frequencies of APOE e2/e3 (14% vs 12%), e2/e4 (4% vs 2%), e3/e4 (29% vs 22%), and e4/e4 (4% vs 2%) genotypes were higher among AAs than EAs. After adjusting for demographic factors, the rate of decline in global cognition was twice as high among participants with the APOE e4/e4 genotype compared to participants with the APOE e3/e3 genotype (0.097 vs 0.048 SD units [SDUs] per year; P < .0001). This doubling was not different between AAs (0.091 vs 0.045 SDUs per year) and EAs (0.118 vs 0.059 SDUs per year) (Pinteraction = .63). The APOE e3/e4 genotype was associated with a higher rate of decline with age (Pinteraction = .021), while the APOE e2/e4 genotype (Pinteraction = .016) and the APOE e2/e3 genotype (Pinteraction = .043) were associated with a lower rate of decline with higher age. The APOE e2/e2 genotype was associated with a lower rate of decline in episodic memory, while the APOE e2/e4 was associated with a higher rate of decline in episodic memory and perceptual speed. CONCLUSIONS The association of the APOE genotypes with cognitive decline was not different between AAs and EAs. However, individuals with different APOE genotypes showed a lower or a higher rate of decline with age. J Am Geriatr Soc 67:734-740, 2019.

Introduction Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. Methodology Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. Results Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). Conclusions As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.

Introduction: Before the availability of levothyroxine (LT4), patients were treated with desiccated thyroid extract (DTE). When switching from DTE to LT4, despite adequate dosing based on serum TSH levels, some patients still feel unwell with fatigue, mental fogginess, weight gain etc. A recent randomized, crossed over study between DTE vs. LT4 conducted in our department showed that once-daily DTE caused modest weight loss and possible improvement in mental health scores without appreciable adverse effects; also, nearly half of the study patients preferred DTE over LT4. A few studies have shown that LT4/T3 combination had beneficial effects in improving quality of life relative to LT4 alone. Furthermore, it has been reported that patients with CC genotype in the deiodinase type 2 polymorphism responded more favorably with LT4/T3 combination than T4 monotherapy. Hypothesis: This study investigated the efficacy and effectiveness of DTE vs. LT4/T3 combination vs. LT4 monotherapy in hypothyroid patients based on genotypic differences of deiodinase type 2. Methodology: This was a prospective, randomized, double-blind, crossover study. 75 subjects completed the study. There were 3 arms: DTE, LT4+T3 combination, and LT4 alone. Each subject was randomly allocated to one of these 3 arms for 12 weeks randomly. The study was powered to detect the primary outcome. The primary endpoint was post-treatment score on the 36-point thyroid symptom questionnaire. Secondary endpoints were weight, general health questionnaire, the Beck depression inventory, Wechsler Memory testing, lipid panels and thyroid function tests. Analysis was performed with a linear mixed model using subject as a random factor and group as a fixed effect. Results: There was no significant difference between the 3 arms on the thyroid symptom questionnaire (p=.32), and the secondary outcomes showed no between group differences. Auditory memory index (p=.008), and visual working memory index (p=.02) were higher in the Hashimoto’s than non-Hashimoto’s group. There was no significant primary or secondary outcome difference among various genotypes of deiodinase 2. There was no relationship between Hashimoto’s vs. non-Hashimoto’s based on genotypes or likelihood of carrying Thr92AlaD2 polymorphism. Though there was no statistically significant preference for any treatment, numerically more patients with Hashimoto’s preferred DTE and LT4/T3 combination than LT4-monotherapy. Conclusions: There was no significant difference between hypothyroid patients taking DTE vs. LT4/T3 combination vs. LT4 monotherapy. Numerically, Hashimoto’s patients tended to prefer DTE and LT4/T3 combination. Also, there was no observed relationship between Hashimoto’s and polymorphism. Further studies with more patients may be needed.

