Outcomes and patients’ perspectives of transition from paediatric to adult care in inflammatory bowel disease

This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/AIM: To describe the disease and psychosocial outcomes of an inflammatory bowel disease (IBD) transition cohort and their perspectives. METHODS: Patients with IBD, aged > 18 years, who had moved from paediatric to adult care within 10 years were identified through IBD databases at three tertiary hospitals. Participants were surveyed regarding demographic and disease specific data and their perspectives on the transition process. Survey response data were compared to contemporaneously recorded information in paediatric service case notes. Data were compared to a similar age cohort who had never received paediatric IBD care and therefore who had not undergone a transition process. RESULTS: There were 81 returned surveys from 46 transition and 35 non-transition patients. No statistically significant differences were found in disease burden, disease outcomes or adult roles and responsibilities between cohorts. Despite a high prevalence of mood disturbance (35%), there was a very low usage (5%) of psychological services in both cohorts. In the transition cohort, knowledge of their transition plan was reported by only 25/46 patients and the majority (54%) felt they were not strongly prepared. A high rate (78%) of discussion about work/study plans was recorded prior to transition, but a near complete absence of discussion regarding sex (8%), and other adult issues was recorded. Both cohorts agreed that their preferred method of future transition practices (of the options offered) was a shared clinic appointment with all key stakeholders. CONCLUSION: Transition did not appear to adversely affect disease or psychosocial outcomes. Current transition care processes could be optimised, with better psychosocial preparation and agreed transition plans

DNA Damage and Cytokine Production in Non-Target Irradiated Lymphocytes

In advanced radiotherapy, treatment of the tumor with high-intensity modulated fields is balanced with normal tissue sparing. However, the non-target dose delivered to surrounding healthy tissue within the irradiated volume is a potential cause for concern. Whether the effects observed are caused after exposure to out-of-field radiation or bystander effects through neighboring irradiated cells is not fully understood. The goal of this study was to determine the effect of exposure to out-of-field radiation in lymphocyte cell lines and primary blood cells. The role of cellular radiosensitivity in altering bystander responses in out-of-field exposed cells was also investigated. Target cells were positioned in a phantom in the center of the radiation field (in-field dose) and exposed to 2 Gy irradiation. Lymphocyte cell lines (C1, AT3ABR, Jurkat, THP-1, AT2Bi and AT3Bi) and peripheral blood were placed 1 cm away from the radiation field edge (out-offield dose) and received an average dose of 10.8 6 4.2 cGy. Double-stranded DNA damage, cell growth and gene expression were measured in the out-of-field cells. Radiosensitive AT3ABR and primary blood cells demonstrated the largest increase in c-H2AX foci after irradiation. Exposure of normal cells to bystander factors from irradiated radiosensitive cell lines also increased DNA damage. Expression of IL-1, IL-6, TNFa and TGFb after addition of bystander factors from radiosensitive cells showed differential effects in normally responding cells, with some evidence of an adaptive response observed. Exposure to out-of-field radiation induces DNA damage and reduces growth in radiosensitive cells. Bystander factors produced by directly irradiated cells in combination with out-of-field exposure may upregulate pro- and anti-inflammatory genes in responding cells of different radiosensitivities, with the potential of affecting the tumor microenvironment. A greater understanding of the radiobiological response in normal cells outside the primary treatment field would assist in radiation treatment planning and in reducing early and late toxicities

MicroRNA Analysis of ATM-Deficient Cells Indicate PTEN and CCDN1 as Potential Biomarkers of Radiation Response

