Data, Social Determinants, and Better Decision-making for Health: the 3-D Commission

More than a decade after the World Health Organization Commission on the Social Determinants of Health (SDoH), it is becoming widely accepted that social and economic factors, including but not limited to education, energy, income, race, ethnicity, and housing, are important drivers of health in populations. Despite this understanding, in most contexts, social determinants are not central to local, national, or global decision-making. Greater clarity in conceptualizing social determinants, and more specificity in measuring them, can move us forward towards better incorporating social determinants in decision-making for health. In this paper, first, we summarize the evolution of the social framing of health. Second, we describe how the social determinants are conceptualized and contextualized differently at the global, national, and local levels. With this, we seek to demonstrate the importance of analyzing and understanding SDoH relative to the contexts in which they are experienced. Third, we problematize the gap in data across contexts on different dimensions of social determinants and describe data that could be curated to better understand the influence of social determinants at the local and national levels. Fourth, we describe the necessity of using data to understand social determinants and inform decision-making to improve health. Our overall goal is to provide a path for our collective understanding of the foundational causes of health, facilitated by advances in data access and quality, and realized through improved decision-making

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

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

Thyroid hormone activation by type2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression in skeletal muscle

Key points In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor- coactivator-1 (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a -adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression.Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. AbstractThyroid hormone promotes expression of peroxisome proliferator-activated receptor- coactivator-1 (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3-triiodothyronine (T-3), the active thyroid hormone. To test whether D2-generated T-3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1mg(100g body weight)(-1) propranolol or 6mg(100g body weight)(-1) iopanoic acid (5.9- vs. 2.8-foldP<0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9-vs. 2.8-foldP<0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1m forskolin (2.2- vs. 1.3-foldP<0.05). Chronic exercise training (6weeks) increased soleus muscle PGC-1a mRNA levels (approximate to 25%) and the mitochondrial enzyme citrate synthase (approximate to 20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by approximate to 30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a -adrenergic receptor-dependent mechanism. The accelerated conversion of T-4 to T-3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.National Institute of Diabetes and Digestive and Kidney DiseasesBrazilian National Research Council (CNPq)Carlos Chagas Filho Foundation for Research Support in Rio de Janeiro (FAPERJ)American Thyroid Association (ATA)Hungarian Research Fund (OTKA)Coordination for the Improvement of Higher Education Personnel (CAPES)Rush Univ, Med Ctr, Div Endocrinol & Metab, Chicago, IL 60612 USAUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilUniv Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, BR-21941 Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Sch Phys Educ & Sports, BR-21941 Rio De Janeiro, BrazilUniv Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USAUniv Prebiteriana Mackenzie, Dev Disorders Program, Ctr Biol & Hlth Sci, Sao Paulo, BrazilHungarian Acad Sci, Dept Endocrine Neurobiol, Inst Expt Med, Budapest, HungaryUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilNIH: R01 65055ATA: M1301627OTKA: K109415Web of Scienc

Motility Evaluation in the Patient with Inflammatory Bowel Disease

Patients with inflammatory bowel disease (IBD) suffer frequently from functional bowel diseases (FBD) and motility disorders. Management of FBD and motility disorders in IBD combined with continued treatment of a patient’s IBD symptoms will likely lead to better clinical outcomes and improve the patient’s quality of life. The goals of this review were to summarize the most recent literature on motility disturbances in patients with IBD and to give a brief overview of the ranges of motility disturbances, from reflux disease to anorectal disorders, and discuss their diagnosis and specific management

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010:a systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs).METHODS: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis.FINDINGS: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa.INTERPRETATION: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world.FUNDING: Bill &amp; Melinda Gates Foundation.</p