Syncytialization and prolonged exposure to palmitate impacts bewo respiration

Placental villous trophoblast mitochondrial respiratory function is critical for a successful pregnancy and environmental influences such as maternal obesity have been associated with respiratory impairment at term. More recently, a gestational high fat diet independent of maternal body composition, has been highlighted as a potential independent regulator of placental mitochondrial metabolism. The current study aimed to characterize the direct impact of a prolonged and isolated exposure to the dietary fatty acids Palmitate (PA) and Oleate (OA) upon placental cell mitochondrial respiratory function. BeWo cytotrophoblast (CT) and syncytiotrophoblast (SCT) cells were treated for 72 h with 100 μM PA, OA or PA+OA (P/O). Live-cell metabolic function was analyzed via the Seahorse XF Mito and Glycolysis Stress tests. Immunoblots and spectrophotometric activity assays were utilized to examine the protein expression and function of electron transport chain (ETC) complexes and key mitochondrial regulatory enzymes. Syncytialization of BeWo cells resulted reduced respiratory activity in conjunction with altered complex I and II activity and decreased pyruvate dehydrogenase (PDH) protein expression and activity. PA and P/O treatments were associated with increased basal and maximal respiratory activities in BeWo CT cells without alterations in protein expression or activity of individual ETC complexes and mitochondrial substrate regulators. The metabolic suppression in BeWo SCTs was consistent with that previously observed in primary human trophoblast cell cultures, while the observed increases in respiratory activity in PA-treated BeWo CTs may be indicative of an early timepoint of specific dietary saturated fat-mediated placental cell mitochondrial dysfunction

Reducing risk of type 2 diabetes after gestational diabetes: a qualitative study to explore the potential of technology in primary care

BACKGROUND: Despite the seven-fold increased risk of type 2 diabetes mellitus (T2DM) among females previously diagnosed with gestational diabetes (GD), annual rates of follow-up in primary care are low. There is a need to consider how to reduce the incidence of progression to T2DM among this high-risk group. AIM: To examine the views of females diagnosed with GD to ascertain how to improve primary care support postnatally, and the potential role of technology in reducing the risk of progression to T2DM. DESIGN AND SETTING: A qualitative study of a purposive sample of 27 postnatal females leaving secondary care with a recent diagnosis of GD. METHOD: Semi-structured interviews were conducted with 27 females, who had been previously diagnosed with GD, at around 6-12 weeks postnatally. Interviews were audiotaped, transcribed, and analysed thematically. RESULTS: Facilitators and barriers to engaging in a healthy postnatal lifestyle were identified, the most dominant being competing demands on time. Although females were generally satisfied with the secondary care they received antenatally, they felt abandoned postnatally and were uncertain what to expect from their GP in terms of follow-up and support. Females felt postnatal care could be improved by greater clarity regarding this, and enhanced by peer support, multidisciplinary input, and subsidised facilities. Technology was seen as a potential adjunct by providing information, enabling flexible and personalised self-management, and facilitating social support. CONCLUSION: A more tailored approach for females previously diagnosed with GD may help reduce the risk of progression to T2DM. A need for future research to test the efficacy of using technology as an adjunct to current care was identified

Evaluation of a Mobile App to Enhance Relational Awareness and Change During Cognitive Analytic Therapy: Mixed Methods Case Series

Background: There has been a lack of technological innovation regarding improving the delivery of integrative psychotherapies. This project sought to evaluate an app designed to replace previous paper-based methods supporting relational awareness and change during cognitive analytic therapy (CAT). Objective: We aimed to assess patients’ and therapists’ experience of using the technology (ie, the “CAT-App”) and to evaluate the relationship between app usage and clinical outcome. Methods: The design was a mixed methods case series. Patients completed the Clinical Outcomes in Routine Evaluation-Outcome Measure pre- and post-CAT. Mood data plus the frequency and effectiveness of relational awareness and change were collected via the app. Therapists and patients were interviewed about their experiences using the app. Results: Ten patients (treated by 3 therapists) were enrolled; seven completed treatment and 4 had a reliable improvement in their mental health. App usage and mood change did not differ according to clinical outcome, but there was a statistically significant difference in app usage between completers and dropouts. The qualitative themes described by the therapists were (1) the challenge of incorporating the technology into their clinical practice and (2) the barriers and benefits of the technology. Clients’ themes were (1) data protection, (2) motivation and engagement, and (3) restrictions versus flexibility. Conclusions: The CAT-App is capable of supporting relational awareness and change and is an upgrade on older, paper-based formats. Further clinical evaluation is required

