Transcriptome analysis of avian livers reveals different molecular changes to three urban pollutants: Soot, artificial light at night and noise.

Identifying key molecular pathways and genes involved in the response to urban pollutants is an important step in furthering our understanding of the impact of urbanisation on wildlife. The expansion of urban habitats and the associated human-introduced environmental changes are considered a global threat to the health and persistence of humans and wildlife. The present study experimentally investigates how short-term exposure to three urban-related pollutants -soot, artificial light at night (ALAN) and traffic noise-affects transcriptome-wide gene expression in livers from captive female zebra finches (Taeniopygia guttata). Compared to unexposed controls, 17, 52, and 28 genes were differentially expressed in soot, ALAN and noise-exposed birds, respectively. In soot-exposed birds, the enriched gene ontology (GO) terms were associated with a suppressed immune system such as interferon regulating genes (IRGs) and responses to external stimuli. For ALAN-exposed birds, enriched GO terms were instead based on downregulated genes associated with detoxification, redox, hormonal-, and metabolic processes. Noise exposure resulted in downregulation of genes associated with the GO terms: cellular responses to substances, catabolic and cytokine responses. Among the individually differentially expressed genes (DEGs), soot led to an increased expression of genes related to tumour progression. Likewise, ALAN revealed an upregulation of multiple genes linked to different cancer types. Both sensory pollutants (ALAN and noise) led to increased expression of genes linked to neuronal function. Interestingly, noise caused upregulation of genes associated with serotonin regulation and function (SLC6A4 and HTR7), which previous studies have shown to be under selection in urban birds. These outcomes indicate that short-term exposure to the three urban pollutants perturbate the liver transcriptome, but most often in different ways, which highlights future studies of multiple-stress exposure and their interactive effects, along with their long-term impacts for urban-dwelling wildlife.

Audiological phenotyping evaluation in KBG syndrome: Description of a multicenter review.

OBJECTIVES: Our objective was to reinforce clinical knowledge of hearing impairment in KBG syndrome. KBG syndrome is a rare genetic disorder due to monoallelic pathogenic variations of ANKRD11.The typical phenotype includes facial dysmorphism, costal and spinal malformation and developmental delay. Hearing loss in KBG patients has been reported for many years, but no study has evaluated audiological phenotyping from a clinical and an anatomical point of view. METHODS: This French multicenter study included 32 KBG patients with retrospective collection of data on audiological features, ear imaging and genetic investigations. RESULTS: We identified a typical audiological profil in KBG syndrome: conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%) hearing loss, with some audiological heterogeneity. Among patients with an abnormality on CT imaging (55%), ossicular chain impairment (67%), fixation of the stapes footplate (33%) and inner-ear malformations (33%) were the most common abnormalities. CONCLUSION: We recommend a complete audiological and radiological evaluation and an ENT-follow up in all patients presenting with KBG Syndrome. Imaging evaluation is necessary to determine the nature of lesions in the middle and inner ear.

Calcite crystal orientation patterns in the bilayers of laminated shells of benthic rotaliid foraminifera.

Shells of calcifying foraminifera play a major role in marine biogeochemical cycles; fossil shells form important archives for paleoenvironment reconstruction. Despite their importance in many Earth science disciplines, there is still little consensus on foraminiferal shell mineralization. Geochemical, biochemical, and physiological studies showed that foraminiferal shell formation might take place through various and diverse mineralization mechanisms. In this study, we contribute to benthic foraminiferal shell calcification through deciphering crystallite organization within the shells. We base our conclusions on results gained from electron backscattered diffraction (EBSD) measurements and describe microstructure/texture characteristics within the laminated shell walls of the benthic, symbiontic foraminifera: Ammonia tepida, Amphistegina lobifera, Amphistegina lessonii. We highlight crystallite assembly patterns obtained on differently oriented cuts and discuss crystallite sizes, morphologies, interlinkages, orientations, and co-orientation strengths. We show that: (i) crystals within benthic foraminiferal shells are mesocrystals, (ii) have dendritic-fractal morphologies and (iii) interdigitate strongly. Based on crystal size, we (iv) differentiate between the two layers that comprise the shells and demonstrate that (v) crystals in the septa have different assemblies relative to those in the shell walls. We highlight that (vi) at junctions of different shell elements the axis of crystal orientation jumps abruptly such that their assembly in EBSD maps has a bimodal distribution. We prove (vii) extensive twin-formation within foraminiferal calcite; we demonstrate (viii) the presence of two twin modes: 60°/[001] and 77°/~[6 -6 1] and visualize their distributions within the shells. In a broader perspective, we draw conclusions on processes that lead to the observed microstructure/texture patterns.