Genetic and epigenetic profile changes associated with individual radiation sensitivity are well documented and have led to enhanced understanding of the mechanisms of the radiation-induced DNA damage response. However, the search continues to identify reliable biomarkers of individual radiation sensitivity. Herein, we report on a multi-biomarker approach using traditional cytogenetic biomarkers, DNA damage biomarkers and transcriptional microRNA (miR) biomarkers coupled with their potential gene targets to identify radiosensitivity in ataxia-telangiectasia mutated (ATM)-deficient lymphoblastoid cell lines (LCL); ATM-proficient cell lines were used as controls. Cells were 0.05 and 0.5 Gy irradiated, using a linear accelerator, with sham-irradiated cells as controls. At 1 h postirradiation, cells were fixed for γ-H2AX analysis as a measurement of DNA damage, and cytogenetic analysis using the G2 chromosomal sensitivity assay, G-banding and FISH techniques. RNA was also isolated for genetic profiling by microRNA (miR) and RT-PCR analysis. A panel of 752 miR were analyzed, and potential target genes, phosphatase and tensin homolog (PTEN) and cyclin D1 (CCND1), were measured. The cytogenetic assays revealed that although the control cell line had functional cell cycle checkpoints, the radiosensitivity of the control and AT cell lines were similar. Analysis of DNA damage in all cell lines, including an additional control cell line, showed elevated γ-H2AX levels for only one AT cell line. Of the 752 miR analyzed, eight miR were upregulated, and six miR were downregulated in the AT cells compared to the control. Upregulated miR-152-3p, miR-24-5p and miR-92-15p and all downregulated miR were indicated as modulators of PTEN and CCDN1. Further measurement of both genes validated their potential role as radiation-response biomarkers. The multi-biomarker approach not only revealed potential candidates for radiation response, but provided additional mechanistic insights into the response in AT-deficient cells

Lateglacial and early Holocene climates of the Atlantic margins of Europe: Stable isotope, mollusc and pollen records from Orkney, Scotland

The margins of mainland Europe, and especially those areas coming under the influence of North Atlantic weather systems, are ideally placed to record changing palaeoclimates. Cores from an infilled lake basin at Crudale Meadow in Mainland, Orkney, revealed basal deposits of calcareous mud (‘marl’) beneath sedge peat. Stable isotope, palynological and molluscan analyses allowed the establishment of palaeoenvironmental changes through the Devensian Lateglacial and the early Holocene. The δ18Omarl record exhibited the existence of possibly four climatic oscillations in the Lateglacial (one of which, within event cf. GI-1c, is not often commented upon), as well as the Preboreal Oscillation and other Holocene perturbations. The cold episodes succeeding the Preboreal Oscillation were demarcated conservatively and one of these (event C5, ∼11.0 ka) may have previously been unremarked, while the putative 9.3 and 8.2 ka events seem not to produce corresponding palynologically visible floristic changes. The events at Crudale Meadow are consistent with those recorded at other sites from Britain, Ireland and elsewhere, and can be correlated with isotopic changes shown by the Greenland ice cores. The multi-proxy approach enriches the environmental reconstructions from the site, although the synchronicity of the response of the various proxies is sometimes equivocal, depending upon the time period concerned, taphonomy, and the nature of the deposits. The site may contain the most northerly Lateglacial isotope record from northwest Europe, and it has yielded one of the best archives for the demonstration of abrupt early Holocene events within Britain

Atypical Epstein-Barr Viral Genomic Structure in Lymphoma Tissue and Lymphoid Cell Lines

Epstein-Barr virus (EBV) DNA is found within the malignant cells of some subtypes of lymphoma, and viral presence is being exploited for improved diagnosis, monitoring, and management of affected patients. Recent work suggests that viral genomic polymorphism, such as partial deletion of the viral genome, could interfere with virus detection in tumor tissues. To test for atypical forms of the EBV genome, 98 lymphomas and 6 infected cell lines were studied using a battery of 6 quantitative polymerase chain reaction assays targeting disparate sections of EBV DNA. Fifty of the lymphomas (51%) had no amplifiable EBV DNA, and 38 lymphomas (39%) had low-level EBV infection that was deemed incidental based on EBV-encoded RNA (EBER) in situ hybridization results. The remaining 10 lymphomas (10%) had high EBV loads and EBER localization to malignant cells by EBER in situ hybridization. All 10 represented lymphoma subtypes were previously associated with EBV (Burkitt, diffuse large B-cell, or T-cell type), whereas no remnants of EBV were detected in other lymphoma subtypes (follicular, small lymphocytic, mantle cell, or marginal zone type). Interestingly, 4 of the 10 infected lymphomas had evidence of atypical viral genomes, including 3 of 4 infected T-cell lymphomas with aberrant loss of LMP2 amplicons, and a single diffuse large B-cell lymphoma lacking the central part of the viral genome spanning BamH1W, BZLF1, and EBNA1 gene segments. A reasonable screening strategy for infected malignancy involves applying EBER1 and LMP1 quantitative polymerase chain reaction assays and confirming that values exceeding 2000 copies of EBV per 100,000 cells have EBER localization to malignant cells

