The necessity and possibility of powerful ‘regional’ knowledge: curriculum change and renewal

© 2016 Taylor & Francis. The paper argues that powerful regional knowledge is necessary and possible and that there are historical precedents supporting these claims. Regional knowledge is being used in a double sense: the first Bernsteinian, the second in relation to knowledge generated outside the academy. Both are important if the debate is not to be confined solely to the global north and if the curriculum is to be responsive to geo-political realities. In order to think critically about access to higher education, we need to consider the sorts of knowledge, engagement, and opportunities that are open to newer actors. This includes recognising the contextual nature of professional practice and also that social movements beyond the academy can and do challenge academic knowledge. The paper concludes that many of issues addressed are not capable of theoretical resolution alone and that we need more empirical work to inform curriculum change and renewal

ACR appropriateness criteria® nasal cavity and paranasal sinus cancers

The American College of Radiology (ACR) Appropriateness Criteria are evidence‐based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer‐reviewed journals and the application of well‐established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Here, we present the Appropriateness Criteria for cancers arising in the nasal cavity and paranasal sinuses (maxillary, sphenoid, and ethmoid sinuses). This includes clinical presentation, prognostic factors, principles of management, and treatment outcomes. Controversies regarding management of cervical lymph nodes are discussed. Rare and unusual nasal cavity cancers, such as esthesioneuroblastoma and sinonasal undifferentiated carcinomas, are included. © 2016 American College of Radiology. Head Neck, 2016 © 2016 Wiley Periodicals, Inc. Head Neck 39: 407–418, 2017Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136245/1/hed24639.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136245/2/hed24639_am.pd

Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching

<p>Abstract</p> <p>Background</p> <p>Antisense oligomer induced exon skipping aims to reduce the severity of Duchenne muscular dystrophy by redirecting splicing during pre-RNA processing such that the causative mutation is by-passed and a shorter but partially functional Becker muscular dystrophy-like dystrophin isoform is produced. Normal exons are generally targeted to restore the dystrophin reading frame however, an appreciable subset of dystrophin mutations are intra-exonic and therefore have the potential to compromise oligomer efficiency, necessitating personalised oligomer design for some patients. Although antisense oligomers are easily personalised, it remains unclear whether all patient polymorphisms within antisense oligomer target sequences will require the costly process of producing and validating patient specific compounds.</p> <p>Methods</p> <p>Here we report preclinical testing of a panel of splice switching antisense oligomers, designed to excise exon 25 from the dystrophin transcript, in normal and dystrophic patient cells. These patient cells harbour a single base insertion in exon 25 that lies within the target sequence of an oligomer shown to be effective at removing exon 25.</p> <p>Results</p> <p>It was anticipated that such a mutation would compromise oligomer binding and efficiency. However, we show that, despite the mismatch an oligomer, designed and optimised to excise exon 25 from the normal dystrophin mRNA, removes the mutated exon 25 more efficiently than the mutation-specific oligomer.</p> <p>Conclusion</p> <p>This raises the possibility that mismatched AOs could still be therapeutically applicable in some cases, negating the necessity to produce patient-specific compounds.</p

Views on and experiences of electronic cigarettes: a qualitative study of women who are pregnant or have recently given birth.

Background Electronic cigarettes (ECs) are increasingly used for reducing or stopping smoking, with some studies showing positive outcomes. However, little is known about views on ECs during pregnancy or postpartum and previous studies have nearly all been conducted in the US and have methodological limitations, such as not distinguishing between smokers and ex/non-smokers. A greater understanding of this topic will help to inform both clinicians and EC interventions. We elicited views and experiences of ECs among UK pregnant or recently pregnant women. Methods We conducted semi-structured telephone interviews, using topic guides, with pregnant or recently pregnant women, who were current or recent ex-smokers. To ensure broad views of ECs were obtained, recruitment was from several geographical locations and via various avenues of recruitment. This included stop smoking services, antenatal and health visitor clinics, a pregnancy website and an informal network. Participants were 15 pregnant and 15 postpartum women, including nine current EC users, 11 ex-users, and 10 never-users. Five women who were interviewed in pregnancy were later interviewed in postpartum to explore if their views had changed. Audio data was transcribed verbatim and framework analysis was applied. Results Five main themes emerged: motivations for use (e.g., for stopping or reducing smoking), social stigma (e.g., avoiding use in public, preferring ‘discrete’ NRT), using the EC (e.g., mostly used at home); consumer aspects (e.g., limited advice available), and harm perceptions (e.g., viewed as less harmful than smoking; concerns about safety and addiction). Conclusions ECs were viewed positively by some pregnant and postpartum women and seen as less harmful than smoking and useful as aids for reducing and stopping smoking. However, due to perceived social stigma, some women feel uncomfortable using ECs in public, especially during pregnancy, and had concerns about safety and nicotine dependence. Health professionals and designers of EC interventions need to provide women with up-to-date and consistent information and advice about safety and dependence, as well as considering the influence of social stigma

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease

Chronic Intestinal Failure in Children : An International Multicenter Cross-Sectional Survey