Gestational age limits for abortion and cross-border reproductive care in Europe: a mixed-methods study.

OBJECTIVES: Little is known about the experiences of women who travel within Europe for abortion care from countries with relatively liberal laws. This paper aims to assess the primary reasons for travel among a sample of women who travelled from European countries with relatively liberal abortion laws to obtain abortion care mainly in the UK and the Netherlands. DESIGN: Multi-country, 5-year mixed methods study on barriers to legal abortion and travel for abortion. SETTING: UK, the Netherlands and Spain. POPULATION OR SAMPLE: We present quantitative data from 204 surveys, and qualitative data from 30 in-depth interviews with pregnant people who travelled to the UK, the Netherlands and Spain from countries where abortion is legal on broad grounds within specific gestational age (GA) limits. METHODS: Mixed-methods. MAIN OUTCOME MEASURES: GA when presenting at abortion clinic, primary reason for abortion-related travel. RESULTS: Study participants overwhelmingly reported travelling for abortion because they had exceeded GA limits in their country of residence. Participants also reported numerous delays and barriers to receiving care. CONCLUSIONS: Our findings highlight the need for policies that support access to abortion throughout pregnancy and illustrate that early access to it is necessary but not sufficient to meet people's reproductive health needs. FUNDING: This study is funded by the European Research Council (ERC). TWEETABLE ABSTRACT: This study shows that GA limits drive women from EU countries where abortion is legal to seek abortions abroad.

Pre-closure assessment of elevated arsenic and other potential environmental constraints to developing aquaculture and fisheries: The case of the Mae Moh mine and power plant, Lampang, Thailand.

Our assessment of 30 water bodies in the vicinity of the Mae Moh coal mine and power station in northern Thailand does not indicate substantial water quality management challenges to developing fisheries/aquaculture in peripheral reservoirs and streams. Negative water quality issues such as high concentrations of arsenic (2-17 µg/L) and ions including sulfate (868-2605 mg/L), sodium (217-552 mg/L), and total ammonia (<1-5 mg/L) were associated with groundwater and surface water resources on the facility, as well as the stream network draining from it. Total dissolved solids were also very high, ranging from 658 to 3610 mg/L. Six of seven ponds tested had As concentrations in the range of 5-17 µg/L. Although these levels are less than the Thai regulation for industrial effluent, they are elevated over background surface water concentrations. The highest concentration in a contaminated stream was 10.54 µg/L As, which is only slightly above the WHO (2017) regulation of 10 µg/L for drinking water. Ponds, contaminated streams, and deep subsurface water should not be used for fisheries/aquaculture without extensive remediation/treatment. Concentrations of these water parameters in peripheral streams and reservoirs were not of environmental concern. High water hardness (161-397 mg/L CaCO3 and potential ionic imbalances may be the greatest hindrances to developing sustainable fisheries and aquaculture in reservoirs in the study area. Routine monitoring of inorganic As species and other contaminants in water is needed to assess the full extent of arsenic risk at the site following closure.

[Efficacy of Disease Management Programs Asthma and COPD? Results of a Cross-Sectional Study]. / Wirksamkeit von Disease-Management-Programmen für Asthma und COPD? Ergebnisse einer Querschnittstudie.

