Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions

To better understand the impact that nonresponse for specimen collection has on the validity of estimates of association, we examined associations between self-reported maternal periconceptional smoking, folic acid use, or pregestational diabetes mellitus and six birth defects among families who did and did not submit buccal cell samples for DNA following a telephone interview as part of the National Birth Defects Prevention Study (NBDPS). Analyses included control families with live born infants who had no birth defects (N = 9,465), families of infants with anorectal atresia or stenosis (N = 873), limb reduction defects (N = 1,037), gastroschisis (N = 1,090), neural tube defects (N = 1,764), orofacial clefts (N = 3,836), or septal heart defects (N = 4,157). Estimated dates of delivery were between 1997 and 2009. For each exposure and birth defect, odds ratios and 95% confidence intervals were calculated using logistic regression stratified by race-ethnicity and sample collection status. Tests for interaction were applied to identify potential differences between estimated measures of association based on sample collection status. Significant differences in estimated measures of association were observed in only four of 48 analyses with sufficient sample sizes. Despite lower than desired participation rates in buccal cell sample collection, this validation provides some reassurance that the estimates obtained for sample collectors and noncollectors are comparable. These findings support the validity of observed associations in gene-environment interaction studies for the selected exposures and birth defects among NBDPS participants who submitted DNA samples

Sex and Gender in Medical Education, and proceedings from the 2015 Sex and Gender Education Summit

The Sex and Gender Medical Education Summit: a roadmap for curricular innovation was a collaborative initiative of the American Medical Women\u27s Association, Laura W. Bush Institute for Women’s Health, Mayo Clinic, and Society for Women\u27s Health Research (www.sgbmeducationsummit.com). It was held on October 18–19, 2015 to provide a unique venue for collaboration among nationally and internationally renowned experts in developing a roadmap for the incorporation of sex and gender based concepts into medical education curricula. The Summit engaged 148 in-person attendees for the 1 1/2-day program. Pre- and post-Summit surveys assessed the impact of the Summit, and workshop discussions provided a framework for informal consensus building. Sixty-one percent of attendees indicated that the Summit had increased their awareness of the importance of sex and gender specific medicine. Other comments indicate that the Summit had a significant impact for motivating a call to action among attendees and provided resources to initiate change in curricula within their home institutions. These educational efforts will help to ensure a sex and gender basis for delivery of health care in the future

Too Much of a Good Thing? Overexertion of Self-Control and Dietary Adherence in Individuals with Type 2 Diabetes

Objectives The resource model of self‐control posits that self‐control is a finite resource that can be depleted. Individuals with diabetes must continually restrict their diet, requiring self‐control. As a result, dietary adherence is difficult, and lapses are common. People with diabetes who overexert self‐control following a lapse may be especially likely to experience a subsequent relapse, as suggested by the resource model. This investigation used the resource model of self‐control to test whether overexertion of dietary self‐control following a lapse would be predictive of a subsequent relapse in dietary control. Design We tested this prediction in a daily diary study of 128 individuals with diabetes (Mage = 66.12). Methods Participants\u27 reports of their daily dietary adherence were used to define lapses in adherence, post‐lapse adherence, and relapses. Results Individuals who overexerted self‐control after a lapse were more likely to experience a subsequent relapse (OR = 3.276, p = .016) and to do so sooner (HR = 2.12, p = .023). Conclusions People with diabetes may seek to compensate for a lapse in adherence by overexerting self‐control, but doing so may deplete their self‐control and increase the risk of a future relapse

Dorsal striatum does not mediate feedback-based, stimulus-response learning: An event-related fMRI study in patients with Parkinson\u27s disease tested on and off dopaminergic therapy

© 2018 Learning associations between stimuli and responses is essential to everyday life. Dorsal striatum (DS) has long been implicated in stimulus-response learning, though recent results challenge this contention. We have proposed that discrepant findings arise because stimulus-response learning methodology generally confounds learning and response selection processes. In 19 patients with Parkinson\u27s disease (PD) and 18 age-matched controls, we found that dopaminergic therapy decreased the efficiency of stimulus-response learning, with corresponding attenuation of ventral striatum (VS) activation. In contrast, exogenous dopamine improved response selection accuracy related to enhanced DS BOLD signal. Contrasts between PD patients and controls fully support these within-subject patterns. These double dissociations in terms of behaviour and neural activity related to VS and DS in PD and in response to dopaminergic therapy, strongly refute the view that DS mediates stimulus-response learning through feedback. Our findings integrate with a growing literature favouring a role for DS in decision making rather than learning, and unite two literature that have been evolving independently

Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue

Background Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumourinduced muscle fatigue. Methods Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER+ /PR+ , n = 6), triple positive (ER+ /PR+ /Her2/neu+ , n = 5), or triple negative (ER/PR/Her2/neu, n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. Results RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. Conclusions Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically

Therapist, Parent, and Youth Perspectives of Treatment Barriers to Family-Focused Community Outpatient Mental Health Services

This exploratory qualitative study describes treatment barriers to receiving family-focused child mental health services for youths with disruptive behavior problems from multiple perspectives. Data were collected during a series of focus groups and interviews, including: 4 therapist focus groups, 3 parent focus groups, and 10 youth semi-structured interviews. Therapist, parent, and youth stakeholder participants discussed perceived barriers to effective treatment, the problems with current child outpatient therapy, and desired changes (i.e., policy, intervention, etc.) to improve mental health services. Results indicate similar themes around treatment barriers and dissatisfaction with services within and across multiple stakeholder groups, including inadequate support and lack of family involvement; however, parents and therapists, in particular, identified different contributing factors to these barriers. Overall, stakeholders reported much frustration and dissatisfaction with current community-based outpatient child therapy services. Study findings can inform service provision, intervention development, and future research

Clinician and Parent Perspectives on Parent and Family Contextual Factors that Impact Community Mental Health Services for Children with Behavior Problems

The present study employed qualitative methods to examine multiple stakeholder perspectives regarding the role of parent and family contextual factors on community child mental health treatment for children with behavior problems. Findings suggest agreement between clinicians and parents on the number, types and importance of parent and family factors in children’s mental health services; however, stakeholders differed in reports of which factors were most salient. Specifically, clinicians endorsed most factors as being equally salient, while parents described a few salient factors, with parental stress and inadequate social support being the most frequently discussed. These qualitative data further elucidate the context of community services and have implications for evidence-based practice implementation and improving community care

Applying phylogenomics to understand the emergence of Shiga Toxin producing Escherichia coli O157:H7 strains causing severe human disease in the United Kingdom

Shiga Toxin producing Escherichia coli (STEC) O157:H7 is a recently emerged zoonotic pathogen with considerable morbidity. Since the serotype emerged in the 1980s, research has focussed on unravelling the evolutionary events from the E. coli O55:H7 ancestor to the contemporaneous globally dispersed strains. In this study the genomes of over 1000 isolates from human clinical cases and cattle, spanning the history of STEC O157:H7 in the United Kingdom were sequenced. Phylogenetic analysis reveals the ancestry, key acquisition events and global context of the strains. Dated phylogenies estimate the time to the most recent common ancestor of the current circulating global clone to 175 years ago, followed by rapid diversification. We show the acquisition of specific virulence determinates occurred relatively recently and coincides with its recent detection in the human population. Using clinical outcome data from 493 cases of STEC O157:H7 we assess the relative risk of severe disease including HUS from each of the defined clades in the population and show the dramatic effect Shiga toxin complement has on virulence. We describe two strain replacement events that have occurred in the cattle population in the UK over the last 30 years; one resulting in a highly virulent strain that has accounted for the majority of clinical cases in the UK over the last decade. This work highlights the need to understand the selection pressures maintaining Shiga-toxin encoding bacteriophages in the ruminant reservoir and the study affirms the requirement for close surveillance of this pathogen in both ruminant and human populations

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer

We have identified a human homolog of the bacterial MutS and S. cerevisiae MSH proteins, called hMSH2. Expression of hMSH2 in E. coli causes a dominant mutator phenotype, suggesting that hMSH2, like other divergent MutS homologs, interferes with the normal bacterial mismatch repair pathway. hMSH2 maps to human chromosome 2p22-21 near a locus implicated in hereditary nonpolyposis colon cancer (HNPCC). A T to C transition mutation has been detected in the -6 position of a splice acceptor site in sporadic colon tumors and in affected individuals of two small HNPCC kindreds. These data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with HNPCC suggest that hMSH2 is the HNPCC gene

UV Absorption Lines from High-Velocity Gas in the Vela Supernova Remnant: New insights from STIS Echelle Observations of HD72089

The star HD72089 is located behind the Vela supernova remnant and shows a complex array of high and low velocity interstellar absorption features arising from shocked clouds. A spectrum of this star was recorded over the wavelength range 1196.4 to 1397.2 Angstroms at a resolving power lambda/Delta lambda = 110,000 and signal-to-noise ratio of 32 by STIS on the Hubble Space Telescope. We have identified 7 narrow components of C I and have measured their relative populations in excited fine-structure levels. Broader features at heliocentric velocities ranging from -70 to +130 km/s are seen in C II, N I, O I, Si II, S II and Ni II. In the high-velocity components, the unusually low abundances of N I and O I, relative to S II and Si II, suggest that these elements may be preferentially ionized to higher stages by radiation from hot gas immediately behind the shock fronts.Comment: 11 pages, 2 figures, Latex. Submitted for the special HST ERO issue of the Astrophysical Journal Letter