Background: The European Society for Clinical Nutrition and Metabolism database for chronic intestinal failure (CIF) was analyzed to investigate factors associated with nutritional status and the intravenous supplementation (IVS) dependency in children. Methods: Data collected: demographics, CIF mechanism, home parenteral nutrition program, z-scores of weight-for-age (WFA), length or height-for-age (LFA/HFA), and body mass index-for-age (BMI-FA). IVS dependency was calculated as the ratio of daily total IVS energy over estimated resting energy expenditure (%IVSE/REE). Results: Five hundred and fifty-eight patients were included, 57.2% of whom were male. CIF mechanisms at age 1-4 and 14-18 years, respectively: SBS 63.3%, 37.9%; dysmotility or mucosal disease: 36.7%, 62.1%. One-third had WFA and/or LFA/HFA z-scores 125%. Multivariate analysis showed that mechanism of CIF was associated with WFA and/or LFA/HFA z-scores (negatively with mucosal disease) and %IVSE/REE (higher for dysmotility and lower in SBS with colon in continuity), while z-scores were negatively associated with %IVSE/REE. Conclusions: The main mechanism of CIF at young age was short bowel syndrome (SBS), whereas most patients facing adulthood had intestinal dysmotility or mucosal disease. One-third were underweight or stunted and had high IVS dependency. Considering that IVS dependency was associated with both CIF mechanisms and nutritional status, IVS dependency is suggested as a potential marker for CIF severity in children.Peer reviewe

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

Background: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results: Single nucleotide variants (P = 7.0 × 10–03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10–06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10–05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10–09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches

Provision of smoking cessation support for pregnant women in England: results from an online survey of NHS Stop Smoking Services for Pregnant women

Background: Smoking during pregnancy is a major public health concern and an NHS priority. In 2010, 26% of UK women smoked immediately before or during their pregnancy and 12% smoked continuously. Smoking cessation support is provided through free at the point of use Stop Smoking Services for Pregnant women (SSSP). However, to date, little is known of how these services provide support across England. The aim of this study was to describe the key elements of support provided through English SSSP. Methods: SSSP managers were invited to participate in this survey by email. Data were then collected via an online questionnaire; one survey was completed for each SSSP. Up to four reminder emails were sent over a two month period. Results: 86% (121 of 141) of services completed the survey. Responding services were, on average, larger than non-responding services in terms of the number of pregnant women setting quit dates and successfully quitting (p&thinsp;&lt;&thinsp;0.01). In line with the 2010 NICE guidelines, Stop Smoking in Pregnancy and following Childbirth, one in five SSSP identified pregnant smokers using carbon monoxide (CO) testing and refer via an opt-out pathway. All services offered nicotine replacement therapy (NRT) to pregnant women and 87% of services also offered dual therapy NRT, i.e. combination of a patch and short acting NRT product.. The 2010 NICE guidelines note that services should be flexible and client-centred. Consistent with this, SSSP offer pregnant women a range of support types (median 4) including couple/family, group (open or closed) or one-to-one. These are available in a number of locations (median 5), including in community venues, clinics and women's homes. Conclusions: English Stop Smoking Services offer behavioural support and pharmacotherapy to pregnant women motivated to quit smoking. Interventions provided are generally evidence-based and delivered in a variety of both social and health care settings

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function

Children admitted to hospital following unintentional injury: perspectives of health service providers in Aotearoa/New Zealand

<p>Abstract</p> <p>Background</p> <p>Unintentional injuries are the leading cause of death and hospitalisation among New Zealand children, with indigenous Māori and ethnic minority Pacific children significantly over represented in these statistics. International research has shown that many children hospitalised for injury, as well as their families experience high levels of stress, and ethnic disparities in the quality of trauma care are not uncommon. The research on which this paper is based sought to identify key issues and concerns for New Zealand's multi-ethnic community following hospitalisation for childhood injury in order to inform efforts to improve the quality of trauma services. This paper reports on service providers' perspectives complementing previously published research on the experiences of families of injured children.</p> <p>Methods</p> <p>A qualitative research design involving eleven in-depth individual interviews and three focus groups was used to elicit the views of 21 purposefully selected service provider key informants from a range of professional backgrounds involved in the care and support of injured children and their families in Auckland, New Zealand. Interviews were transcribed and data were analysed using thematic analysis.</p> <p>Results</p> <p>Key issues identified by service providers included limited ability to meet the needs of children with mild injuries, particularly their emotional needs; lack of psychological support for families; some issues related to Māori and Pacific family support services; lack of accessible and comprehensive information for children and families; poor staff continuity and coordination; and poor coordination of hospital and community services, including inadequacies in follow-up plans. There was considerable agreement between these issues and those identified by the participant families.</p> <p>Conclusions</p> <p>The identified issues and barriers indicate the need for interventions for service improvement at systemic, provider and patient levels. Of particular relevance are strategies that enable families to have better access to information, including culturally appropriate oral and written sources; improve communication amongst staff and between staff and families; and carefully developed discharge plans that provide care continuity across boundaries between hospital and community settings. Māori and Pacific family support services are important and need better resourcing and support from an organisational culture responsive to the needs of these populations.</p