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To disrupt cycles of health inequity, traceable to dietary inequities in the earliest stages of life, public health interventions should target improving nutritional wellbeing in preconception/pregnancy environments. This requires a deep engagement with pregnant/postpartum people (PPP) and their communities (including their health and social care providers, HSCP). We sought to understand the factors that influence diet during pregnancy from the perspectives of PPP and HSCP, and to outline intervention priorities.
We carried out thematic network analyses of transcripts from ten focus group discussions (FGD) and one stakeholder engagement meeting with PPP and HSCP in a Canadian city. Identified themes were developed into conceptual maps, highlighting local priorities for pregnancy nutrition and intervention development.
FGD and the stakeholder meeting were run in predominantly lower socioeconomic position (SEP) neighbourhoods in the sociodemographically diverse city of Hamilton, Canada.
All local, comprising twenty-two lower SEP PPP and forty-three HSCP.
Salient themes were resilience, resources, relationships and the embodied experience of pregnancy. Both PPP and HSCP underscored that socioeconomic-political forces operating at multiple levels largely determined the availability of individual and relational resources constraining diet during pregnancy. Intervention proposals focused on cultivating individual and community resilience to improve early-life nutritional environments. Participants called for better-integrated services, greater income supports and strengthened support programmes.
Hamilton stakeholders foregrounded social determinants of inequity as main factors influencing pregnancy diet. They further indicated a need to develop interventions that build resilience and redistribute resources at multiple levels, from the household to the state.
Evidence supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis indicates that improving early life environments can reduce non-communicable disease risks and improve health over the lifecourse. A widespread understanding of this evidence may help to reshape structures, guidelines and individual behaviors to better the developmental conditions for the next generations. Yet, few efforts have yet been made to translate the DOHaD concept beyond the research community. To understand why, and to identify priorities for DOHaD Knowledge Translation (KT) programs, we review here a portion of published descriptions of DOHaD KT efforts and critiques thereof. We focus on KT targeting people equipped to apply DOHaD knowledge to their everyday home or work lives. We identified 17 reports of direct-to-public DOHaD KT that met our inclusion criteria. Relevant KT programs have been or are being initiated in nine countries, most focusing on secondary school students or care-workers-in-training; few target parents-to-be. Early indicators suggest that such programs can empower participants. Main critiques of DOHaD KT suggest it may overburden mothers with responsibility for children’s health and health environments, minimizing the roles of other people and institutions. Simultaneously, though, many mothers-to-be seek reliable guidance on prenatal health and nutrition, and would likely benefit from engagement with DOHaD KT. We thus recommend emphasizing solidarity, and bringing together people likely to one day become parents (youth), people planning pregnancies, expecting couples, care workers and policymakers into empowering conversation about DOHaD and about the importance and complexity of early life environments.
To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children.
Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children.
Children discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children.
SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73).
Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.
Eta Carinae is the most massive active binary within 10,000 light-years. While famous for the largest non-terminal stellar explosion ever recorded, observations reveal a supermassive (∼120 M⊙) binary consisting of an LBV and either a WR or extreme O star in a very eccentric orbit (e=0.9) with a 5.54-year period. Dramatic changes across multiple wavelengths are routinely observed as the stars move about in their highly elliptical orbits, especially around periastron when the hot (∼40 kK) companion star delves deep into the denser and much cooler (∼15 kK) extended wind photosphere of the LBV primary. Many of these changes are due to a dynamic wind-wind collision region (WWCR) that forms between the stars, plus expanding radiation-illuminated fossil WWCRs formed one, two, and three 5.54-year orbital cycles ago. These fossil WWCRs have been spatially and spectrally resolved by the Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS) at multiple epochs, resulting in data cubes that spatially map Eta Carinae’s innermost WWCRs and follow temporal changes in several forbidden emission lines (e.g. [Fe iii] 4659 Å, [Fe ii] 4815 Å) across the 5.54-year cycle. We present initial results of 3D time-dependent hydrodynamical and radiative-transfer simulations of the Eta Carinae binary and its WWCRs with the goal of producing synthetic data cubes of forbidden emission lines for comparison to the available HST/STIS observations. Comparison of the theoretical models to the observations reveals important details about the binary’s orbital motion, photoionization properties, and recent (5–15year) mass loss history. Such an analysis also provides a baseline for following future changes in Eta Carinae, essential for understanding the late-stage evolution of a nearby supernova progenitor. Our modeling methods can also be adapted to a number of other colliding wind binary systems (e.g. WR 140) that are scheduled to be studied with future observatories (e.g. the James Webb Space Telescope).
