Continuous glucose monitoring in pregnant women with Type 1 diabetes: benefits for mothers, using pumps or pens, and their babies

Aims: To review the current literature on the use of continuous glucose monitoring during pregnancy in women with Type 1 diabetes. Methods: We searched the literature for randomized controlled trials using continuous glucose monitoring during pregnancy in women with Type 1 diabetes. Results: Three randomized trials were found and discussed in this review. One UK study found a reduction in large-for-gestational-age infants; however, only masked continuous glucose monitoring was used in that study. A Danish study used intermittent real-time continuous glucose monitoring and found no differences. The present authors conducted the CONCEPTT trial, in which pregnant women and women planning pregnancy were randomized to receive continuous glucose monitoring or standard care. We found a greater drop in HbA1c, more time spent in the target range, and a reduction in some adverse neonatal outcomes in women using continuous glucose monitoring. Numbers-needed-to-treat to prevent a large-for-gestational-age infant, a neonatal intensive care unit admission for >24 h, and a neonatal hypoglycaemia event were low. These findings were seen in both injection and pump users and across all countries. Possible reasons for differences in study findings are discussed. In addition, several issues need further study. Glycaemic variability and differences in dietary intake may also have played a role. Despite excellent glycaemic control, babies continue to be large. More research is needed to understand the role of glucose targets and the dynamic placental processes involved in fetal growth. Conclusions: The use of continuous glucose monitoring in women with Type 1 diabetes in pregnancy is associated with improved glycaemic control and neonatal outcomes. Further research examining the glycaemic and non-glycaemic variables involved in fetal growth and the cost–benefit of using continuous glucose monitoring in pregnancy is warranted

Dietary intakes of women with Type 1 diabetes before and during pregnancy: A pre‐specified secondary subgroup analysis among CONCEPTT participants

Aim To describe the dietary intakes of women with Type 1 diabetes before and during pregnancy. Methods This was a pre‐specified subgroup analysis of CONCEPTT involving 63 women planning pregnancy and 93 pregnant women from 14 sites in England, Scotland and Ireland. Two hundred and forty‐six 3‐day food diaries (104 planning pregnancy, 142 pregnant) were matched to data source and food reference codes, and analysed using dietary software. Participants were informed that food diaries would be de‐identified and used only for research purposes. Results Mean (sd) daily energy intake was 1588 (346) kcal and 1673 (384) kcal in women planning pregnancy and pregnant women respectively. Total carbohydrate intake was consistent with dietary guideline recommendations [180 (52) g planning pregnancy, 198 (54) g pregnant], but non‐recommended sources (e.g. sugars, preserves, confectionery, biscuits, cakes) contributed to 46% of total daily carbohydrate intake. Fat consumption exceeded guideline recommendations [70 (21) g planning pregnancy, 72 (21) g pregnant]. Fibre [15.5 (5.3) g planning pregnancy, 15.4 (5.1) g pregnant], fruit and vegetable intakes [3.5 (2.2) and 3.1 (1.8) serves/day] were inadequate. Twelve women planning pregnancy (19%) and 24 pregnant women (26%) did not meet micronutrient requirements. Conclusions The diets of pregnant women from England, Scotland and Ireland are characterized by high fat, low fibre and poor‐quality carbohydrate intakes. Fruit and vegetable consumption is inadequate, with one in four women at risk of micronutrient deficiencies. Further research is needed to optimize maternal nutrition for glycaemic control and for maternal and offspring health

Entanglement area laws for long-range interacting systems

We prove that the entanglement entropy of any state evolved under an arbitrary 1/r^α long-range-interacting D-dimensional lattice spin Hamiltonian cannot change faster than a rate proportional to the boundary area for any α>D+1. We also prove that for any α>2D+2, the ground state of such a Hamiltonian satisfies the entanglement area law if it can be transformed along a gapped adiabatic path into a ground state known to satisfy the area law. These results significantly generalize their existing counterparts for short-range interacting systems, and are useful for identifying dynamical phase transitions and quantum phase transitions in the presence of long-range interactions

Geometric-Phase-Effect Tunnel-Splitting Oscillations in Single-Molecule Magnets with Fourth-Order Anisotropy Induced by Orthorhombic Distortion

We analyze the interference between tunneling paths that occurs for a spin system with both fourth-order and second-order transverse anisotropy. Using an instanton approach, we find that as the strength of the second-order transverse anisotropy is increased, the tunnel splitting is modulated, with zeros occurring periodically. This effect results from the interference of four tunneling paths connecting easy-axis spin orientations and occurs in the absence of any magnetic field.Comment: 6 pages, 5 eps figures. Version published in EPL. Expanded from v1: Appendix added, references added, 1 figure added, others modified cosmeticall

CHARMM36m: An improved force field for folded and intrinsically disordered proteins.

The all-atom additive CHARMM36 protein force field is widely used in molecular modeling and simulations. We present its refinement, CHARMM36m (http://mackerell.umaryland.edu/charmm_ff.shtml), with improved accuracy in generating polypeptide backbone conformational ensembles for intrinsically disordered peptides and proteins

Finite temperature phase diagram of spin-1/2 bosons in two-dimensional optical lattice

We study a two-species bosonic Hubbard model on a two-dimensional square lattice by means of quantum Monte Carlo simulations and focus on finite temperature effects. We show in two different cases, ferro- and antiferromagnetic spin-spin interactions, that the phase diagram is composed of solid Mott phases, liquid phases and superfluid phases. In the antiferromagnetic case, the superfluid (SF) is polarized while the Mott insulator (MI) and normal Bose liquid (NBL) phases are not. On the other hand, in the ferromagnetic case, none of the phases is polarized. The superfluid-liquid transition is of the Berezinsky-Kosterlitz-Thouless type whereas the solid-liquid passage is a crossover.Comment: 9 pages, 13 figure

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.)

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8+ T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP+ stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP+ cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP+ CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and in flammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP+ CAF, may direct tumor immune evasion in a model of human PDA