Effects of maternal stress and obesity on human feto-placental glucocorticoid exposure

Fetal exposure to excess glucocorticoids has been proposed as a key determinant of pregnancy outcome, as well as a predictor of long term health of the offspring through a phenomenon known as ‘developmental programming’. Obesity and ‘stress’ during pregnancy are two potential sources of altered fetal exposure to glucocorticoids. One in five pregnant women is obese at antenatal booking, and maternal obesity increases risk of offspring complications including higher birth weight, potentially leading to long-term programming effects on the offspring. Likewise, maternal anxiety during pregnancy has been identified as a programming factor, increasing the risk of psychopathology in the offspring. This thesis tests the hypothesis that in humans this association is mediated by altered action of glucocorticoids, by examining circulating levels of maternal glucocorticoids during pregnancy and through measurement of key genes in the placenta regulating fetal glucocorticoid exposure. Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n=173 class III obese (BMI 44.0±4.5kg/m2) and n=107 lean (BMI 22.8±1.6kg/m2) pregnant women. Serial corticosteroid binding globulin (CBG) concentrations were measured in a subset (n=39 lean, 26 obese) and free cortisol levels calculated using Coolen’s equation. CRH concentrations were measured at the same time points in obese (n=20) and lean (n=22) pregnant women Salivary cortisol was measured in samples collected at bed-time, waking and 30 minutes after waking. mRNA levels of candidate genes regulating glucocorticoids and fetal/placental growth including 11-beta hydroxysteroid dehydrogenase type 2 (11βHSD2), which inactivates cortisol, insulin-like growth factor 2 (IGF2) and glucocorticoid receptor (GR) were measured in first trimester (n=32), second trimester (n=15) and term (n=60) placental samples. DNA methylation of key regions controlling the expression of the IGF2, GR and 11βHSD2 genes was measured by pyrosequencing in first trimester and term samples. Levels of mRNAs encoding 11βHSD1, 11βHSD2, GR and MR were measured in term placentas collected from women from Helsinki, Finland in whom anxiety during pregnancy had been prospectively assessed using validated questionnaires. Term placental samples from a subset of the obese and lean women who had also completed stress questionnaires during pregnancy were used to examine replication of findings. Cortisol levels rose similarly during pregnancy in obese and lean but were significantly lower throughout pregnancy in obese women (p<0.05). The diurnal rhythm of cortisol was maintained. CBG levels also increased, though this change was lower in obese (1.21-fold (±0.9) vs 1.56-fold (±0.07), p<0.01). In obese women, lower calculated free cortisol at 16 weeks gestation was associated with higher birth weight after adjustment for other factors (r=-0.46, p<0.05). Placental mRNA encoding 11βHSD2 increased in association with increasing obesity in early pregnancy (r=0.44, p<0.01) and was highest in term placenta in obese women with macrosomic (>4000g) offspring (p<0.05). Placental transcript abundance of GR also increased in association with increasing obesity in early pregnancy (r=0.38, p<0.05), but was lowest in term placenta from obese with macrosomic offspring (p<0.05). IGF2 mRNA abundance was lower in the placentas of obese women with macrosomic offspring at term compared to both lean women and obese women with normal weight offspring (p<0.01). Methylation results are reported. Placental mRNA levels encoding 11βHSD1 (which converts inactive cortisone to active cortisol) at term was found to positively associate with maternal anxiety measured in the first trimester of pregnancy in a group of pregnant Finnish women (β=0.3, p<0.05). Findings were similar in the replication sample in lean women only (β=4.6, p<0.05). Lower circulating and bioavailable cortisol levels in early pregnancy, together with a greater placental ‘barrier’ to maternal glucocorticoids represent key mechanisms contributing to higher birth weight in offspring of obese women. Regeneration of active glucocorticoids in placenta and increasing placental sensitivity to glucocorticoids increases fetal glucocorticoid exposure and offers insight into the biological mechanisms underlying adverse offspring effects of maternal prenatal anxiety

Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005-2019), by area deprivation profile : linked electronic health records cohort study on 965,905 individuals

Funding: This work was supported by Health Data Research UK (HDRUK) Measuring and Understanding Multimorbidity using Routine Data in the UK (MUrMuRUK, HDR-9006; CFC0110). Health Data Research UK (HDR-9006) is funded by: UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, the National Institute for Health Research (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. This work also was co-funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR) through grant number MR/S027750/1. The work was supported by the ADR Wales programme of work, part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1).Background  Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK. Methods  Population-wide electronic linked cohort study, following Welsh residents for up to 20 years (2000-2019). Chronic disease diagnoses were obtained from general practice and hospitalisation records using the CALIBER disease phenotype register. Multi-state models were used to examine trajectories of accrual of 132 diseases and mortality, adjusted for sex, age and area-level deprivation. Restricted mean survival time was calculated to measure time spent free of chronic disease(s) or mortality between socioeconomic groups. Findings  In total, 965,905 individuals aged 5-104 were included, from a possible 2·9m individuals following a 5-year clearance period, with an average follow-up of 13·2 years (12·7 million person-years). Some 673,189 (69·7 %) individuals developed at least one chronic disease or died within the study period. From ages 10 years upwards, the individuals living in the most deprived areas consistently experienced reduced time between health states, demonstrating accelerated transitions to first and subsequent morbidities and death compared to their demographic equivalent living in the least deprived areas. The largest difference were observed in 10 and 20 year old males developing multimorbidity (-0·45 years (99%CI:-0·45,-0·44)) and in 70 year old males dying after developing multimorbidity (-1·98 years (99%CI:-2·01,-1·95)). Interpretation  This study adds to the existing literature on health inequalities by demonstrating that individuals living in more deprived areas consistently experience accelerated time to diagnosis of chronic disease and death across all ages, accounting for competing risks.Publisher PDFPeer reviewe