BackgroundCoronavirus disease 2019 (COVID-19) has devastated global populations and has had a large impact in the United States. The objective of this manuscript is to study the relation of population demographics, social characteristics, and social distancing on the number of infections and deaths in the US.MethodsData came from publicly available sources. Social distancing was measured by the change in the rate of human encounters per km2 relative to the pre-COVID-19 national average. A smooth generalized additive model for counts of total infections and deaths at US county-level included population demographics, social characteristics, and social distancing.ResultsThe model strongly predicted the geo-spatial variations in COVID-19 infections and deaths, 97.2% of variation in infections and 99.3% of variation in deaths from March 15, 2020. US counties with higher population density, poverty index, civilian population, and minorities, especially African Americans, had a higher rate of infections and deaths, and social distancing was associated with a slower rate of infections and deaths. The number of people infected was increasing; however, the rate of increase of new infections was showing signs of plateauing from the second week of April. Our model estimates that 1,865,580 US residents will test positive for infections and 117,246 fatalities by June 1, 2020. Importantly, our model suggests significant social differences in the infections and deaths across US communities. Areas with a larger African American population and a higher poverty index are expected to show higher rates of infections and deaths.ConclusionPreventive steps, including social distancing and community closures, have been a cornerstone in slowing the transmission and potentially reducing the spread of the disease. Crucial knowledge of the role of social characteristics in disease transmission is essential to understand and predict current and future disease distribution and plan additional preventive steps.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease., Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.

The current state of the diagnosis and management of thyroid disease cannot be separated from the larger context of women’s health for the following reasons: (1) the disproportionate incidence and prevalence of functional and structural thyroid diseases among women vs men; (2) the role of thyroid health on fertility, pregnancy, and postpartum; and (3) the challenge posed in managing the nonspecific symptoms of functional thyroid disease in the context of menopause. Here, we explore the hypothesis that sex bias has played a role in the management of thyroid diseases historically and has extended into the modern medical era. Once knowledge gaps that may have resulted from sex bias are recognized, we can strive to overcome this bias and develop better treatments to improve patient outcomes universally., Sex bias played a role in the history of thyroid disease. We hypothesize that sex bias may persist today and contribute to patient dissatisfaction in hypothyroidism.

Summary: Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. : Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL. Keywords: deiodinase, steatosis, cholesterol, triglycerides, zinc finger protein 125, liver, hepatocytes, transcriptional repressor

Objectives To examine the difference in the association between apolipoprotein (APO)E allele and overall and cardiovascular mortality between African Americans (AAs) and European Americans (EAs). Design Longitudinal, cohort study of 18 years. Setting Biracial urban US population sample. Participants 4,917, 68% AA and 32% EA. Measurements APOE genotype and mortality based on National Death Index. Results A higher proportion of AAs than of EAs had an APOE e2 allele (e2e2/e2e3/e2e4; 22% vs 13%) and an APOE e4 allele (e3e4/e4e4; 33% vs 24%). After adjusting for known risk factors, the risk of mortality was 19% less with the APOE e2 allele (hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.76–0.87), and the risk of cardiovascular mortality was 35% less (HR = 0.65, 95% CI = 0.58–0.76) than with the e3e3 allele. The risk of mortality was 10% greater with the APOE e4 allele (HR = 1.10, 95% CI = 1.04–1.16), and the risk of cardiovascular mortality was 20% greater (HR = 1.20, 95% CI = 1.07–1.29) than with the e3e3 allele. No difference in the association between APOE allele and mortality was observed between AAs and EAs. Conclusion The APOE e4 allele increased the risk of overall and cardiovascular mortality, whereas the APOE e2 allele decreased the risk of overall and cardiovascular mortality. There was no racial difference in the association between these alleles and mortality.

