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- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Kisa, Phyllis, et al.
(författare)
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Unifying Children's Surgery and Anesthesia Stakeholders Across Institutions and Clinical Disciplines : Challenges and Solutions from Uganda
- 2019
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 43:6, s. 1435-1449
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere is a significant unmet need for children's surgical care in low- and middle-income countries (LMICs). Multidisciplinary collaboration is required to advance the surgical and anesthesia care of children's surgical conditions such as congenital conditions, cancer and injuries. Nonetheless, there are limited examples of this process from LMICs. We describe the development and 3-year outcomes following a 2015 stakeholders' meeting in Uganda to catalyze multidisciplinary and multi-institutional collaboration.MethodsThe stakeholders' meeting was a daylong conference held in Kampala with local, regional and international collaborators in attendance. Multiple clinical specialties including surgical subspecialists, pediatric anesthesia, perioperative nursing, pediatric oncology and neonatology were represented. Key thematic areas including infrastructure, training and workforce retention, service delivery, and research and advocacy were addressed, and short-term objectives were agreed upon. We reported the 3-year outcomes following the meeting by thematic area.ResultsThe Pediatric Surgical Foundation was developed following the meeting to formalize coordination between institutions. Through international collaborations, operating room capacity has increased. A pediatric general surgery fellowship has expanded at Mulago and Mbarara hospitals supplemented by an international fellowship in multiple disciplines. Coordinated outreach camps have continued to assist with training and service delivery in rural regional hospitals.ConclusionCollaborations between disciplines, both within LMICs and with international partners, are required to advance children's surgery. The unification of stakeholders across clinical disciplines and institutional partnerships can facilitate increased children's surgical capacity. Such a process may prove useful in other LMICs with a wide range of children's surgery stakeholders.
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| 4. |
- Clave, Emmanuel, et al.
(författare)
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Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus
- 2018
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:457
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Tidskriftsartikel (refereegranskat)abstract
- The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
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| 5. |
- Duffy, David L., et al.
(författare)
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Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis. © 2018, The Author(s).
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| 6. |
- Linderholm, Anna, et al.
(författare)
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A novel MC1R allele for black coat colour reveals the Polynesian ancestry and hybridization patterns of Hawaiian feral pigs
- 2016
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Ingår i: Royal Society Open Science. - : The Royal Society. - 2054-5703. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- Pigs (Sus scrofa) have played an important cultural role in Hawaii since Polynesians first introduced them in approximately AD 1200. Additional varieties of pigs were introduced following Captain Cook's arrival in Hawaii in 1778 and it has been suggested that the current pig population may descend primarily, or even exclusively, from European pigs. Although populations of feral pigs today are an important source of recreational hunting on all of the major islands, they also negatively impact native plants and animals. As a result, understanding the origins of these feral pig populations has significant ramifications for discussions concerning conservation management, identity and cultural continuity on the islands. Here, we analysed a neutral mitochondrial marker and a functional nuclear coat colour marker in 57 feral Hawaiian pigs. Through the identification of a new mutation in the MC1R gene that results in black coloration, we demonstrate that Hawaiian feral pigs are mostly the descendants of those originally introduced during Polynesian settlement, though there is evidence for some admixture. As such, extant Hawaiian pigs represent a unique historical lineage that is not exclusively descended from feral pigs of European origin.
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| 7. |
- Piasecka, Barbara, et al.
(författare)
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Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges
- 2017
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:3, s. 488-497
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
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| 8. |
- Schunemann, Holger J., et al.
(författare)
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Methods for Development of the European Commission Initiative on Breast Cancer Guidelines Recommendations in the Era of Guideline Transparency
- 2019
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 171:4, s. 273-280
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Tidskriftsartikel (refereegranskat)abstract
- Neither breast cancer prevention and early-detection programs, nor their outcomes, are uniform across Europe. This article describes the rationale, methods, and process for development of the European Commission ( EC) Initiative on Breast Cancer Screening and Diagnosis Guidelines. To be consistent with standards set by the Institute of Medicine and others, the EC followed 6 general principles. First, the EC selected, via an open call, a panel with broad representation of areas of expertise. Second, it ensured that all recommendations were supported by systematic reviews. Third, the EC separately considered important subgroups of women, included patient advocates in the guidelines development group, and focused on good communication to inform women's decisions. Fourth, EC rules on conflicts of interest were followed and the GRADE ( Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests. Fifth, it focused its recommendations on outcomes that matter to women, and certainty of the evidence is rated for each. Sixth, the EC elicited stakeholder feedback to ensure that the recommendations remain up to date and relevant to practice. This article describes the approach and highlights ways of disseminating and adapting the recommendations both within and outside Europe, using innovative information technology tools.
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| 9. |
- Urrutia, Alejandra, et al.
(författare)
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Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 16:10, s. 2777-2791
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Tidskriftsartikel (refereegranskat)abstract
- Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.
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| 10. |
- Zhang, Tongwu, et al.
(författare)
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Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 28:11, s. 1621-1635
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Tidskriftsartikel (refereegranskat)abstract
- Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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