Factors that influence excessive gestational weight gain: Moving beyond assessment and counselling

One in four Canadian adults is obese, and more women are entering pregnancy with a higher body mass index (BMI) than in the past. Pregnant women who are overweight or obese have a higher risk of pregnancy-related complications than women of normal weight. Gestational weight gain (GWG) is also associated with childhood obesity. Although the factors influencing weight gain during pregnancy are multifaceted, little is known about the social inequality of GWG. This review will address some of the socioeconomic factors and maternal characteristics influencing weight gain and the impact that excessive GWG has on health outcomes such as post-partum weight retention. The effects of an overweight or obese pre-pregnancy BMI on GWG and neonatal outcomes will also be addressed. The timing of weight gain is also important, as recommendations now include trimester-specific guidelines. While not conclusive, preliminary evidence suggests that excessive weight gain during the first trimester is most detrimental

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood–brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.</p

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia

Background: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. Methods: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. Findings: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0–91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20–0·42]). Interpretation: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. Funding: Gates Ventures

Framing alleged Islamist plots: a case study of British press coverage since 9/11

In the decade post 9/11 , the UK terrorist threat was associated with a series of high profile counter terrorism operations, linked to specific plots. These terrorism related episodes received significant media attention and, as a consequence, were a visible sign of the contemporary terrorist threat. This paper seeks to identify the dominant frames rendered in news media reporting on these episodes. Through a longitudinal study of UK press coverage, the analysis reveals that two prominent frames were present, an inevitability and preparedness frame, with alleged plots serving to underline the risk posed by contemporary terrorism,and a belonging and responsibility frame, which cast later episodes as belonging to the Muslim communities disrupted by polic

Development and Validation of a Surgical Workload Measure: The Surgery Task Load Index (SURG-TLX)

Background: The purpose of the present study was to develop and validate a multidimensional, surgery-specific workload measure (the SURG-TLX), and to determine its utility in providing diagnostic information about the impact of various sources of stress on the perceived demands of trained surgical operators. As a wide range of stressors have been identified for surgeons in the operating room, the current approach of considering stress as a unidimensional construct may not only limit the degree to which underlying mechanisms may be understood but also the degree to which training interventions may be successfully matched to particular sources of stress. Methods: The dimensions of the SURG-TLX were based on two current multidimensional workload measures and developed via focus group discussion. The six dimensions were defined as mental demands, physical demands, temporal demands, task complexity, situational stress, and distractions. Thirty novices were trained on the Fundamentals of Laparoscopic Surgery (FLS) peg transfer task and then completed the task under various conditions designed to manipulate the degree and source of stress experienced: task novelty, physical fatigue, time pressure, evaluation apprehension, multitasking, and distraction. Results: The results were supportive of the discriminant sensitivity of the SURG-TLX to different sources of stress. The sub-factors loaded on the relevant stressors as hypothesized, although the evaluation pressure manipulation was not strong enough to cause a significant rise in situational stress. Conclusions: The present study provides support for the validity of the SURG-TLX instrument and also highlights the importance of considering how different stressors may load surgeons. Implications for categorizing the difficulty of certain procedures, the implementation of new technology in the operating room (man-machine interface issues), and the targeting of stress training strategies to the sources of demand are discussed. Modifications to the scale to enhance clinical utility are also suggested. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Mediator and cohesin connect gene expression and chromatin architecture

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator–cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell.National Institutes of Health (U.S.) (Fellowship)Canadian Institutes of Health Research (Research Fellowship)National Institutes of Health (U.S.) (Grant R01 HG002668

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Mixed-strain housing for female C57BL/6, DBA/2, and BALB/c mice: validating a split-plot design that promotes refinement and reduction

Abstract Background Inefficient experimental designs are common in animal-based biomedical research, wasting resources and potentially leading to unreplicable results. Here we illustrate the intrinsic statistical power of split-plot designs, wherein three or more sub-units (e.g. individual subjects) differing in a variable of interest (e.g. genotype) share an experimental unit (e.g. a cage or litter) to which a treatment is applied (e.g. a drug, diet, or cage manipulation). We also empirically validate one example of such a design, mixing different mouse strains -- C57BL/6, DBA/2, and BALB/c -- within cages varying in degree of enrichment. As well as boosting statistical power, no other manipulations are needed for individual identification if co-housed strains are differentially pigmented, so also sparing mice from stressful marking procedures. Methods The validation involved housing 240 females from weaning to 5 months of age in single- or mixed- strain trios, in cages allocated to enriched or standard treatments. Mice were screened for a range of 26 commonly-measured behavioural, physiological and haematological variables. Results Living in mixed-strain trios did not compromise mouse welfare (assessed via corticosterone metabolite output, stereotypic behaviour, signs of aggression, and other variables). It also did not alter the direction or magnitude of any strain- or enrichment-typical difference across the 26 measured variables, or increase variance in the data: indeed variance was significantly decreased by mixed- strain housing. Furthermore, using Monte Carlo simulations to quantify the statistical power benefits of this approach over a conventional design demonstrated that for our effect sizes, the split- plot design would require significantly fewer mice (under half in most cases) to achieve a power of 80 %. Conclusions Mixed-strain housing allows several strains to be tested at once, and potentially refines traditional marking practices for research mice. Furthermore, it dramatically illustrates the enhanced statistical power of split-plot designs, allowing many fewer animals to be used. More powerful designs can also increase the chances of replicable findings, and increase the ability of small-scale studies to yield significant results. Using mixed-strain housing for female C57BL/6, DBA/2 and BALB/c mice is therefore an effective, efficient way to promote both refinement and the reduction of animal-use in research

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Abstract: Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status