The stellar winds of hot stars have an important impact on both stellar and galactic evolution, yet their structure and internal processes are not fully understood in detail. One of the best nearby laboratories for studying such massive stellar winds is the O4I(n)fp star ζ Pup. After briefly discussing existing X-ray observations from Chandra and XMM, we present a simulation of X-ray emission line profile measurements for the upcoming 840 kilosecond Chandra HETGS observation. This simulation indicates that the increased S/N of this new observation will allow several major steps forward in the understanding of massive stellar winds. By measuring X-ray emission line strengths and profiles, we should be able to differentiate between various stellar wind models and map the entire wind structure in temperature and density. This legacy X-ray spectrum of ζ Pup will be a useful benchmark for future X-ray missions.
Eta Carinae is one of the most massive observable binaries. Yet determination of its orbital and physical parameters is hampered by obscuring winds. However the effects of the strong, colliding winds changes with phase due to the high orbital eccentricity. We wanted to improve measures of the orbital parameters and to determine the mechanisms that produce the relatively brief, phase-locked minimum as detected throughout the electromagnetic spectrum. We conducted intense monitoring of the He ii λ4686 line in η Carinae for 10 months in the year 2014, gathering ~300 high S/N spectra with ground- and space-based telescopes. We also used published spectra at the FOS4 SE polar region of the Homunculus, which views the minimum from a different direction. We used a model in which the He ii λ4686 emission is produced by two mechanisms: a) one linked to the intensity of the wind-wind collision which occurs along the whole orbit and is proportional to the inverse square of the separation between the companion stars; and b) the other produced by the ‘bore hole’ effect which occurs at phases across the periastron passage. The opacity (computed from 3D SPH simulations) as convolved with the emission reproduces the behavior of equivalent widths both for direct and reflected light. Our main results are: a) a demonstration that the He ii λ4686 light curve is exquisitely repeatable from cycle to cycle, contrary to previous claims for large changes; b) an accurate determination of the longitude of periastron, indicating that the secondary star is ‘behind’ the primary at periastron, a dispute extended over the past decade; c) a determination of the time of periastron passage, at ~4 days after the onset of the deep light curve minimum; and d) show that the minimum is simultaneous for observers at different lines of sight, indicating that it is not caused by an eclipse of the secondary star, but rather by the immersion of the wind-wind collision interior to the inner wind of the primary.
The objective is to determine the nature of the unseen companion of the single-lined spectroscopic binary, WR 148 (= WN7h+?). The absence of companion lines supports a compact companion (cc) scenario. The lack of hard X-rays favours a non-compact companion scenario. Is WR 148 a commonplace WR+OB binary or a rare WR+cc binary?
Eta Carinae is the most massive active binary within 10,000 light-years and is famous for the largest non-terminal stellar explosion ever recorded. Observations reveal that the supermassive (~120 M⊙) binary, consisting of an LBV and either a WR or extreme O star, undergoes dramatic changes every 5.54 years due to the stars’ very eccentric orbits (e ≈ 0.9). Many of these changes are caused by a dynamic wind-wind collision region (WWCR) between the stars, plus expanding fossil WWCRs formed one, two, and three 5.54-year cycles ago. The fossil WWCRs can be spatially and spectrally resolved by the Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS). Starting in June 2009, we used the HST/STIS to spatially map Eta Carinae’s fossil WWCRs across one full orbit, following temporal changes in several forbidden emission lines (e.g. [Feiii] 4659 Å, [Feii] 4815 Å), creating detailed data cubes at multiple epochs. Multiple wind structures were imaged, revealing details about the binary’s orbital motion, photoionization properties, and recent (~5 − 15 year) mass-loss history. These observations allow us to test 3-D hydrodynamical and radiative-transfer models of the interacting winds. Our observations and models strongly suggest that the wind and photoionization properties of Eta Carinae’s binary have not changed substantially over the past several orbital cycles. They also provide a baseline for following future changes in Eta Carinae, essential for understanding the late-stage evolution of this nearby supernova progenitor. For more details, see Gull et al. (2016) and references therein.
Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.
Glioblastoma (GBM), an aggressive primary adult brain tumor, is feared for its near uniformly fatal prognosis. Despite the use of aggressive treatment including surgical resection, radiotherapy and chemotherapy, the outcome of patients with GBM has failed to improve significantly. Numerous studies have implicated CD133+GBM subpopulation as driver of chemo- and radio-resistance. CD133 expression correlates with disease progression, recurrence, and poor overall survival of GBM patients. Here, we describe the preclinical evaluation of a recombinant CD133xCD3 bispecific T-cell engager (BiTE) antibody that redirects human polyclonal T cells to CD133+GBM cells, inducing very potent anti-tumor response. CD133-specific BiTE was constructed; with one arm recognizing the tumor antigen (CD133) while the second is specific to CD3 antigen. Using CD133high and CD133low primary GBM lines, we validated the binding of BiTEs to CD133+GBMs and CD3+T cells. In order to test the ability of BiTEs to functionally elicit CD133-specific cytotoxic responses in vitro, we performed killing assays. We observed CD133-specific BiTE mediated T cell activation and redirection to kill CD133-expressing GBM cells in a co-culture of T cells and GBM cells. The killing was more efficient in CD133high GBMs compared to CD133low GBMs, validating its specificity to target CD133+BTICs. Treatment with BiTEs yielded significant reductions in brain tumor burden in vivo. These data offers compelling evidence that BiTE-mediated cytotoxicity against treatment-resistant CD133+GBMs could provide a very potent, specific and can be a novel therapeutic strategy for GBM patients.
Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.
• All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R)
• Magnetic resonance and computed tomography imaging should be performed. (R)
• Patients should undergo audiological assessment. (R)
• Carotid angiography is recommended in select patients. (G)
• The modified Pittsburg T-staging system is recommended. (G)
• The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R)
• Facial nerve rehabilitation should be initiated at primary surgery. (G)
• Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G)
• For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R)
To determine factors affecting facial nerve outcome of vestibular schwannoma surgery.
This retrospective cohort study comprised 652 patients. The outcome measure was House–Brackmann classification at two years post-operatively. Univariate and multivariate analyses were carried out to determine the factors affecting facial nerve outcome. The incidence rates of hemifacial spasm, metallic taste and crocodile tear syndrome were recorded.
For tumours less than 1.5 cm, 95 per cent of outcomes were normal, 100 per cent were satisfactory (House–Brackmann grades I–III) and 0 per cent were unsatisfactory (grades IV–VI). For tumours 1.5–2.4 cm, 83 per cent of outcomes were normal, 99 per cent were satisfactory and 1 per cent were unsatisfactory. For tumours 2.5–3.4 cm, 68 per cent of outcomes were normal, 96 per cent were satisfactory and 4 per cent were unsatisfactory. For tumours 3.5–4.4 cm, 52 per cent of outcomes were normal, 80 per cent were satisfactory and 20 per cent were unsatisfactory. For tumours larger than 4.4 cm, 50 per cent of outcomes were normal, 72 per cent were satisfactory and 28 per cent were unsatisfactory.
Tumour size and operation year were significant predictors of facial nerve outcome. The surgical learning curve was steepest for the first 50 patients.
Wolf-Rayet (WR) stars are the evolved descendants of massive O-type stars and are considered to be progenitor candidates for Type Ib/c core-collapse supernovae (SNe). Recent results of our HST/WFC3 survey of Wolf-Rayet stars in M101 are summarised based on the detection efficiency of narrow-band optical imaging compared to broad-band methods. We show that on average 42% of WR stars, increasing to ~85% in central regions, are only detected in the narrow-band imaging. Hence, the non-detection of a WR star at the location of ~10 Type Ib/c SNe in broad-band imaging is no longer strong evidence for a non-WR progenitor channel.
