Fetal hyperglycemia and a high fat diet contribute to aberrant glucose tolerance and hematopoiesis in adulthood

Background Children exposed to gestational diabetes mellitus (GDM) during pregnancy are at increased risk of obesity, diabetes, and hypertension. Our goal was to identify metabolic and hematopoietic alterations after intrauterine exposure to maternal hyperglycemia that may contribute to the pathogenesis of chronic morbidities. Methods Streptozotocin treatment induced maternal hyperglycemia during the last third of gestation in rat dams. Offspring of control mothers (OCM) and diabetic mothers (ODM) were evaluated for weight, glucose tolerance, insulin tolerance, and hematopoiesis defects. The effects of aging were examined in normal and high fat diet (HFD)-fed young (8-week-old) and aged (11-month-old) OCM and ODM rats. Results Young adult ODM males on a normal diet, but not females, displayed improved glucose tolerance due to increased insulin levels. Aged ODM males and females gained more weight than OCM on a HFD and had worse glucose tolerance. Aged ODM males fed a HFD were also neutrophilic. Increases in bone marrow cellularity and myeloid progenitors preceded neutrophilia in ODM males fed a HFD. Conclusion When combined with other risk factors like HFD and aging, changes in glucose metabolism and hematopoiesis may contribute to the increased risk of obesity, type 2 diabetes, and hypertension observed in children of GDM mothers

Patterns of Local-Regional Management Following Neoadjuvant Chemotherapy in Breast Cancer: Results From ACOSOG Z1071 (Alliance)

AXXXXX ZXXXX was a prospective trial evaluating the false negative rate of sentinel node (SLN) surgery after neoadjuvant chemotherapy (NAC) in breast cancer patients with initial node-positive disease. Radiation therapy (RT) decisions were at the discretion of treating physicians, providing an opportunity to evaluate variability in practice patterns following NAC

Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly

Introduction: Periodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome. / Methods: A total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect‐size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups. / Results: At genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P‐tau. / Discussion: We show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ

Breast cancer and aging: results of the U13 conference breast cancer panel

Breast cancer is predominantly a disease of older women, yet there is a knowledge gap due to the persisting misalignment between the age distribution of women with breast cancer and the age distribution of participants in clinical trials. The purpose of this report is to state the U13 conference breast cancer panel’s recommendations regarding therapeutic clinical trials that will fill gaps in knowledge regarding the care of older patients with breast cancer. The U13 conference was a collaboration between the Cancer and Aging Research Group and the National Institute on Aging and the National Cancer Institute (NCI). Clinical trials should be developed for frail and vulnerable patients who would not enroll on the standard phase III trials, as well as efforts need to be made to increase enrollment of fit older patients on standard phase III trials. As a result of this conference, panel members are working with the NCI and cooperative groups to address these knowledge gaps. With the aging population and increasing incidence of breast cancer with age, it is essential to study the feasibility, toxicity, and efficacy of cancer therapy in this at-risk population

Video feedback for young babies and maternal perinatal mental illness: intervention adaptation, feasibility and acceptability

Aims/Background We aimed to adapt, pilot and explore experiences of receiving and delivering the video feedback intervention for positive parenting (VIPP) for 2 to 6 month old babies, mothers experiencing moderate to severe perinatal mental health difficulties and perinatal mental health clinicians. Design/Methods The VIPP intervention was adapted to include developmentally appropriate activities and developmental psychoeducation for 2 to 6 month olds, alongside psychoeducation on emotion regulation, and then piloted in 14 mothers experiencing moderate to severe perinatal mental health difficulties (registration ISRCTN64237883). Observational and self-reported pre-post outcome data on parenting and parent-infant mental health was collected, and post-intervention qualitative interviews were conducted with participating mothers and clinicians. Results Consent (67%), intervention completion (79%) and follow-up rates (93%) were high. Effect sizes on pre-post outcome measures indicated large improvements in parenting confidence and perceptions of the parent-infant relationship, and a medium-size improvement in maternal sensitivity. In qualitative interviews, clinicians and mothers described how mothers’ initial anxieties about being filmed were allayed through receiving positive and strengths-focussed feedback, boosting their self-confidence, and that the video feedback facilitated identification of young babies’ subtle behavioural cues and moments of mother-infant connection. Streamlining the information provided on maternal emotion regulation, and allowing increased use of clinical judgement to tailor intervention delivery, were suggested to optimise intervention feasibility and acceptability. Conclusion It is feasible and acceptable to implement VIPP with very young babies and their mothers experiencing perinatal mental health difficulties. A fully powered randomised controlled trial is required to establish intervention efficacy

Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial

The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology)

Mirror Symmetry and Other Miracles in Superstring Theory

The dominance of string theory in the research landscape of quantum gravity physics (despite any direct experimental evidence) can, I think, be justified in a variety of ways. Here I focus on an argument from mathematical fertility, broadly similar to Hilary Putnam's 'no miracles argument' that, I argue, many string theorists in fact espouse. String theory leads to many surprising, useful, and well-confirmed mathematical 'predictions' - here I focus on mirror symmetry. These predictions are made on the basis of general physical principles entering into string theory. The success of the mathematical predictions are then seen as evidence for framework that generated them. I attempt to defend this argument, but there are nonetheless some serious objections to be faced. These objections can only be evaded at a high (philosophical) price.Comment: For submission to a Foundations of Physics special issue on "Forty Years Of String Theory: Reflecting On the Foundations" (edited by G. `t Hooft, E. Verlinde, D. Dieks and S. de Haro)

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial

Background Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis. Methods In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12–20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774. Findings Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1–18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45–5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86–3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35–0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference −33·6% [95% CI −45·3 to −21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7–16·0, 69 deaths) for SRS and 11·6 months (9·9–18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76–1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths. Interpretation Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population. Funding National Cancer Institute