BACKGROUND: The efficacy of the German disease management programs (DMP) asthma and chronic obstructive pulmonary disease (COPD) cannot be shown with the legally bound documentations. Studies with control groups are rare. Aim of this work was to investigate in a cross-sectional study whether the disease control differs in participants (DMP+) and non-participants (DMP - ) of the DMPs asthma and COPD. METHODS: The study was a prospective multicenter cross-sectional study. Primary endpoints were the Asthma Control Test™ (ACT) in the asthma part of the study and the COPD Assessment Test™ (CAT) for the COPD part. RESULTS: A total of 1038 asthma patients and 846 COPD patients were included, of whom about 70 % participated in the corresponding DMP. The ACT total score was higher in asthma DMP+ patients than in DMP- patients (mean difference 0.86; 95 % CI: 0.29 - 1.43;p = 0.003), but not clinically relevant. For COPD there was no clinically relevant difference in COPD disease impact (0.52; 95 % CI: - 0.71 - 1.75; p = 0.405). Although DMP patients had to be enrolled in the respective DMP for at least one year, only 60 % of these patients had participated in a structured education. We did not observe a difference in disease control in DMP patients who respectively participated and did not participate in a structured education. DISCUSSION: There was no clinically relevant difference in disease control between DMP+ and DMP- patients. The efficacy of DMPs has been demonstrated internationally in randomized controlled trials. Randomized controlled trials should be conducted in Germany for demonstrating efficacy of DMPs asthma and COPD. REGISTRATION: drks.de, DRKS00007664, Registration date: Jan 15, 2015.

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.

An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise.

Visceral adipose tissue is an immunogenic tissue, which turns detrimental during obesity by activation of proinflammatory macrophages. During aging, chronic inflammation increases proportional to visceral adipose tissue (VAT) mass and associates with escalating morbidity and mortality. Here, we utilize a mouse model to investigate the inflammatory status of visceral adipose tissue in lean aging mice and assess the effects of exercise training interventions. We randomized adult (11 months; n = 21) and old (23 months; n = 27) mice to resistance training (RT) or endurance training (ET), or to a sedentary control group (S). Strikingly, we observed an anti-inflammatory phenotype in the old mice, consisting of higher accumulation of M2 macrophages and IL-10 expression, compared to the adult mice. In concordance, old mice also had less VAT mass and smaller adipocytes compared to adult mice. In both age groups, exercise training enhanced the anti-inflammatory phenotype and increased PGC1-α mRNA expression. Intriguingly, the brown adipose tissue marker UCP1 was modestly higher in old mice, while remained unchanged by the intervention. In conclusion, in the absence of obesity, visceral adipose tissue possesses a pronounced anti-inflammatory phenotype during aging which is further enhanced by exercise.

Terebratulide brachiopod shell biomineralization by mantle epithelial cells.

To understand mineral transport pathways for shell secretion and to assess differences in cellular activity during mineralization, we imaged with TEM and FE-SEM ultrastructural characteristics of outer mantle epithelium (OME) cells. Imaging was carried out on Magellania venosa shells embedded/etched, chemically fixed/decalcified and high-pressure frozen/freeze-substituted samples from the commissure, central shell portions and from puncta. Imaging results are complemented with morphometric evaluations of volume fractions of membrane-bound organelles. At the commissure the OME consists of several layers of cells. These cells form oblique extensions that, in cross-section, are round below the primary layer and flat underneath fibres. At the commissure the OME is multi-cell layered, in central shell regions it is single-cell layered. When actively secreting shell carbonate extrapallial space is lacking, because OME cells are in direct contact with the calcite of the forming fibres. Upon termination of secretion, OME cells attach via apical hemidesmosomes to extracellular matrix membranes that line the proximal surface of fibres. At the commissure volume fractions for vesicles, mitochondria and lysosomes are higher relative to single-cell layered regions, whereas for endoplasmic-reticulum and Golgi apparatus there is no difference. FE-SEM, TEM imaging reveals the lack of extrapallial space between OME cells and developing fibres. In addition, there is no indication for an amorphous precursor within fibres when these are in active secretion mode. Accordingly, our results do not support transport of minerals by vesicles from cells to sites of mineralization, rather by transfer of carbonate ions via transport mechanisms associated with OME cell membranes.

Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity - indications of immune cell activation.

Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes. For islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns. We identified the pentose phosphate pathway and pyrimidine metabolism - both involved in nucleotide synthesis and cell proliferation - to be differentially expressed in children born by Cesarean section and after islet autoimmunity. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. Moreover, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes. In conclusion, we identified shared molecular changes relating to immune cell activation in children born by Cesarean section and children who developed autoimmunity. Our results serve as a starting point for further investigations on how a type 1 diabetes risk factor impacts the young immune system at a molecular level.

The effect of resistance exercise upon age-related systemic and local skeletal muscle inflammation.

AIM: Chronic inflammation increases with age and is correlated positively to visceral fat mass, but inversely to muscle mass. We investigated the hypothesis that resistance training would increase muscle mass and strength together with a concomitant drop in local and systemic inflammation level independent of any changes in visceral fat tissue in elderly. METHODS: 25 subjects (mean 67, range 62-70 years) were randomized to 1 year of heavy resistance training (HRT) or control (CON), and tested at 0, 4 and 12 months for physical performance, body composition (DXA), vastus lateralis muscle area (MRI) local and systemic inflammation (blood and muscle). In addition, systemic and local muscle immunological responses to acute exercise was determined before and after the training period. RESULTS: Increases in muscle mass (≈2%, p < 0.05), vastus lateralis area (≈9%. P < 0.05), isometric (≈15%) and dynamic (≈15%) muscle strength (p < 0.05) were found in the HRT group after 12 months training. HRT did not alter overall or visceral fat mass (p > 0.05). Blood C-Reactive Protein declined over time in both groups (p < 0.05), whereas muscle inflammation markers were unchanged to 1 year of HRT. Acute exercise increased plasma IL-6 and FGF-19 (p < 0.05), decreased FGF-21 (p < 0.05) and CCL-20 (p < 0.05), and increased GDNF in muscle (p < 0.001) similarly before and after 1 year in both groups. CONCLUSION: Long term resistance training increased muscle strength and improved muscle mass, but did not alter visceral fat mass and did not show any specific effect upon resting or exercise induced markers of inflammation.

Multicentre, blinded, randomised clinical trial comparing the use of flunixin meglumine with firocoxib in horses with small intestinal strangulating obstruction.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E2 (PGE2 ), thromboxane B2 (TXB2 ), TNF⍺ and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE2 . There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Physical activity is associated with lower insulin and C-peptide during glucose challenge in children and adolescents with family background of diabetes.

AIMS: Children and adolescents with a family history of diabetes are at increased risk of overweight, but little is known about the potentially beneficial effects of physical activity on these children. The objective of this study was to investigate the association between moderate to vigorous physical activity (MVPA) and metabolic and inflammatory risks in children and adolescents with a family background of Type 1 diabetes or gestational diabetes. METHODS: Valid MVPA measurements, made with accelerometers, were available from 234 participants (median age, 10.2 years) who had a first-degree relative with either Type 1 or gestational diabetes. Anthropometric and metabolic measurements were made and cytokines measured, and were correlated with MVPA measurements, with stepwise adjustment for confounding factors, in a cross-sectional analysis. RESULTS: MVPA was negatively associated with insulin and C-peptide during challenge with an oral glucose tolerance test. MVPA was also significantly positively associated with the insulin sensitivity index, whereas no consistently significant associations were found between MVPA and BMI, blood pressure or cytokine levels. DISCUSSION: Our findings indicate that physical activity may have beneficial effects on insulin and C-peptide metabolism in children and adolescents with a family background of diabetes, but show no evidence of a protective association with other health-related outcomes.

Impaired intestinal barrier function and relapsing digestive disease: Lessons from a porcine model of early life stress.

Within this issue of Neurogastroenterology and Motility, an article by Pohl et al highlights new insights from a powerful porcine model of the link between early life adversity and relapsing functional gastrointestinal disorders. Early weaning stress closely mimics the early life psychosocial stressors that have been linked to adult onset gastrointestinal dysfunction. This early weaning model provides reproducible and highly translatable outcomes in young stress-challenged pigs. Due to the convincingly comparable neurological and gastroenterological anatomy and physiology between pigs and human beings, gastrointestinal stress and injury studies utilizing swine models will provide invaluable insights to improve our understanding and treatment of gastrointestinal disease in human beings. Future studies to examine mechanisms underlying this link between early life adversity and functional gastrointestinal disorders will explore the roles of gender and hypomaturity in gastrointestinal responses to stress.

In vitro effects of the toll-like receptor agonists monophosphoryl lipid A and CpG-rich oligonucleotides on cytokine production by equine cells.

