Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

Functional dissection of the c-myc mRNA coding region instability determinant

The c-myc oncogene encodes a transcription factor that promotes cell proliferation and whose overexpression leads to cancer. As seen with other tightly regulated genes, c-myc mRNA contains AU-rich elements in its 3\u27-untranslated region (UTR) that maintain its expression at a low level by destabilizing the mRNA. In addition, the c-myc mRNA is unique in that it also contains a coding region destabilizing element that functions independently from typical 3\u27-UTR instability elements. This 249 nt coding region instability determinant (CRD) is bound by the IMP-1 RNA-binding protein and contains endonuclease cleavage sites identified in vitro. In order to characterize the cis-acting sequences responsible for the destabilizing function of this element, we produced a number of CRD deletions for studying the sequences required for both the in vitro protein-binding activity of IMP-1 and for the ability of the CRD to function as a destabilizing element in cells. The decay of a β-globin reporter mRNA containing the CRD was measured during HL-60 and K562 cell differentiation and arsenite-induced cell stress in an attempt to identify cell systems where the CRD was specifically targeted. The role of the IMP family as trans-acting factors on the destabilizing activity of the CRD was analyzed by measuring CRD-mediated decay following IMP overexpression or siRNA-mediated knock-down. Based on UV-crosslinking data with cell extracts, we also determined that IMP-1 is not the only protein to bind this region. We identify several of the additional RNA-binding proteins as AUF1, nucleolin, and UNR. We verified the ability of these proteins to interact with the CRD using recombinant proteins in RNA electromobility shift assays as well as examining the potential role of these proteins in CRD-mediated instability following siRNA-mediated knockdown in HL-60 cells. We conclude that while IMP-1, AUF1, nucleolin, and UNR can all bind the CRD, only AUF1 is directly involved in the destabilizing mechanism of the CRD

Reproductive strategies among extant amphibian species.

<p>Numbers represent estimates of the total number of species in each group, the percent of known species thought to have internal fertilization, and the number of species thought to be either viviparous or ovoviviparous. In groups with no number in the “viviparous or ovoviviparous” column, all species are oviparous. The * denotes a single oviparous species with unconfirmed accounts of it giving birth to free swimming larvae under abnormal laboratory conditions <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Briegleb1" target="_blank">[12]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Greven1" target="_blank">[13]</a>. Salamander families are shown in black, and the current study focuses on species in the Ambystomatidae family. Branch lengths are not meaningful <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Sever1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Bruce1" target="_blank">[9]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Larson1" target="_blank">[31]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091919#pone.0091919-Frost1" target="_blank">[33]</a>.</p

<i>Ambystoma jeffersonianum-laterale</i> embryos.

<p>A) Typical <i>Ambystoma jeffersonianum-laterale</i> eggs in cleavage stage 4 laid in a pond in western Massachusetts. B) A portion of a clutch extracted from a road-killed unisexual <i>Ambystoma jeffersonianum-laterale</i>. C) Fluorescence image of a DAPI-stained embryo from the clutch of the road-killed individual in approximately development stage 10. The blue dots are cell nuclei, the pink dots are surface reflections of the light source. D) A sectioned embryo showing a fluid-filled center with nuclei distributed around the periphery. E) A close up of nuclei in an embryo.</p

CONCEPTT : Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol

Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. NCT01788527 December 19, 2012

The cataract and Glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter

Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis-Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition

Continuous glucose monitoring time-in-range and HbA1c targets in pregnant women with type 1 diabetes

The CONCEPTT trial compared real-time Continuous Glucose Monitoring (RT-CGM) to capillary glucose monitoring in pregnant women with type 1 diabetes. We analyzed CGM and glycated hemoglobin (HbA1c) measures in first (n = 221), second (n = 197), and third (n = 172) trimesters, aiming to examine target glucose attainment and associations with pregnancy outcomes. CGM targets were Time-in-range (TIR) &gt; 70%, Time-above-range (TAR) &lt;25%, and Time-below-range (TBR) &lt; 4%, and HbA1c targets &lt; 6.5% (National Institute for Health and Care Excellence [NICE]) and HbA1c &lt; 6.0% in second and third trimesters (American Diabetes Association [ADA]). TIR/TAR/TBR targets were achieved by 7.7/14.5/30.3% participants in first, 10.2/14.2/52.8% in second, and 35.5/37.2/52.9% in third trimesters. CGM target attainment was low but increased during pregnancy and with RT-CGM use. In the adjusted analyses, achieving TBR target was associated with a higher risk of pre-eclampsia and neonatal hypoglycemia. ADA HbA1c target attainment was low and unchanged during pregnancy (23.5/27.9/23.8%) but increased with RT-CGM use. In the adjusted analyses, HbA1c target attainment was associated with a lower risk of preterm birth, large-for-gestational age and neonatal hypoglycemia. We conclude that CONCEPTT trial participants had a low rate of CGM and of HbA1c target attainment. Attainment of CGM and NICE HbA1c targets increased throughout gestation and all targets (both NICE/ADA HbA1c and CGM) were more likely to be achieved by RT-CGM users, at 34 weeks' gestation. ADA HbA1c target achievement was independently associated with better perinatal outcomes, while the independent association of TBR target achievement with increased risk warrants further study. ClinicalTrials.gov Registration Identifier NCT01788527

Erratum : CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol [BMC Pregnancy Childbirth., 16, (2016) (167)] doi: 10.1186/s12884-016-0961-5

After publication of the original article [1], it came to the authors' attention that an incorrect affiliation was inadvertently added in the Acknowledgements section for the CONCEPTT Collaborative Group. The authors would like to amend the following statement in the CONCEPTT Collaborative Group section as follows: The correct affiliation for Julia Lowe and Anna Rogowsky should read Sunnybrook Health Sciences Centre, Toronto