Metabolic Changes Following a 1-Year Diet and Exercise Intervention in Patients With Type 2 Diabetes

Objective—To characterize the relationships among longterm improvements in peripheral insulin sensitivity (glucose disposal rate [GDR]), fasting glucose, and free fatty acids (FFAs) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes. Research Design And Methods—We measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss. Results—Weight and fasting glucose decreased significantly (P _ 0.0001) and significantly more in men than in women (_12 vs. _8% and _16 vs. _7%, respectively; P _ 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (P _ 0.00001) and similarly in both sexes (_53 vs. _41% and 63 vs. 43%; P _ NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (P _ 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. Conclusions—Patients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements.Jeanine B. Albu, Leonie K. Heilbronn, David E. Kelley, Steven R. Smith, Koichiro Azuma, Evan S. Berk, F. Xavier Pi-Sunyer, Eric Ravussin, and the Look AHEAD Adipose Research Grou

Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors

PURPOSE: Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression. METHODS: Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured. RESULTS: Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: -0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: -0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover. CONCLUSIONS: Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI

Genotyping concordance in DNA extracted from formalin‐fixed paraffin embedded (FFPE) breast tumor and whole blood for pharmacogenetic analyses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135708/1/mol22015991868.pd

Propagation of squeezed radiation through amplifying or absorbing random media

We analyse how nonclassical features of squeezed radiation (in particular the sub-Poissonian noise) are degraded when it is transmitted through an amplifying or absorbing medium with randomly located scattering centra. Both the cases of direct photodetection and of homodyne detection are considered. Explicit results are obtained for the dependence of the Fano factor (the ratio of the noise power and the mean current) on the degree of squeezing of the incident state, on the length and the mean free path of the medium, the temperature, and on the absorption or amplification rate.Comment: 8 pages, 4 figure

Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154957/1/bcp14192.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154957/2/bcp14192_am.pd

Mock juror perceptions of child witnesses on the autism spectrum: the impact of providing diagnostic labels and information about autism

Research suggests that autistic children can provide accurate and forensically useful eyewitness evidence. However, members of a jury also rely on non-verbal behaviours when judging the credibility of a witness, and this could determine the verdict of a case. We presented mock jurors with videos (from an experimental study) of one of two child witnesses on the autism spectrum being interviewed about a mock minor crime. Results demonstrated that providing jurors with generic information about autism and/or informing them of the child’s diagnostic label differentially affected credibility ratings, but not for both children. Implications for how to present information about child witnesses with autism to a jury – highlighting the need for approaches tailored to individual children – are discussed

Effects of CYP3A4 and CYP2C9 genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes

Understanding and identifying ways to improve hospital-based cancer care and treatment for people with dementia: an ethnographic study

Background: Providing cancer care and treatment for ageing populations with complicating comorbidities like dementia is a growing global challenge. This study aimed to examine the hospital-based cancer care and treatment challenges and support needs of people with dementia, and identify potential ways to address these. Methods: Two-site ethnographic study in England involving semi-structured interviews, observations and accompanying conversations, and medical-record review. Participants (N=58) were people with dementia and comorbid cancer (n=17), informal caregivers (n=22) and hospital staff (n=19). Ethnographically informed thematic analysis was conducted. Results: There was an accumulated complexity of living with both illnesses simultaneously. People with dementia and families could feel confused and uninformed due to difficulties understanding, retaining and using cancer information, which impacted their informed treatment decision-making. Dementia increased the complexity and burden of travelling to and navigating unfamiliar hospital environments, frequent lengthy periods of waiting in hospital, and self-managing symptoms and side-effects at home. Oncology staff were often working without the full picture, due to variable documenting of dementia in medical-records; dementia training was limited; and time and resource pressures impeded the highly-individualised, flexible cancer care required by people with dementia. Supportive family carers were crucial in enabling people with dementia to access, navigate and undergo cancer treatment and care Conclusions: Dementia complicates cancer care in a range of ways accumulating across the cancer pathway. Our findings suggest there are several strategies and interventions, which we list here, with potential to improve cancer care and treatment for people with dementia and their families

Characteristics and general practice resource use of people with comorbid cancer and dementia in England: a retrospective cross-sectional study

Background Cancer and dementia are common in older people and management of the conditions as comorbidities can be challenging, yet little is known about the size or characteristics of this group. We aimed to estimate the prevalence, characteristics and general practice resource usage of people living with both conditions in England. Methods Anonymised electronic healthcare records from 391 National Health Service general practices across England using the TPP SystmOne general practice system were obtained from ResearchOne. Data included demographic and clinical characteristics, and general practice healthcare useage (appointments, prescriptions, referrals and secondary care contacts) for people aged 50 and over with a cancer and/or dementia diagnosis consistent with the Quality and Outcomes Framework between 2005 and 2016. Multi-level negative binomial regression was used to analyse the association between having cancer and/or dementia and the number of general practice appointments. Results Data from 162,371 people with cancer and/or dementia were analysed; 3616 (2.2%) people were identified as having comorbid cancer and dementia. Of people with cancer, 3.1% also had dementia, rising to 7.5% (1 in 13 people) in those aged 75 and over. Fewer people with both conditions were female (50.7%) compared to those with dementia alone (65.6%) and those with comorbid cancer and dementia were older than those with cancer alone [mean ages 83 (sd = 7), 69 (sd = 12) respectively]. Those with both conditions were less likely to have lung cancer than those with cancer alone (7.5% vs. 10.3%) but more likely to have prostate cancer (20.9% vs. 15.8%). Additional comorbidities were more prevalent for those with both conditions than those with cancer or dementia alone (68.4% vs. 50.2% vs. 54.0%). In the year following the first record of either condition, people with cancer and dementia had 9% more general practice appointments (IRR:1.09, 95% CI:1.01–1.17) than those with cancer alone and 37% more appointments than those with dementia alone (IRR: 1.37, 95% CI: 1.28–1.47). Conclusions A significant number of people are living with comorbid cancer and dementia in England. This group have additional comorbidity and higher general practice usage than those with cancer/dementia alone. The needs of this group should be considered in future general practice care planning and research

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies