Dissecting the Workforce and Workplace for Clinical Endocrinology, and the Work of Endocrinologists Early in Their Careers

[Excerpt] No national mechanism is in place for an informed, penetrating, and systematic assessment of the physician workforce such as that achieved by the National Science Foundation (NSF) for the periodic evaluation of the nation’s scientists and engineers. Likewise, knowledge of the workforce for clinical research is enigmatic and fragmentary despite the serial recommendations of “blue-ribbon” panels to establish a protocol for the recurrent assessment of clinical investigators early in their careers. Failure to adopt a national system for producing timely, high-quality data on the professional activities of physicians limits the application of improvement tools for advancing clinical investigation and ultimately improving clinical practice. The present study was designed as a pilot project to test the feasibility of using Web-based surveys to estimate the administrative, clinical, didactic, and research work of subspecialty physicians employed in academic, clinical, federal, and pharmaceutical workplaces. Physician members of The Endocrine Society (TES) were used as surrogate prototypes of a subspecialty workforce because of their manageable number and investigative tradition. The results establish that Web-based surveys provide a tool to assess the activities of a decentralized workforce employed in disparate workplaces and underscore the value of focusing on physician work within the context of particular workplaces within a subspecialty. Our report also provides a new and timely snapshot of the amount and types of research performed by clinically trained endocrinologists and offers an evidenced-based framework for improving the investigative workforce in this medical subspecialty

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Subclinical thyroid dysfunction and cognitive decline in old age

<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p> <p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p> <p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p> <p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p&gt

Subclinical thyroid dysfunction and cognitive decline in old age

<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p> <p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p> <p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p> <p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p&gt

Defining Optimal Health Range for Thyroid Function Based on the Risk of Cardiovascular Disease.

Reference ranges of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are defined by their distribution in apparently healthy populations (2.5th and 97.5th percentiles), irrespective of disease risk, and are used as cutoffs for defining and clinically managing thyroid dysfunction. To provide proof of concept in defining optimal health ranges of thyroid function based on cardiovascular disease (CVD) mortality risk. In all, 9233 participants from the Rotterdam Study (mean age, 65.0 years) were followed up (median, 8.8 years) from baseline to date of death or end of follow-up period (2012), whichever came first (689 cases of CVD mortality). We calculated 10-year absolute risks of CVD mortality (defined according to the SCORE project) using a Fine and Gray competing risk model per percentiles of TSH and FT4, modeled nonlinearly and with sex and age adjustments. Overall, FT4 level >90th percentile was associated with a predicted 10-year CVD mortality risk >7.5% (P = 0.005). In men, FT4 level >97th percentile was associated with a risk of 10.8% (P < 0.001). In participants aged ≥65 years, absolute risk estimates were <10.0% below the 30th percentile (∼14.5 pmol/L or 1.10 ng/dL) and ≥15.0% above the 97th percentile of FT4 (∼22 pmol/L or 1.70 ng/dL). We describe absolute 10-year CVD mortality risks according to thyroid function (TSH and FT4) and suggest that optimal health ranges for thyroid function can be defined according to disease risk and are possibly sex and age dependent. These results need to be replicated with sufficient samples and representative populations

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes

Defining optimal health range for thyroid function based on the risk of cardiovascular disease.

Context Reference ranges of thyroid stimulating hormone (TSH) and free thyroxine (FT4) are defined by their distribution in apparently healthy populations, (2.5th and 97.5th percentiles) irrespective of disease risk and used as cut-offs for defining and clinically managing thyroid dysfunction. Objective To provide a proof of concept in defining thyroid function optimal health ranges based on cardiovascular disease (CVD) mortality risk. Design and Participants 9,233 participants from the Rotterdam Study (mean age 65.0 years) were followed up (median 8.8 years) from baseline to date of death or end of follow-up (2012), which ever came first (689 cases of CVD mortality). Main Outcomes We calculated 10-year absolute risks of CVD mortality (defined according to SCORE project) using a Fine and Grey competing risk model per percentile of TSH and FT4, modelled non-linearly and sex- and age-adjusted. Results Overall, FT4 > 90th percentile was associated with a predicted 10-year CVD mortality risk >7.5% (p =0.005). In men, FT4 > 97th percentile was associated with a risk of 10.8% (p<0.001). In participants ≥ 65 years, absolute risk estimates were <10.0% below the 30th percentile (∼14.5 pmol/L or 1.10 ng/dL) and ≥15.0% above the 97th percentile of FT4 (∼22 pmol/L or 1.70 ng/dL). Conclusions We describe absolute 10-year CVD mortality risks according to thyroid function (TSH and FT4) and suggest optimal health ranges for thyroid function can be defined according to disease risk and are possibly sex and age-dependent. These results need to be replicated with sufficient samples and representative populations

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

Background Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. Objective To investigate the association between subclinical thyroid dysfunction and bone loss. Methods Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946–2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45–4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50–19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. Results Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = −0.18 (95% CI: −0.34, −0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = −0.14 (95% CI: −0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: −0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = −0.59; [95% CI: −0.99, −0.19]) and total hip region (%ΔBMD = −0.46 [95% CI: −1.05, −0.13]). In contrast, SHypo was not associated with bone loss at any site. Conclusion Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk

Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute.

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular (LV) hypertrophy without dilatation and without apparent cause (ie, it occurs in the absence of severe hypertension, aortic stenosis, or other cardiac or systemic diseases that might cause LV hypertrophy). Numerous excellent reviews and consensus documents provide a wealth of additional background.1–8 HCM is the leading cause of sudden death in young people and leads to significant disability in survivors. It is caused by mutations in genes that encode components of the sarcomere. Cardiomyocyte and cardiac hypertrophy, myocyte disarray, interstitial and replacement fibrosis, and dysplastic intramyocardial arterioles characterize the pathology of HCM. Clinical manifestations include impaired diastolic function, heart failure, tachyarrhythmia (both atrial and ventricular), and sudden death. At present, there is a lack of understanding of how the mutations in genes encoding sarcomere proteins lead to the phenotypes described above. Current therapeutic approaches have focused on the prevention of sudden death, with implantable cardioverter defibrillator placement in high-risk patients. But medical therapies have largely focused on alleviating symptoms of the disease, not on altering its natural history. The present Working Group of the National Heart, Lung, and Blood Institute brought together clinical, translational, and basic scientists with the overarching goal of identifying novel strategies to prevent the phenotypic expression of disease. Herein, we identify research initiatives that we hope will lead to novel therapeutic approaches for patients with HCM