BACKGROUND: The association of the APOE ε4 allele with incident Alzheimer’s dementia is higher among European Americans (EAs) than African Americans (AAs), but similar for the rate of cognitive decline. OBJECTIVE: To examine the racial differences in the association of the APOE ε4 allele with incident Alzheimer’s dementia and cognitive decline. METHODS: Using a population-based sample of 5,117 older adults (66% AAs and 63% females), we identified cognitive trajectory groups from a latent class mixed model and examined the association of the APOE ε4 allele with these groups. RESULTS: The frequency of the APOE ε4 allele was higher among AAs than EAs (37% versus 26%). Four cognitive trajectories were identified: slow, mild, moderate, and rapid. Overall, AAs had a lower baseline global cognition than EAs, and a higher proportion had rapid (7% versus 5%) and moderate (20% versus 15%) decline, but similar mild (44% versus 46%), and lesser slow (29% versus 34%) decline compared to EAs. Additionally, 25% of AAs (13% of EAs) with mild and 5% (

Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3, and/or T4. “Combination therapy” involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late nineteenth and the early Twentieth centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract, or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine “monotherapy” as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgment by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.

In the United States, hospital rating system usefulness is limited by heterogeneity and conflicting results. US News Best Hospitals, Vizient Quality and Accountability Study, Centers for Medicare & Medicaid Services (CMS) Star Rating, Leapfrog Hospital Safety Grade, and the Truven Top 100 Hospitals ratings were compared using Spearman correlations. Rank aggregation was used to combine the scores generating a Quality Composite Rank (QCR). The highest correlation between rating systems was shown between the Leapfrog Safety Grade and the CMS Star Rating. In a proportional odds logistic regression, a greater discordance between the CMS Star Rating, Vizient rank, US News, and Leapfrog was associated with a lower overall rank in the QCR. Lack of transparency and understanding about the differences and similarities for these hospital ranking systems complicates use of the measures. By combining the results of these ranking systems into a composite, the measurement of hospital quality can be simplified.

Context: Levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism. Objective: To determine whether LT4 at doses that normalize the serum TSH is associated with normal markers of thyroid status. Design: Cross-sectional data from the US National Health and Nutrition Examination Survey (2001–2012) was used to evaluate 52 clinical parameters. LT4 users were compared to healthy controls and controls matched for age, sex, race, and serum TSH. Regression was used to evaluate for correlation with T4 and T3 levels. Participants: A total of 9981 participants with normal serum TSH were identified; 469 were LT4-treated. Results: Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to approximately 15–20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants had higher body mass index despite report of consuming fewer calories/day/kg; were more likely to be taking beta-blockers, statins, and antidepressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum high-density lipoprotein and lower serum low-density lipoprotein, triglycerides, and C-reactive protein. Age was negatively associated with serum free T3:free T4 ratio in all participants; caloric intake was positively associated in LT4-treated individuals. Conclusions: In a large population study, participants using LT4 exhibited lower serum T3:T4 ratios and differed in 12/52 objective and subjective measures.

The American Thyroid Association (ATA) has recently revised its guidance pertaining to thyroid nodules and follicular cell-derived thyroid cancer. The 2015 guidelines are massive in both scope and scale, with changes in the organizational approach to risk stratification of nodules and cancer, as well as multiple sections covering new material. This review highlights the major structural and organizational changes, focusing attention on the most dramatically changed recommendations, that is, those recommendations that clinicians will find striking because they call for significant divergence from prior clinical practice.The revised approach to thyroid nodule risk stratification is based on sonographic pattern, with an emphasis on pattern rather than growth in the long-term surveillance of nodules. Accumulating data have also been incorporated into an updated risk stratification scheme for thyroid cancer that increases the size of the low-risk pool, in part because low-volume lymph nodal metastases are now considered low risk. The most fundamentally altered recommendation is that lobectomy might be considered as the initial surgical approach for follicular cell-derived thyroid cancers from 1 to 4 cm in size.The underlying theme of the 2015 ATA guidelines is that "less is more." As these new recommendations are adopted, fewer fine-needle aspiration biopsies will need to be done, less extensive surgeries will become more common, less radioactive iodine will be used either for treatment or for diagnostics, and less stimulated thyroglobulin testing will be done. Mastery of these guidelines will help clinicians know when it is reasonable to do less, thus providing responsibly individualized therapy for their patients.