Transplantation in Remission Improves the Disease-Free Survival of Patients with Advanced Myelodysplastic Syndromes Treated with Myeloablative T Cell-Depleted Stem Cell Transplants from HLA-Identical Siblings

AbstractFrom 1985 to 2004, 49 patients with advanced myelodysplastic syndromes (MDS) (≥5% blasts) or acute myeloid leukemia (AML) transformed from MDS underwent T cell depleted bone marrow or peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings following conditioning with a myeloablative regimen that included total body irradiation (44 patients) or busulfan (5 patients). Thirty-six patients received chemotherapy (3 low dose and 33 induction doses) before conditioning, and 13 patients did not receive any chemotherapy. Prior to transplantation, 22 of the 36 treated patients were in hematologic remission; 4 were in a second refractory cytopenia phase (26 responders); 8 had failed to achieve remission; and 2 of the responders had progression or relapse of their MDS (10 failures). No post-transplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD) was given. The median age was 48 yrs (range 13-61). Forty-five of the 49 patients engrafted; 2 had primary graft failure; and 2 died before engraftment. Only 3 patients developed acute GVHD (aGVHD) (grades I and III) and 1 chronic GVHD (cGVHD). At 3 yrs post-transplantation, the overall survival (OS) was 54% in the responders; 31% in the untreated group; and 0% in the failure group (P=.0004). The disease free survival (DFS) was 50%, 15% and 0% in each group respectively (P=.0008). In multivariate analysis, disease status before cytoreduction remained highly correlated with DFS (P<.001). The cumulative incidence (CI) of relapse at 2-yrs post-transplantation for the responders was 23%; for the untreated group was 38%; and for the failures was 50%. The CI of non-relapse mortality at 2-yrs post-transplantation, for the responders was 23%; for the untreated group was 38%; and for the failures was 40%. All survivors achieved a Karnofsky Performance Status (KPS) of ≥90. These results indicate that patients with advanced MDS who achieve and remain in remission or a second refractory cytopenia phase with chemotherapy before conditioning can achieve successful long-term remissions following a myeloablative T cell depleted allogeneic HSCT

Long-term prognosis for 1-year relapse-free survivors of CD34 cell-selected allogeneic hematopoietic stem cell transplantation : a landmark analysis

Altres ajuts: This research was supported in part by National Institutes of Health award number P01 CA23766 and NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.CD34 selection significantly improves GVHD-free survival in allogeneic hematopoietic cell transplantation (allo-HSCT). Specific information regarding long-term prognosis and risk factors for late mortality after CD34-selected allo-HSCT is lacking, however. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34-selected allo-HSCT for AML (n=164), ALL (n=33), or MDS (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated RFS was 73% and OS 76%. The 5-year cumulative incidence of relapse and NRM were 11% and 16%, respectively. In multivariate analysis, HCT-CI score ≥ 3 correlated with marginally worse RFS (HR 1.78, 95% CI 0.97-3.28, p=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, p=0.004). Despite only 24% of patients with acute GVHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GVHD associating with increasingly poorer survival on multivariate analysis (p<0.0001). Of 63 deaths after the landmark, GVHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. While prognosis is excellent for patients alive without relapse 1 year after CD34-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GVHD

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial

Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown

Evaluation of effectiveness and safety of pharmacist independent prescribers in care homes : cluster randomised controlled trial

Acknowledgments We thank all participating care home residents, care homes, and general practices; the pharmacist independent prescribers; our patient and public involvement group; our pharmacist trainers and assessors; Norwich Clinical Trials Unit; Comprehensive Research Network Eastern; our sponsor (Norfolk and Waveney CCG); members of our Programme Steering Committee and Data Monitoring and Ethics Committee; our funders; and all the many other people who supported the delivery of the programme of research that culminated in this trial. Funding: This work was funded by National Institutes of Health Research (NIHR) through their Programme Grant for Applied Research (PGfAR) stream (RP-PG-0613-20007). The funder had no role in design, data collection, data analysis, data interpretation, or writing of this paper.Peer reviewedPublisher PD

In ricordo di Paolo Sylos Labini

Background: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age. Methods/Findings: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhiça, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged 93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1–2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India. Conclusions: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved

Sanitation and Hygiene-Specific Risk Factors for Moderate-to-Severe Diarrhea in Young Children in the Global Enteric Multicenter Study, 2007-2011: Case-Control Study.

Background: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age. Methods/Findings: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhiça, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged 93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1–2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India. Conclusions: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved

The Care Home Independent Pharmacist Prescriber Study (CHIPPS) : Development and implementation of an RCT to estimate safety, effectiveness and cost-effectiveness

This research was supported by the National Institute for Health and Care Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR YH PSTRC). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This report is dedicated to Kate Massey, an active and enthusiastic member of the CHIPPS patient and public involvement team who sadly passed away during the delivery of this study.Peer reviewedPublisher PD