Insect bite hypersensitivity (IBH) is an equine allergic dermatitis to Culicoides spp. antigens. Attempts at using allergen-specific immunotherapy (AIT) as a treatment for IBH have so far proven unsuccessful. Toll-like receptor (TLR) agonists can promote a shift in the immune response from the allergy-promoting T helper cell 2 (Th2) response towards a Th1 and/or regulatory response. The aim of this study was to evaluate two immunomodulatory TLR agonists in vitro as potential vaccine adjuvants for a more efficacious AIT in IBH. Peripheral blood mononuclear cells (PBMCs) from healthy and IBH-affected horses were stimulated with the TLR-agonists monophosphoryl lipid A (MPLA) or CpG-rich oligodeoxynucleotides (CpG-ODN) in the presence or absence of Culicoides spp. allergens. Cytokine concentrations of interferon (IFN)-α, IFN-γ, interleukin (IL)-4, IL-10 and IL-17 were quantified in the supernatants of stimulated PBMCs. MPLA induced IL-10 secretion in all horses, regardless of presence and nature of antigens, while suppressing antigen-induced production of IFN-γ, IL-4 and IL-17. CpG-ODN significantly increased IFN-α, IFN-γ and IL-4 production, but had little effect on IL-10 production. In conclusion, MPLA promotes a regulatory immune response and is therefore a promising adjuvant candidate for allergy vaccines in horses. While C-class CpG-ODN is an unsuitable adjuvant for AIT, it induces IFN-γ and IFN-α, and thus may be a useful adjuvant in combination with vaccines for equine infectious or neoplastic diseases.

[Job stress of nursing aides in Swiss nursing homes : Nonlinear canonical analysis]. / Arbeitsbelastung von Pflegehelfenden in Schweizer Alters- und Pflegeheimen : Nichtlineare kanonische Korrelationsanalyse.

BACKGROUND: Due to demographic changes, the demand for care in nursing homes for the elderly and infirmed is growing. At the same time nursing staff shortages are also increasing. Nursing aides are the primary care providers and comprise the largest staff group in Swiss nursing homes. They are exposed to various forms of job stress, which threaten job retention. OBJECTIVE: The aim of this study was to discover which features of the work situation and which personal characteristics of the nursing aides were related to the workload. MATERIAL AND METHODS: Data from nursing aides in Swiss nursing homes were investigated through a secondary analysis of a national quantitative cross-sectional study, using descriptive statistics and a nonlinear canonical correlation analysis. RESULTS: A total of 1054 nursing aides were included in the secondary analysis, 94.6 % of whom were women between the ages of 42 and 61 years. The job stress most frequently mentioned in the descriptive analysis, almost 60 % of the participants referred to it, was staff shortage. The nonlinear canonical correlation analysis revealed that many job strains are caused by social and organizational issues. In particular, a lack of support from supervisors was associated with staff not feeling appreciated. These job strains correlated with a high level of responsibility, the feeling of being unable to work independently and a feeling of being exploited. These strains were predominant in the nursing aides between 32 and 51 years old who had part time jobs but workloads of 80-90 %. CONCLUSION: Middle-aged nursing aides who worked to 80-90 % are particularly at risk to resign from the position prematurely. Measures need to be mainly implemented in the social and organizational areas. It can be assumed that a targeted individual support, recognition and promotion of nursing aides may decrease the level of job strain.

Primary prevention of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives.