Objective: We present a case and a review of relevant literature demonstrating that pituitary apoplexy rarely presents with syndrome of inappropriate antidiuretic hormone secretion (SIADH)-induced hyponatremia. We discuss management strategies, including consideration of pituitary surgery in the absence of visual disturbance if conservative management fails to control profound hyponatremia.Methods: Case report with literature review.Results: A previously healthy, 32-year-old female with a history of regular menses presented with fatigue, lethargy, severe headache, and intractable nausea with emesis. At presentation she was clinically euvolemic with intact visual fields and had hypoosmolar hyponatremia with serum sodium 109 mmol/L, serum osmolality 232 mOsm/kg, urine sodium 114 mmol/L, and urine osmolality 374 mOsm/kg. Her thyroid-stimulating hormone concentration was low normal, with a free thyroxine concentration of 0.6 ng/dL and a random serum cortisol measurement of 8.7μmg/dL. Pituitary magnetic resonance imaging revealed a macroadenoma potentially harboring a hemorrhagic component. Administration of hypertonic saline eliminated her symptoms within hours; however, she remained profoundly hyponatremic despite 72 hours of oral fluid restriction and treatment with glucocorticoids and levothyroxine. The patient underwent transsphenoidal resection, which resulted in an intraoperative rise in serum sodium and postoperative diabetes insipidus.Conclusion: Although hyponatremia as a consequence of central adrenal or thyroid insufficiency is prevalent in pituitary apoplexy, SIADH-associated hyponatremia in apoplexy is rare. If conservative approaches fail, treatment of pituitary apoplexy-induced SIADH with severe hyponatremia includes acute medical management of hyponatremia. Definitive strategies can be considered to control hyponatremia. In the few previously reported cases, SIADH was eliminated or improved by surgery; however, the risks of surgery may outweigh the benefits, as the present patient developed postoperative diabetes insipidus.Abbreviations: SIADH = syndrome of inappropriate antidiuretic hormone secretion TSH = thyroid-stimulating hormone T4 = thyroxine

Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by the type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here we report that D2 is a cargo protein in endoplasmic reticulum Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92 to Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR); Ala92-D2 accumulated in the trans-Golgi and generated less T3, all of which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.

Although amiodarone is considered the most effective antiarrhythmic agent, its use is limited by a wide variety of potential toxicities. The purpose of this review is to provide a comprehensive "bench to bedside" overview of the ways amiodarone influences thyroid function. We performed a systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1950 and 2017. Amiodarone was searched using the terms adverse effects, hypothyroidism, myxedema, hyperthyroidism, thyroid storm, atrial fibrillation, ventricular arrhythmia, and electrical storm. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. We included 163 germane references in this review. Because amiodarone is one of the most frequently prescribed antiarrhythmic drugs in the United States, the mechanistic, diagnostic and therapeutic information provided is relevant for practicing clinicians in a wide range of medical specialties.

Context The standard of care for overt hypothyroidism is levothyroxine at doses that normalize serum TSH levels. Whether this approach universally restores thyroid hormone signaling is unknown. Objective To review studies of overt hypothyroidism in which participants were treated with levothyroxine to normalize serum TSH levels and measured other objective markers of thyroid hormone signaling. Design Databases were searched for studies that reported objective markers of thyroid hormone signaling (serum low-density lipoprotein (LDL), total cholesterol (TC), sex hormone-binding globulin (SHBG), creatine kinase and/or ferritin levels; cognition, energy expenditure, and/or renal function) in levothyroxine monotherapy for overt, primary hypothyroidism among nonpregnant adults with normal serum TSH levels. For studies with LDL, TC and SHBG outcomes, data were pooled using random effects meta-analysis. Results A total of 99 studies met inclusion criteria, including 65 that reported serum cholesterol data. Meta-analysis showed that levothyroxine-treated hypothyroid participants with normal serum TSH levels had 3.31 ± 1.64 mg/dL higher serum LDL levels (p=0.044) and 9.60 ± 3.55 mg/dL higher serum TC levels (p=0.007) compared to controls. In studies that did not concomitantly assess healthy controls, serum LDL levels were 138.3 ± 4.6 mg/dL (p

Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.

Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.

Thyroid hormone (T3) has been known to regulate the basal metabolic rate for more than a century, but mechanistic understanding is lacking both at the level of the intact organism and in terms of how T3 alters energy expenditure in individual tissues. The current studies investigate the question of which metabolically relevant genes respond acutely as T3 concentrations increase through the physiologic range in liver cells. Because this has been technically unfeasible historically, we developed a modified protocol for extracellular flux analysis using a 96-well Extracellular Flux Analyzer (Seahorse Bioscience). Using a modified extracellular flux protocol and LH86 human hepatoma cells, we established an experimental system where small but significant changes in O2 consumption could be reproducibly quantified as hypothyroid cells were exposed to near-physiologic final concentrations of T3 approximately 2 orders of magnitude lower than most studies (0.04nM free T3), in only 6–7 hours. Taking advantage of the nondestructive nature of 96-well Extracellular Flux Analyzer measurements, the acute, direct, transcriptional changes that occur were measured in the exact same cells demonstrating increased O2 consumption. An unbiased, genome-wide microarray analysis identified potential candidate genes related to fatty acid oxidation, angiogenesis, nucleotide metabolism, immune signaling, mitochondrial respiration, and cell proliferation. The identified transcriptome is likely enriched in the genes most important for mediating the energetic effects of T3 in hepatoma cells.

Objective To explore the transcriptome of epicardial adipose tissue (EAT) as compared to subcutaneous adipose tissue (SAT) and its modifications in a small number of patients with coronary artery disease (CAD) versus valvulopathy. Methods SAT and EAT samples were obtained during elective cardiothoracic surgeries. The transcriptome of EAT was evaluated, as compared to SAT, using an unbiased, whole-genome approach in subjects with CAD (n = 6) and without CAD (n = 5), where the patients without CAD had cardiac valvulopathy. Results Relative to SAT, EAT is a highly inflammatory tissue enriched with genes involved in endothelial function, coagulation, immune signaling, potassium transport, and apoptosis. EAT is lacking in expression of genes involved in protein metabolism, tranforming growth factor-beta (TGF-beta) signaling, and oxidative stress. Although underpowered, in subjects with severe CAD, there is an expression trend suggesting widespread downregulation of EAT encompassing a diverse group of gene sets related to intracellular trafficking, proliferation/transcription regulation, protein catabolism, innate immunity/lectin pathway, and ER stress. Conclusions The EAT transcriptome is unique when compared to SAT. In the setting of CAD versus valvulopathy, there is possible alteration of the EAT transcriptome with gene suppression. This pilot study explores the transcriptome of EAT in CAD and valvulopathy, providing new insight into its physiologic and pathophysiologic roles.

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.

Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.

Osteoporosis remains a challenging disease to treat due to a number of barriers including patient adherence to therapies. One of the most recent advances has been the development of the Fracture Risk Assessment Tool, which is helpful in conveying fracture risk to patients and providing treatment guidance to clinicians. The decision to use an anti-osteoporosis therapy must be tailored to the patient's specific clinical scenario. The bisphosphonates are first-line agents in the treatment of osteoporosis and are efficacious in substantially reducing fracture risk between 25% and 70% on average depending on fracture site. Compliance with oral bisphosphonate pills can be poor, resulting in a significant deterrent to the proper management of osteoporosis. Non-pill forms of bisphosphonate and nonbisphosphonate therapy are available for the treatment of osteoporosis and may increase compliance. Among these is Binosto, a new formulation of weekly effervescent alendronate, as well as intravenous bisphosphonates, teriparatide, and subcutaneously administered denosumab, which are all costly medications and are unlikely to become the mainstay of treatment over the oral bisphosphonate pills. Having a detailed conversation between the patient and physician is essential to the development of a tailored treatment plan that will decrease fracture risk.