Self-organising aggregates of zebrafish retinal cells for investigating mechanisms of neural lamination

To investigate the cell-cell interactions necessary for the formation of retinal layers, we cultured dissociated zebrafish retinal progenitors in agarose microwells. Within these wells, the cells re-aggregated within hours, forming tight retinal organoids. Using a Spectrum of Fates zebrafish line, in which all different types of retinal neurons show distinct fluorescent spectra, we found that by 48 h in culture, the retinal organoids acquire a distinct spatial organisation, i.e. they became coarsely but clearly laminated. Retinal pigment epithelium cells were in the centre, photoreceptors and bipolar cells were next most central and amacrine cells and retinal ganglion cells were on the outside. Image analysis allowed us to derive quantitative measures of lamination, which we then used to find that Müller glia, but not RPE cells, are essential for this process.This work was funded by a Wellcome Trust Senior Investigator Award to W.A.H. (100329/Z/12/Z) and a Biotechnology and Biological Sciences Research Council Studentship Award to M.K.E. (BB/J014540/1)

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study.

BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001). INTERPRETATION: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants. FUNDING: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study

BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001). INTERPRETATION: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants. FUNDING: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre

Coincidence between transcriptome analyses on different microarray platforms using a parametric framework

A parametric framework for the analysis of transcriptome data is demonstrated to yield coincident results when applied to data acquired using two different microarray platforms. Discrepancies among transcriptome studies are frequently reported, casting doubt on the reliability of collected data. The inconsistency among observations can be largely attributed to differences among the analytical frameworks employed for data analysis. The existing frameworks normalizes data against a standard determined from the data to be analyzed. In the present study, a parametric framework based on a strict model for normalization is applied to data acquired using an in-house printed chip and GeneChip. The framework is based on a common statistical characteristic of microarray data, and each data is normalized on the basis of a linear relationship with this model. In the proposed framework, the expressional changes observed and genes selected are coincident between platforms, achieving superior universality of data compared to other methods

The influence of fine-scale topography on the impacts of Holocene fire in a Tasmanian montane landscape

Copyright © 2019 John Wiley & Sons, Ltd. Tasmania's montane temperate rainforests contain some of Australia's most ancient and endemic flora. Recent landscape-scale fires have impacted a significant portion of these rainforest ecosystems. The complex and rugged topography of Tasmania results in a highly variable influence of fire across the landscape, rendering predictions of ecosystem response to fire difficult. We assess the role of topographic variation in buffering the influence of fire in these endemic rainforest communities. We developed a new 14000-year (14-ka) palaeoecological dataset from Lake Perry, southern Tasmania, and compared it to neighbouring Lake Osborne

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Leadership and decision-making practices in public versus private universities in Pakistan

The goal of this study is to examine differences in leadership and decision-making practices in public and private universities in Pakistan, with a focus on transformational leadership (TL) and participative decision-making (PDM). We conducted semi-structured interviews with 46 deans and heads of department from two public and two private universities in Pakistan. Our findings indicate that leadership and decision-making practices are different in public and private universities. While differences were observed in all six types of TL-behaviour, the following three approaches emerged to be crucial in both public and private universities: (1) articulating a vision, (2) fostering the acceptance of group goals, and (3) high-performance expectations. In terms of PDM, deans and heads of department in public and private universities adopt a collaborative approach. However, on a practical level this approach is limited to teacher- and student-related matters. Overall, our findings suggest that the leadership and decision-making practices in Pakistani public and private universities are transformational and participative in nature

The process of developing a management system for subsistence fisheries in South Africa: recognizing and formalizing a marginalized fishing sector in South Africa

Subsistence fishers were first recognized as a formal fishing sector in South Africa when new fishing legislation, aimed at redressing past inequalities, was enacted in 1998. Little information was available about these fishers, their activities, and the resources upon which they rely. Recognizing the imperative to gain an understanding of the fishers and to consult broadly, the national agency responsible for the management of marine living resources, Marine and Coastal Management (MCM) of the Department of Environmental Affairs and Tourism, appointed a Subsistence Fisheries Task Group (SFTG) in December 1998 to provide advice on the implementation of appropriate management systems for subsistence fisheries. This paper describes the process followed to formulate recommendations that were presented by the SFTG to MCM in February 2000. The activities of the SFTG fell into two categories: research aimed at identifying subsistence fishers and gaining an understanding of their activities and socio-economic profiles; and consultation aimed at ensuring that the needs and aspirations of fishers and the experience of local managers were incorporated. Research included both field-based studies and synthesis of information about comparative fisheries elsewhere. Consultation took the form of local interviews and focusgroup discussions, meetings with fishers and a national workshop. A pivotal activity was the development of a clear definition and qualifying criteria for subsistence fishers. A significant outcome was the identification of a separate small-scale commercial sector, previously erroneously lumped with subsistence fishers. Needs of fishers and problems identified during the process provided the basis for recommendations in the following areas: definitions, assessment and categorization of resources, management systems, communication mechanisms, application and allocation procedures, capacity building, compliance, research and monitoring, and funding and staff required for the management of this new sector. An evaluation is made of the opportunities presented by the SFTG process, constraints experienced and lessons learnt, giving important insights that are applicable to other similar processes, yet seldom documented in formal literature. Keywords: management of fisheries, subsistence fisheriesAfrican Journal of Marine Science 2002, 24: 405–42

A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes

Aim We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: i) 45mg loading-weeks 0/4/16, ii) 45mg maintenance-weeks 0/4/16/28/40, iii) 90mg loading-weeks 0/4/16 and iv) 90mg maintenance-weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90mg maintenance dosing cohort had the smallest mean decline in C-peptide AUC (0.1pmol/mL). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1 and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response

Extreme Food-Plant Specialisation in Megabombus Bumblebees as a Product of Long Tongues Combined with Short Nesting Seasons

© 2015 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. http://creativecommons.org/licenses/by/4.0/ The attached file is the published version of the article