Incidental Finding of Sickle Cell Trait From an Everyday Diabetes Test: Should General Health Care Providers and testing centres report, retest, or refer?

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.The HbA1c test is increasingly widely used as a diagnostic and screening test for diabetes mellitus type 2 (T2DM) but the presence of haemoglobin variants, such as sickle haemoglobin, can interfere with results in some analytical systems. These interferences are occasionally reported by laboratories, leading unprepared patients to suspect they may be sickle cell carriers and seek confirmation through a sickle cell test. Incidental findings of Hb variants, and the reporting thereof, present multiple ethical challenges to laboratories, medical practitioners, patients and their family members, but there appear to be no international or national guidelines on how to deal with the reporting of these findings. This paper explores issues such as whether informed consent is necessary, how the results should be communicated, how the patient may be affected by knowing their carrier status, the timing of communications, complications caused by partial results, and being a ‘healthy carrier’ at the same time as potentially experiencing symptoms

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooq

A Csf1r-EGFP transgene provides a novel marker for monocyte subsets in sheep

Expression of Csf1r in adults is restricted to cells of the macrophage lineage. Transgenic reporters based upon the Csf1r locus require inclusion of the highly conserved Fms-intronic regulatory element for expression.We have created Csf1r-EGFP transgenic sheep via lentiviral transgenesis of a construct containing elements of the mouse Fms-intronic regulatory element and Csf1r promoter. Committed bone marrow macrophage precursors and blood monocytes express EGFP in these animals. Sheep monocytes were divided into three populations, similar to classical, intermediate, and nonclassical monocytes in humans, based upon CD14 and CD16 expression. All expressed EGFP, with increased levels in the nonclassical subset. Because Csf1r expression coincides with the earliest commitment to the macrophage lineage, Csf1r-EGFP bone marrow provides a tool for studying the earliest events in myelopoiesis using the sheep as a model

Neonatal invasive candidiasis in low-and-middle-income countries: data from the NeoOBS study

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole resistant Candida spp. isolates in low-and-middle-income -countries (LMICs) compared to high-income-countries (HIC). We describe the epidemiology, Candida spp. distribution, treatment and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalised infants < 60 days postnatal age with sepsis (August 2018-February 2021). 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34) and median birth weight was 1270 g (IQR: 990-1692). Only a minority had high risk criteria, such as being born < 28 weeks, 19% (24/127), or birth weight < 1000 g, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%) and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrolment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines

Rapid Diagnosis of Tuberculosis with the Xpert MTB/RIF Assay in High Burden Countries: A Cost-Effectiveness Analysis

A cost-effectiveness study by Frank Cobelens and colleagues reveals that Xpert MTB/RIF is a cost-effective method of tuberculosis diagnosis that is suitable for use in low- and middle-income settings

Germline Transgenic Pigs by Sleeping Beauty Transposition in Porcine Zygotes and Targeted Integration in the Pig Genome

Genetic engineering can expand the utility of pigs for modeling human diseases, and for developing advanced therapeutic approaches. However, the inefficient production of transgenic pigs represents a technological bottleneck. Here, we assessed the hyperactive Sleeping Beauty (SB100X) transposon system for enzyme-catalyzed transgene integration into the embryonic porcine genome. The components of the transposon vector system were microinjected as circular plasmids into the cytoplasm of porcine zygotes, resulting in high frequencies of transgenic fetuses and piglets. The transgenic animals showed normal development and persistent reporter gene expression for >12 months. Molecular hallmarks of transposition were confirmed by analysis of 25 genomic insertion sites. We demonstrate germ-line transmission, segregation of individual transposons, and continued, copy number-dependent transgene expression in F1-offspring. In addition, we demonstrate target-selected gene insertion into transposon-tagged genomic loci by Cre-loxP-based cassette exchange in somatic cells followed by nuclear transfer. Transposase-catalyzed transgenesis in a large mammalian species expands the arsenal of transgenic technologies for use in domestic animals and will facilitate the development of large animal models for human diseases

Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate

Rethinking activism: tourism, mobilities and emotion

This article seeks to trouble distinctions between activism and tourism, and activism and regionality. It does this by exploring the role of tourism, mobilities and emotion for a regional Australian queer collective, and their 1400 km return journey to the Sydney Gay and Lesbian Mardi Gras Parade. In illustrating the ways this touristic journey represents alternative ways of performing queer activism, I argue that the existence of regional activism deconstructs notions that non-normative sexualities and queer politics do not exist beyond urban centres. Granting attention to the alternative ways the queer collective utilises tourism mobilities as part of their activism strengthens characterisations of leisure as always more than a space of hedonism and escape. Understanding the broader significance of events enables scholars to rethink festivals as spatially and temporally bounded, one off events but rather crucial to the ongoing sustainability of regional queer collectives and performances of queer activism in peripheral areas

Sequestration of Highly Expressed mRNAs in Cytoplasmic Granules, P-Bodies, and Stress Granules Enhances Cell Viability

Transcriptome analyses indicate that a core 10%–15% of the yeast genome is modulated by a variety of different stresses. However, not all the induced genes undergo translation, and null mutants of many induced genes do not show elevated sensitivity to the particular stress. Elucidation of the RNA lifecycle reveals accumulation of non-translating mRNAs in cytoplasmic granules, P-bodies, and stress granules for future regulation. P-bodies contain enzymes for mRNA degradation; under stress conditions mRNAs may be transferred to stress granules for storage and return to translation. Protein degradation by the ubiquitin-proteasome system is elevated by stress; and here we analyzed the steady state levels, decay, and subcellular localization of the mRNA of the gene encoding the F-box protein, UFO1, that is induced by stress. Using the MS2L mRNA reporter system UFO1 mRNA was observed in granules that colocalized with P-bodies and stress granules. These P-bodies stored diverse mRNAs. Granules of two mRNAs transported prior to translation, ASH1-MS2L and OXA1-MS2L, docked with P-bodies. HSP12 mRNA that gave rise to highly elevated protein levels was not observed in granules under these stress conditions. ecd3, pat1 double mutants that are defective in P-body formation were sensitive to mRNAs expressed ectopically from strong promoters. These highly expressed mRNAs showed elevated translation compared with wild-type cells, and the viability of the mutants was strongly reduced. ecd3, pat1 mutants also exhibited increased sensitivity to different stresses. Our interpretation is that sequestration of highly expressed mRNAs in P-bodies is essential for viability. Storage of mRNAs for future regulation may contribute to the discrepancy between the steady state levels of many stress-induced mRNAs and their proteins. Sorting of mRNAs for future translation or decay by individual cells could generate potentially different phenotypes in a genetically identical population and enhance its ability to withstand stress

Realising consilience: How better communication between archaeologists, historians and natural scientists can transform the study of past climate change in the Mediterranean

This paper reviews the methodological and practical issues relevant to the ways in which natural scientists, historians and archaeologists may collaborate in the study of past climatic changes in the Mediterranean basin. We begin by discussing the methodologies of these three disciplines in the context of the consilience debate, that is, attempts to unify different research methodologies that address similar problems. We demonstrate that there are a number of similarities in the fundamental methodology between history, archaeology, and the natural sciences that deal with the past (“palaeoenvironmental sciences”), due to their common interest in studying societal and environmental phenomena that no longer exist. The three research traditions, for instance, employ specific narrative structures as a means of communicating research results. We thus present and compare the narratives characteristic of each discipline; in order to engage in fruitful interdisciplinary exchange, we must first understand how each deals with the societal impacts of climatic change. In the second part of the paper, we focus our discussion on the four major practical issues that hinder communication between the three disciplines. These include terminological misunderstandings, problems relevant to project design, divergences in publication cultures, and differing views on the impact of research. Among other recommendations, we suggest that scholars from the three disciplines should aim to create a joint publication culture, which should also appeal to a wider public, both inside and outside of academia.This paper emerged as a result of a workshop at Costa Navarino and the Navarino Environmental Observatory (NEO), Greece in April 2014, which addressed Mediterranean Holocene climate and human societies. The workshop was co-sponsored by IGBP/PAGES, NEO, the MISTRALS/PaleoMex program, the Labex OT-Med, the Bolin Centre for Climate Research at Stockholm University, and the Institute of Oceanography at the Hellenic Centre for Marine Research. We also acknowledge funding from the National Science Centre, Poland, within the scheme of the Centre's postdoctoral fellowships (DEC-2012/04/S/HS3/00226 (A.I)); the Swedish Research Council (grant numbers 421-2014-1181 (E.W.) and 621-2012-4344 (K.H.)); CSIC-Ramón y Cajal post-doctoral program RYC-2013-14073 and Clare Hall College, Cambridge, Shackleton Fellowship (B.M.); the EU/FP7 Project ‘Sea for Society’ (Science and Society - 2011-1, 289066)