"Post-GDM support would be really good for mothers": A qualitative interview study exploring how to support a healthy diet and physical activity after gestational diabetes.

BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM). They are therefore recommended to follow a healthy diet and be physically active in order to reduce that risk. However, achieving and maintaining these behaviours in the postpartum period is challenging. This study sought to explore women's views on suggested practical approaches to achieve and maintain a healthy diet and physical activity to reduce T2DM risk. METHODS: Semi-structured interviews with 20 participants in Cambridgeshire, UK were conducted at three to 48 months after GDM. The participants' current diet and physical activity, intentions for any changes, and views on potential interventions to help manage T2DM risk through these behaviours were discussed. Framework analysis was used to analyse the transcripts. The interview schedule, suggested interventions, and thematic framework were based on a recent systematic review. RESULTS: Most of the participants wanted to eat more healthily and be more active. A third of the participants considered that postpartum support for these behaviours would be transformative, a third thought it would be beneficial, and a third did not want additional support. The majority agreed that more information about the impact of diet and physical activity on diabetes risk, support to exercise with others, and advice about eating healthily, exercising with a busy schedule, monitoring progress and sustaining changes would facilitate a healthy diet and physical activity. Four other suggested interventions received mixed responses. It would be acceptable for this support to be delivered throughout pregnancy and postpartum through a range of formats. Clinicians were seen to have important roles in giving or signposting to support. CONCLUSIONS: Many women would appreciate more support to reduce their T2DM risk after GDM and believe that a variety of interventions to integrate changes into their daily lives would help them to sustain healthier lifestyles.RAD was funded by a PhD studentship from the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR; SPCR-S-S102). This paper presents independent research funded by the NIHR SPCR. The views expressed are those of the author(s) and not necessarily those of the NIHR, the NHS or the Department of Health. JAUS was funded by a Cancer Research UK Cancer Prevention Fellowship (C55650/A21464). SJG is supported by the Medical Research Council (MC_UU_12015/4). The University of Cambridge has received salary support in respect of SJG from the NHS in the East of England through the Clinical Academic Reserve. CEA is supported by an Action Medical Research Grant (GN2778) and a Medical Research Council New Investigator Research Grant (MR/T016701/1). CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the European Foundation for the Study of Diabetes – Novo Nordisk Foundation Future Leaders’ Award (NNF19SA058974). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs

Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA

‘Oh, I’ve got an appointment’: A qualitative interview study exploring how to support attendance at diabetes screening after gestational diabetes

Funder: NIHR School for Primary Care Research; Id: http://dx.doi.org/10.13039/501100013374Funder: Cancer Research UK; Id: http://dx.doi.org/10.13039/501100000289Funder: Action Medical Research; Id: http://dx.doi.org/10.13039/501100000317Funder: European Foundation for the Study of Diabetes; Id: http://dx.doi.org/10.13039/501100001648Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265Funder: Diabetes UK; Id: http://dx.doi.org/10.13039/501100000361Abstract: Aims: To explore the views of women with a history of gestational diabetes mellitus (GDM) on suggested practical approaches to support diabetes screening attendance after GDM, which is recommended but poorly attended. Methods: We conducted semi‐structured interviews with 20 participants in Cambridgeshire, UK who had been diagnosed with GDM and were 3–48 months postpartum. Interviews covered whether participants had been screened and why, plans for future screening and their views on potential interventions to facilitate attendance (at the first postpartum test and annual testing). Framework analysis was used to analyse the transcripts. The interview schedule, suggested interventions and thematic framework were based on a recent systematic review. Results: Sixteen participants had undergone screening since pregnancy, explaining that they had an appointment arranged and wanted reassurance that they did not have diabetes. The participants who had not been tested were not aware that it was recommended. Only 13 had planned to attend subsequent tests at the start of the interview. Eight themes to support future attendance were discussed. The majority of the participants agreed that changing the processes for arranging tests, offering choice in test location and combining appointments would facilitate attendance. Child‐friendly clinics, more opportunities to understand GDM and the role of postpartum testing, stopping self‐testing and increasing their GP’s awareness of their pregnancy received inconsistent feedback. The nature of the test used did not appear to influence attendance. Conclusions: The participants wanted to be screened for diabetes after GDM. We have identified interventions that could be relatively simply incorporated into routine practice to facilitate screening attendance, such as flexibility in the appointment location or time and sending invitations for tests

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

Prisoners’ Families’ Research: Developments, Debates and Directions

After many years of relative obscurity, research on prisoners’ families has gained significant momentum. It has expanded from case-oriented descriptive analyses of family experiences to longitudinal studies of child and family development and even macro analyses of the effects on communities in societies of mass incarceration. Now the field engages multi-disciplinary and international interest although it arguably still remains on the periphery of mainstream criminological, psychological and sociological research agendas. This chapter discusses developments in prisoners’ families’ research and its positioning in academia and practice. It does not aim to provide an all-encompassing review of the literature rather it will offer some reflections on how and why the field has developed as it has and on its future directions. The chapter is divided into three parts. The first discusses reasons for the historically small body of research on prisoners’ families and for the growth in research interest over the past two decades. The second analyses patterns and shifts in the focus of research studies and considers how the field has been shaped by intersecting disciplinary interests of psychology, sociology, criminology and socio-legal studies. The final part reflects on substantive and ethical issues that are likely to shape the direction of prisoners’ families’ research in the future

Multilaboratory Comparison of Pneumococcal Multiplex Immunoassays Used in lmmunosurveillance of Streptococcus pneumoniae across Europe

Surveillance studies are required to estimate the impact of pneumococcal vaccination in both children and the elderly across Europe. The World Health Organization (WHO) recommends use of enzyme immunoassays (EIAs) as standard methods for immune surveillance of pneumococcal antibodies. However, as levels of antibodies to multiple serotypes are monitored in thousands of samples, a need for a less laborious and more flexible method has evolved. Fluorescent-bead-based multiplex immunoassays (MIAs) are suitable for this purpose. An increasing number of public health and diagnostic laboratories use MIAs, although the method is not standardized and no international quality assessment scheme exists. The EU Pneumo Multiplex Assay Consortium was initiated in 2013 to advance harmonization of MIAs and to create an international quality assessment scheme. In a multilaboratory comparison organized by the consortium, agreement among nine laboratories that used their own optimized MIA was assessed on a panel of 15 reference sera for 13 pneumococcal serotypes with the new WHO standard 007sp. Agreement was assessed in terms of assay accuracy, reproducibility, repeatability, precision, and bias. The results indicate that the evaluated MIAs are robust and reproducible for measurement of vaccine-induced antibody responses. However, some serotype-specific variability in the results was observed in comparisons of polysaccharides from different sources and of different conjugation methods, especially for serotype 4. On the basis of the results, the consortium has contributed to the harmonization of MIA protocols to improve reliability of immune surveillance of Streptococcus pneumoniae

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival