False-negative PD-L1 immunostaining in ethanol-fixed EBUS-TBNA specimens of non-small cell lung cancer patients

Aims Programmed death-ligand 1 (PD-L1) immunostaining is used to predict which non-small-cell lung cancer (NSCLC) patients will respond best to treatment with programmed cell death protein 1/PD-L1 inhibitors. PD-L1 immunostaining is sometimes performed on alcohol-fixed cytological specimens instead of on formalin-fixed paraffin-embedded (FFPE) biopsies or resections. We studied whether ethanol prefixation of clots from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) results in diminished PD-L1 immunostaining as compared with formalin fixation. Methods and results FFPE cell blocks from EBUS-TBNA specimens of 54 NSCLC patients were identified. For each case, paired samples were available, consisting of clots directly immersed in formalin and clots prefixed in Fixcyt (50% ethanol). Serial sections were immunostained for PD-L1 by use of the standardised SP263 assay and the 22C3 antibody as a laboratory-developed test (LDT). PD-L1 positivity was determined with two cut-offs (1% and 50%). Concordance of PD-L1 positivity between the formalin-fixed (gold standard) and ethanol-prefixed material was assessed. When the 22C3 LDT was used, 30% and 36% of the ethanol-prefixed specimens showed false-negative results at the 1% and 50% cut-offs, respectively (kappa 0.64 and 0.68). When SP263 was used, 22% of the ethanol-prefixed specimens showed false-negative results at the 1% cut-off (kappa 0.67). At the 50% cut-off, concordance was higher (kappa 0.91), with 12% of the ethanol-prefixed specimens showing false-negative results. Conclusion Ethanol fixation of EBUS-TBNA specimens prior to formalin fixation can result in a considerable number of false-negative PD-L1 immunostaining results when a 1% cut-off is used and immunostaining is performed with SP263 or the 22C3 LDT. The same applies to use of the 50% cut-off when immunostaining is performed with the 22C3 LDT

A survey of trainee specialists experiences at the University of Cape Town (UCT): Impacts of race and gender

<p>Abstract</p> <p>Background</p> <p>Efforts to redress racial and gender inequalities in the training of medical specialists has been a central part of a dedicated programme in the Faculty of Health Sciences at the University of Cape Town (UCT). This study aimed to describe trends in race and gender profiles of postgraduate students in medical specialties (registrars) from 1999 to 2006 and to identify factors affecting recruitment and retention of black and female trainees.</p> <p>Method</p> <p>Review of faculty databases for race and gender data from 1999 to 2006. Distribution of an anonymous self-administered questionnaire to all registrars in 2005/2006.</p> <p>Results</p> <p>The percentage of African registrars doubled from 10% to 19% from 1999 to beyond 2002. The percentages of Africans, Coloureds and Indians rose steadily from 26% to 46% from 1999 to 2005, as did that of women from 27% to 44%. The institution's perceived good reputation, being an alumnus and originating from Cape Town were common reasons for choosing UCT for training. A quarter of respondents reported knowledge of a friend who decided against studying at UCT for reasons which included anticipated racial discrimination. Black respondents (23%), particularly African (50%), were more likely to describe registrarship at UCT as unwelcoming than white respondents (12%). Specific instances of personal experience of discrimination were uncommon and not associated with respondents' race or gender. Registrars who had had a child during registrarship and those reporting discrimination were more likely to rate the learning and research environment as poor (Odds Ratio, 4.01; 95% CI 0.98 – 16.47 and 1.99 95% CI 0.57 – 6.97, respectively).</p> <p>Conclusion</p> <p>The proportion of black and female registrars at the University of Cape Town has increased steadily from 1999 to 2006, most likely a result of systematic equity policies and procedures adopted in the faculty during this period. The data point to a need for policies to make the institution more welcoming to diversity and for strategies to address institutional culture and mentorship, with an aim to develop examples of best practices to share within and between institutions.</p

Schooling for conflict transformation : a case study from Northern Uganda

Civil wars impede progress towards the Millennium Development Goals. As many conflicts erupt within a short time, it is important to know what may increase the chances of sustainable peace. Access to education is a factor but relatively little is known about the contribution of what students learn in school. This thesis aims to respond to a research gap by addressing the foll owing question: 'How can schooling contribute to conflict transformation?' Significant curricular approaches that may be used after civil war - peace education, human rights education and citizenship education - are assessed for their strengths and weaknesses. As no single approach is found to be sufficient for conflict transformation, a framework is proposed based on three fundamental concepts: (i) truth seeking; (ii) reconciliation; and (iii) inclusive citizenship. This framework is examined through a qualitative case study of curriculum in seven schools in a district in northern Uganda that is emerging from a twenty-year civil war. The curriculum of four primary schools, two secondary schools, one special school and one teacher training college was studied over a three-month period. A structure of knowledge, skills and values was used to research the framework at a detailed level. It is found that schools exhibit good socialization of reconciliation values and some development of problem-solving and communication skills. There is some understanding of human rights, but little knowledge of history, or of local, national and international political/legal systems. There is minimal development of discussion and critical thinking skills. It is argued that the framework can be used to investigate other schools and to inform the design of a curriculum that can contribute to conflict transformation, with the ultimate aim of reducing the risk of civil war re-eruption

DLG4-related synaptopathy: a new rare brain disorder

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.Genetics of disease, diagnosis and treatmen

Mercury in Fish and Fish-eating Birds near Sites of Industrial Contamination

Volume: 85Start Page: 211End Page: 22

Nonspherocytic Congenital Hemolytic Anemia

Abstract 1. The clinical and hematological features of seven cases of nonspherocytic congenital hemolytic anemia occurring in four different families are presented, together with family studies. Four cases resemble Selwyn and Dacie’s Type I and three cases their Type II. Cases in the literature similar to our cases are reviewed. 2. The Type I cases showed the following features: normocytic or slightly macrocytic anemia with mild hypochromia and some stippling; a decreased or normal osmotic fragility of fresh blood and a decreased fragility of incubated blood; a slightly increased autohemolysis corrected by glucose and by ATP. The family history was positive and clinical onset was usually in adult life. Survival studies suggest that splenectomy may result in partial remission. 3. The Type II cases showed the following features: a marked uniform macrocytosis with numerous Pappenheimer bodies (postsplenectomy); a normal osmotic fragility of fresh blood and an increased fragility of incubated blood; an increased autohemolysis uncorrected by glucose but corrected by ATP. The family history was often negative and clinical onset was usually in infancy. Splenectomy in general appeared to produce no benefit. 4. The classification and pathogenesis of these anemias is discussed. It is pointed out that Type I is not a homogeneous group, and that our cases simply represent one subgroup of this type. Type II appears to be a more homogeneous group. Preliminary biochemical studies suggest the difference in clinical types may be determined by differences in biochemical defects.</jats:p

Economists as political philosophers : a critique of normative trade theory

Economists are political philosophers. This claim is defended based on an investigation of normative arguments made in economics textbooks. The paper aims to explain, reconstruct and contest the neoclassical vision implicit in mainstream economic trade theory. Analyzing arguments made by international economists from the perspective of political philosophy, I show how the contemporary defence of free markets and trade liberalization is linked to a specific normative ideal of the political and social good.Political philosophy, Neoclassical economics, Normative trade theory, Free trade, Efficienc