The genome sequence of <i>Trypanosoma brucei gambiense</i>, causative agent of chronic Human African Trypanosomiasis

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; &lt;i&gt;Trypanosoma brucei gambiense&lt;/i&gt; is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a &lt;i&gt;T. b. brucei&lt;/i&gt; isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between &lt;i&gt;T. b. gambiense&lt;/i&gt; and the reference genome. We sought to identify features that were uniquely associated with &lt;i&gt;T. b. gambiense&lt;/i&gt; and its ability to infect humans.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and findings:&lt;/b&gt; An improved high-quality draft genome sequence for the group 1 &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with &lt;i&gt;T. b. brucei&lt;/i&gt; showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972. A comparison of the variant surface glycoproteins (VSG) in &lt;i&gt;T. b. brucei&lt;/i&gt; with all &lt;i&gt;T. b. gambiense&lt;/i&gt; sequence reads showed that the essential structural repertoire of VSG domains is conserved across &lt;i&gt;T. brucei&lt;/i&gt;.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This study provides the first estimate of intraspecific genomic variation within &lt;i&gt;T. brucei&lt;/i&gt;, and so has important consequences for future population genomics studies. We have shown that the &lt;i&gt;T. b. gambiense&lt;/i&gt; genome corresponds closely with the reference, which should therefore be an effective scaffold for any &lt;i&gt;T. brucei&lt;/i&gt; genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in &lt;i&gt;T. b. brucei&lt;/i&gt;, no &lt;i&gt;T. b. gambiense&lt;/i&gt;-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.&lt;/p&gt

Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library

The present study reports the discovery of a small-molecule negative allosteric modulator for the β2-adrenergic receptor (β2AR) via in vitro affinity-based iterative selection of highly diverse DNA-encoded small-molecule libraries. Characterization of the compound demonstrates its selectivity for the β2AR and that it negatively modulates a wide range of receptor functions. More importantly, our findings establish a generally applicable, proof-of-concept strategy for screening DNA-encoded small-molecule libraries against purified G-protein–coupled receptors (GPCRs), which holds great potential for discovering therapeutic molecules

Surgical and medical second trimester abortion in South Africa: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>A high percentage of abortions performed in South Africa are in the second trimester. However, little research focuses on women's experiences seeking second trimester abortion or the efficacy and safety of these services.</p> <p>The objectives are to document clinical and acceptability outcomes of second trimester medical and surgical abortion as performed at public hospitals in the Western Cape Province.</p> <p>Methods</p> <p>We performed a cross-sectional study of women undergoing abortion at 12.1-20.9 weeks at five hospitals in Western Cape Province, South Africa in 2008. Two hundred and twenty women underwent D&E with misoprostol cervical priming, and 84 underwent induction with misoprostol alone. Information was obtained about the procedure and immediate complications, and women were interviewed after recovery.</p> <p>Results</p> <p>Median gestational age at abortion was earlier for D&E clients compared to induction (16.0 weeks vs. 18.1 weeks, p < 0.001). D&E clients reported shorter intervals between first clinic visit and abortion (median 17 vs. 30 days, p < 0.001). D&E was more effective than induction (99.5% vs. 50.0% of cases completed on-site without unplanned surgical procedure, p < 0.001). Although immediate complications were similar (43.8% D&E vs. 52.4% induction), all three major complications occurred with induction. Early fetal expulsion occurred in 43.3% of D&E cases. While D&E clients reported higher pain levels and emotional discomfort, most women were satisfied with their experience.</p> <p>Conclusions</p> <p>As currently performed in South Africa, second trimester abortions by D&E were more effective than induction procedures, required shorter hospital stay, had fewer major immediate complications and were associated with shorter delays accessing care. Both services can be improved by implementing evidence-based protocols.</p

The Concise Guide to PHARMACOLOGY 2023/24:Catalytic receptors

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p