Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response.

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study.

INTRODUCTION: The easily-imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia. METHODS: In a population-based study of 12,482 adults aged 50-73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993-1995) with incident all-cause dementia (1993-1995 to 2011-2013) and with etiologic subtype of dementia/mild cognitive impairment (2011-13). RESULTS: A total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36-2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09-1.45) were associated with all-cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular-related, but not Alzheimer's disease-related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24-4.23). DISCUSSION: Exploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia.

Rationale, design, and methods for the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes (MOMPOD) study.

BACKGROUND: Annually in the US, over 100,000 pregnant women with overt type 2 diabetes give birth. Strict maternal glycemic control is the key to optimizing infant outcomes. Medical treatment of type 2 diabetes in pregnancy is generally restricted to insulin, as data on the safety and efficacy of oral hypoglycemic agents in pregnancy are limited. However, over one-third of infants born to women with type 2 diabetes experience an adverse outcome, such as premature delivery, large-for-gestational age, hypoglycemia, hyperbilirubinemia, or birth trauma, suggesting that current treatment regimens fall short of optimizing outcomes. Metformin is the pharmacologic treatment of choice for type 2 diabetes outside of pregnancy. Metformin is favored over insulin because it results in less weight gain, fewer hypoglycemic episodes, and is administered orally rather than injected. However, metformin is not typically used for treatment of type 2 diabetes complicating pregnancy, mainly because no large clinical studies have been conducted to examine its use in this context. METHODS/DESIGN: This is a randomized double-blind multi-center clinical trial of insulin plus metformin versus insulin plus placebo for the treatment of type 2 diabetes complicating pregnancy. A total of 1200 women with type 2 diabetes will be randomized between 10 weeks 0 days' and 20 weeks 6 days' gestation and followed until 30 days after delivery. Neonate outcomes will be followed until 30 days of age. The primary aim is to compare the effect of insulin and metformin versus insulin and placebo on composite adverse neonatal outcomes, comprising perinatal mortality, preterm delivery, neonatal hypoglycemia, hyperbilirubinemia, large-for-gestational age small for gestational age, low birth weight, and/or birth trauma. Key secondary aims are to compare treatment groups for neonatal fat mass and rate of maternal hypoglycemia. Additional aims are to assess the side effects and safety of insulin and metformin among pregnant women with overt type 2 diabetes and to compare gestational weight gain among women treated with metformin plus insulin versus insulin alone. DISCUSSION: Successful completion of this study will result in high-quality, contemporary evidence for management of overt type 2 diabetes complicating pregnancy to improve neonatal outcomes. TRIAL REGISTRATION: NCT02932475 (05/17/2016).