We evaluated use of the periodically rotated overlapping parallel lines with enhanced reconstruction diffusion-weighted imaging sequence, compared with conventional echo planar magnetic resonance imaging, in the detection of middle-ear cholesteatoma.
Material and methods:
Sixteen patients awaiting second-stage combined approach tympanoplasty and three patients awaiting first-stage combined approach tympanoplasty underwent magnetic resonance imaging with both (1) the periodically rotated overlapping parallel lines with enhanced reconstruction sequence (i.e. non echo planar imaging) and (2) the array spatial sensitivity encoding technique sequence (i.e. echo planar imaging). Two neuroradiologists independently evaluated the images produced by both sequences. Radiology findings were correlated with surgical findings.
Results and analysis:
Seven cholesteatomas were found at surgery. Neither of the assessed imaging sequences were able to detect cholesteatoma of less than 4 mm. Rates for sensitivity, specificity, and positive and negative predictive values are presented.
Decisions on whether or not to operate for cholesteatoma cannot be made based on the two imaging sequences assessed, as evaluated in this study. Other contributing factors are discussed, such as the radiological learning curve and technical limitations of the magnetic resonance imaging equipment.
To report a rare condition affecting the temporal bone. Immunoglobulin G4 related systemic sclerosing disease is a recently described autoimmune condition with manifestations typically involving the pancreas, biliary system, salivary glands, lungs, kidneys and prostate. Histologically, it is characterised by T-cell infiltration, fibrosis and numerous immunoglobulin G4-positive plasma cells. This condition previously fell under the umbrella diagnosis of inflammatory pseudotumour and inflammatory myofibroblastic tumour.
We present the case of a 58-year-old woman with multiple inflammatory masses involving the pharynx, gall bladder, lungs, pelvis, omentum, eyes and left temporal bone, over a seven-year period. We describe this patient's unusual clinical course and pathological features, which resulted in a change of diagnosis from metastatic inflammatory myofibroblastic tumour to immunoglobulin G4 related systemic sclerosing disease. We also review the literature regarding the management of inflammatory pseudotumours of the temporal bone, and how this differs from the management of immunoglobulin G4 related systemic sclerosing disease.
We would recommend a full review of all histological specimens in patients with a diagnosis of temporal bone inflammatory pseudotumour or inflammatory myofibroblastic tumour. Consideration should be given to immunohistochemical analysis for anaplastic lymphoma kinase and immunoglobulin G4, with measurement of serum levels of the latter. Management of the condition is medical, with corticosteroids and immunosuppression, rather than surgical excision.
In this chapter, Moffat reviews observational research in older men that examines serum testosterone concentrations in relation to cognitive aging or Alzheimer's disease (AD) risk. Prospective cohort studies, such as the Baltimore Longitudinal Study of Aging, provide particularly useful data. Despite methodological limitations and conflicting findings, Moffat tentatively concludes that age-associated reductions in testosterone concentrations are a risk factor for cognitive decline and dementia. Cognitive vulnerability may be limited to specific domains of cognitive performance and may be modified by apolipoprotein E genotype. As he suggests, more definitive answers may require well designed randomized clinical trials that target cognitive effects of testosterone therapy. Any future trial must also consider other health outcomes that may be beneficially or adversely affected by testosterone.
Forty-one children in an Edinburgh nursery were observed for evidence of respiratory illness from November 1963 to April 1964. During this period serial specimens of serum from these children were examined for virus antibodies and serial throat swabs were investigated for the presence of virus. Well-defined outbreaks of respiratory illness occurred and could be associated with respiratory syncytial virus, parainfluenza 3 virus and influenza C virus infection. Infection with adenovirus followed a more endemic pattern. The antibody response in infants to respiratory syncytial virus as measured by the standard complement-fixation test was found to be much poorer than the response to parainfluenza 3 virus. It is suggested that this may play a part in the severity of respiratory syncytial virus infection in infants.