Early conscious prone positioning in patients with COVID-19 receiving continuous positive airway pressure: A retrospective analysis

The global pandemic of COVID-19 has challenged the management of hypoxaemic respiratory failure and strained intensive care unit resources. While prone positioning (PP) is an established therapy in mechanically ventilated patients with acute respiratory distress syndrome (ARDS), its role in conscious patients is less well defined. We retrospectively reviewed our experience of implementing early PP in a cohort of 24 patients with acute hypoxaemic respiratory failure due to COVID-19 who required support with continuous positive airway pressure (CPAP). The use of PP alongside CPAP significantly increased both the ROX index and arterial oxygen pressure:fractional inspired oxygen (PaO 2:FiO 2) ratio from baseline values (ROX index: 7.0±2.5 baseline vs 11.4±3.7 CPAP+PP,

The UK DNA banking network: a “fair access” biobank

The UK DNA Banking Network (UDBN) is a secondary biobank: it aggregates and manages resources (samples and data) originated by others. The network comprises, on the one hand, investigator groups led by clinicians each with a distinct disease specialism and, on the other hand, a research infrastructure to manage samples and data. The infrastructure addresses the problem of providing secure quality-assured accrual, storage, replenishment and distribution capacities for samples and of facilitating access to DNA aliquots and data for new peer-reviewed studies in genetic epidemiology. ‘Fair access’ principles and practices have been pragmatically developed that, unlike open access policies in this area, are not cumbersome but, rather, are fit for the purpose of expediting new study designs and their implementation. UDBN has so far distributed >60,000 samples for major genotyping studies yielding >10 billion genotypes. It provides a working model that can inform progress in biobanking nationally, across Europe and internationally

Exile Vol. VIIb

FICTION Himself by James Kennedy 9-30 Sardo by Joan Harrington 34-36 Doll House by Bruce Tracy 37-42 The Della Baby by Brenda Dean 47-53 Cruel White by Carolyn Colley 57-66 Almost Every Sunday by Sara Easton Curtis 69-74 A Family by William Weaver 78-86 POETRY Spring Songs by Janet Tallman 32-33 Poem by Katherine Lardner 42 Four Poems by Elizabeth Surbeck 43 Indian Pike Mask by James Funaro 44 The Windigo by James Funaro 45 Query by Barbara Purdy 53 A Taste of Eden by Barbara Purdy 53 The Passion of Jeremiah by Barbara Purdy 53 Statement and Comment by Enid Larimer 54-55 Poem by Barbara Thiele 56 Poem by Catherine Thompson 68 Drifting into a Museum Case by Catherine Thompson 68 To Judy by Tanya Shriver 76-77 Sun One by Sara Easton Curtis 86 Poem by Christine Cooper 87 GRAPHICS woodcut by Catherine Thompson 8 etching by Catherine Thompson 17 Two Models (aquatint) by Virginia Piersol 31 woodcut by Elizabeth Surbeck 46 woodcut by Virginia Piersol 67 linocut by John Hand 75 EDITORIAL Wintering by James W Kennedy 5-7 Poem 68 Drifting into a Museum Case 68 and To Judy 76 are all incorrectly attributed to Barbara Thiele in the published Table of Contents. The attributions given above are taken from the pages on which the works are published. The Contributors section of this issue confirms this interpretation. Awarded the EXILE-Denison Bookstore Writing Prize: Himself by James Kennedy 9-3

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants repo

Using human genetics to understand the disease impacts of testosterone in men and women.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.A.R.W. and T.M.F. are supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. R.B. is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. J.T. is supported by the Academy of Medical Sciences Springboard award which is supported by the Wellcome Trust and GCRF [SBF004\1079]. This work was supported by the Medical Research Council [Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2]

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management