OBJECTIVE: Type 1 diabetes can be identified by the presence of beta-cell autoantibodies that often arise in the first few years of life. The purpose of this perspective is to present the case for primary prevention of beta-cell autoimmunity and to provide a study design for its implementation in Europe. METHODS: We examined and summarized recruitment strategies, enrollment rates, and outcomes in published TRIGR, FINDIA and BABYDIET primary prevention trials, and the TEDDY intensive observational study. A proposal for a recruitment and implementation strategy to perform a phase II/III primary prevention randomized controlled trial in infants with genetic risk for developing beta-cell autoimmunity is outlined. RESULTS: Infants with a family history of type 1 diabetes (TRIGR, BABYDIET, TEDDY) and infants younger than age 3 months from the general population (FINDIA, TEDDY) were enrolled into these studies. All studies used HLA genotyping as part of their eligibility criteria. Predicted beta-cell autoimmunity risk in the eligible infants ranged from 3% (FINDIA, TEDDY general population) up to 12% (TRIGR, BABYDIET). Amongst eligible infants, participation was between 38% (TEDDY general population) and 97% (FINDIA). Outcomes, defined as multiple beta-cell autoantibodies, were consistent with predicted risks. We subsequently modeled recruitment into a randomized controlled trial (RCT) that could assess the efficacy of oral insulin treatment as adapted from the Pre-POINT pilot trial. The RCT would recruit infants with and without a first-degree family history of type 1 diabetes and be based on general population genetic risk testing. HLA genotyping and, for the general population, genotyping at additional type 1 diabetes susceptibility SNPs would be used to identify children with around 10% risk of beta-cell autoimmunity. The proposed RCT would have 80% power to detect a 50% reduction in multiple beta-cell autoantibodies by age 4 years at a two-tailed alpha of 0.05, and would randomize around 1160 infants to oral insulin or placebo arms in order to fulfill this. It is estimated that recruitment would require testing of between 400,000 and 500,000 newborns or infants. CONCLUSION: It is timely and feasible to establish a platform for primary prevention trials for type 1 diabetes in Europe. This multi-site European infrastructure would perform RCTs, supply data coordination and biorepository, provide cohorts for mechanistic and observational studies, and increase awareness for autoimmune diabetes.

Untangling the Complexity of Liver Fluke Infection and Cholangiocarcinoma in NE Thailand Through Transdisciplinary Learning.

This study demonstrates how a transdisciplinary learning approach provided new insights for explaining persistent Opisthorchis viverrini infection in northern Thailand, as well as elucidating problems of focusing solely on the parasite as a means of addressing high prevalence of cholangiocarcinoma. Researchers from diverse backgrounds collaborated to design an investigative homestay program for 72 Singaporean and Thai university students in five northeast Thai villages. The students explored how liver fluke infection and potential cholangiocarcinoma development are influenced by local landscape dynamics, aquatic ecology, livelihoods, food culture and health education. Qualitative fieldwork was guided daily by the researchers in a collaborative, co-learning process that led to viewing this health issue as a complex system, influenced by interlinked multidimensional factors. Our transdisciplinary experience has led us to believe that an incomplete understanding of these linkages may reduce the efficacy of interventions. Further, viewing liver fluke infection and cholangiocarcinoma as the same issue is inadvisable. Although O. viverrini infection is an established risk factor for the development of cholangiocarcinoma, multiple factors are known to influence the likelihood of acquiring either. Understanding the importance of the current livelihood transition, landscape modification and the resulting mismatch between local cultures and new socio-ecological settings on cholangiocarcinoma initiation and liver fluke transmission is of critical importance as it may help readjust our view of the respective role of O. viverrini and other socioeconomic risk factors in cholangiocarcinoma etiology and refine intervention strategies. As demonstrated in this study, transdisciplinary approaches have the potential to yield more nuanced perspectives to complex diseases than research that focuses on specific aspects of their epidemiology. They may therefore be valuable when designing effective solutions to context-sensitive diseases such as liver fluke infection and cholangiocarcinoma.

In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History.

Niemann-Pick type C (NPC) disease is a recessive disorder that results in unesterified cholesterol accumulating in the lysosomal and late endosomal system. It is caused by mutations in NPC1 or NPC2 genes and leads to systemic and neurodegenerative symptoms. Few cases of prenatal presentation of NPC have been reported and only two cases in the absence of previous family history, indicating the diagnosis is particularly difficult in such a situation. We report a prenatal diagnosis of NPC in a couple without family history. An ultrasound screening at 22 weeks of gestation (WG) detected fetal ascites and hepatomegaly, which were still present at 25, 27, and 29 WG, and a splenomegaly progressively appeared. No placentomegaly or other signs of hydrops fetalis were observed. The diagnostic of NPC was prenatally confirmed by a filipin test and NPC1 sequencing and multiplex ligation-dependent probe amplification assay which revealed a maternal missense mutation (c.2608T>C; p.Ser870Pro) and a paternal deletion of exons 5 to 25. This additional prenatal case of NPC suggests that even in the absence of family history, fetal ascites associated with splenomegaly but no hydrops should nonetheless arouse suspicion concerning this disease as a possible diagnosis.