| 1. |
- 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. |
- Parry, Marina, et al.
(författare)
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Genetics and Prognostication in Splenic Marginal Zone Lymphoma : Revelations from Deep Sequencing
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 21:18, s. 4174-4183
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03). Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Aizawa, Kunihiko, et al.
(författare)
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Reservoir Pressure Integral Is Independently Associated With the Reduction in Renal Function in Older Adults
- 2022
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Ingår i: Hypertension. - 0194-911X. ; 79:10, s. 2364-2372
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arterial hemodynamic parameters derived from reservoir-excess pressure analysis exhibit prognostic utility. Reservoir-excess pressure analysis may provide useful information about an influence of altered hemodynamics on target organ such as the kidneys. We determined whether the parameters derived from the reservoir-excess pressure analysis were associated with the reduction in estimated glomerular filtration rate in 542 older adults (69.4±7.9 years, 194 females) at baseline and after 3 years. Methods: Reservoir-excess pressure parameters, including reservoir pressure integral, excess pressure integral, systolic, and diastolic rate constants, were obtained by radial artery tonometry. Results: After 3 years, and in a group of 94 individuals (72.4±7.6 years, 26 females), there was an estimated glomerular filtration rate reduction of >5% per year (median reduction of 20.5% over 3 years). A multivariable logistic regression analysis revealed that higher baseline reservoir pressure integral was independently associated with a smaller reduction in estimated glomerular filtration rate after accounting for conventional cardiovascular risk factors and study centers (odds ratio: 0.660 [95% CIs, 0.494-0.883]; P=0.005). The association remained unchanged after further adjustments for potential confounders and baseline renal function (odds ratio: 0.528 [95% CIs, 0.351-0.794]; P=0.002). No other reservoir-excess pressure parameters exhibited associations with the reduction in renal function. Conclusions: This study demonstrates that baseline reservoir pressure integral was associated with the decline in renal function in older adults at 3-year follow-up, independently of conventional cardiovascular risk factors. This suggests that reservoir pressure integral may play a role in the functional decline of the kidneys.
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| 7. |
- Baliakas, Panagiotis, 1977-, et al.
(författare)
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Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
- 2019
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 104:2, s. 360-369
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.
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| 8. |
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| 9. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 10. |
- Johansson, Lennarth, et al.
(författare)
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Informal Caregiving for Elders in Sweden : An Analysis of Current Policy Developments
- 2011
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Ingår i: Journal of Aging & Social Policy. - : Informa UK Limited. - 0895-9420 .- 1545-0821. ; 23:4, s. 335-53
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Tidskriftsartikel (refereegranskat)abstract
- In Sweden, care of elderly people is a public responsibility. There are comprehensive public policies and programs providing health care, social services, pensions, and other forms of social insurance. Even so, families are still the major providers of care for older people. In the 1990s, the family was “rediscovered” regarding eldercare in Sweden. New policies and legislative changes were promoted to support family caregivers. The development of services and support for caregivers at the municipal level has been stimulated through the use of national grants. As a result, family caregivers have received more recognition and are now more visible. However, the “Swedish model” of publicly financed services and universal care has difficulty addressing caregivers. Reductions in institutional care and cutbacks in public services have had negative repercussions for caregivers and may explain why research shows that family caregiving is expanding. At the same time, a growing “caregivers movement” is lobbying local and national governments to provide more easily accessible, flexible, and tailored support. In 2009, the Swedish Parliament passed a new law that states: “Municipalities are obliged to offer support to persons caring for people with chronic illnesses, elderly people, or people with functional disabilities.” The question is whether the new legislation represents a paradigm shift from a welfare system focused on the individual to a more family-oriented system. If so, what are the driving forces, motives, and consequences of this development for the different stakeholders? This will be the starting point for a policy analysis of current developments in family caregiving of elderly people in Sweden.
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| 11. |
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| 12. |
- Leeksma, Alexander C., et al.
(författare)
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Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity : A multi-center study
- 2020
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Ingår i: Haematologica. - 0390-6078. ; 105:5
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Tidskriftsartikel (refereegranskat)abstract
- Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as 5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.
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| 13. |
- Lindblad-Toh, Kerstin, et al.
(författare)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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| 14. |
- Long, Joanna, et al.
(författare)
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Frugal filtering optical lenses for point-of-care diagnostics
- 2020
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Ingår i: Biomedical Optics Express. - : OPTICAL SOC AMER. - 2156-7085. ; 11:4, s. 1864-1875
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Tidskriftsartikel (refereegranskat)abstract
- Infectious diseases are the leading cause of morbidity and mortality in low and middle income countries (LMICs). Rapid diagnosis of infections in LMICs presents many challenges, especially in rural areas where access to health care, including diagnostics, is poor. Microscopy is one of the most commonly used platforms to diagnose bacterial infections on clinical samples. Fluorescence microscopy has high sensitivity and specificity but to date is mostly performed within a laboratory setting due to the high-cost, low portability and highly specialist nature of equipment. Point-of-care diagnostics could offer a solution to the challenge of infection diagnosis in LMICs. In this paper we present frugal, easy to manufacture, doped polydimethylsiloxane filtering optical lenses that can be integrated into smartphone microscopes for immediate detection of fluorescently labelled bacteria. This provides a breakthrough technology platform for point-of-care diagnostics. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License.
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| 15. |
- Mills, Bethany, et al.
(författare)
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Molecular detection of Gram-positive bacteria in the human lung through an optical fiber-based endoscope
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Nature. - 1619-7070 .- 1619-7089. ; 48:3, s. 800-807
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber-based delivery/imaging endoscopic device. Methods We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber-based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. Results The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging ofS. aureuswithin the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. Conclusion This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.
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| 16. |
- Parker, Helen, et al.
(författare)
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Core crosstalk in ordered imaging fibre bundles
- 2020
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Ingår i: Optics Letters. - : Optica Publishing Group. - 0146-9592 .- 1539-4794. ; 45:23, s. 6490-6493
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Tidskriftsartikel (refereegranskat)abstract
- Coherent fiber bundles are used widely for imaging. Commonly, disordered arrays of randomly sized fiber cores avoid proximity between like-cores, which would otherwise result in increased core crosstalk and a negative impact on imaging. Recently, stack-and-draw fiber manufacture techniques have been used to produce fibers with a controlled core layout to minimize core crosstalk. However, one must take manufacturing considerations into account during stack-and-draw fiber design in order to avoid impractical or unachievable fabrication. This comes with a set of practical compromises, such as using only a small number of different core sizes. Through characterization of core crosstalk patterns, this Letter aims to aid the understanding of crosstalk limitations imposed by such compromises in the core layout made for ease of fabrication.
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| 17. |
- Parker, Helen E., et al.
(författare)
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A Lab-in-a-Fiber optofluidic device using droplet microfluidics and laser-induced fluorescence for virus detection
- 2022
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Microfluidics has emerged rapidly over the past 20 years and has been investigated for a variety of applications from life sciences to environmental monitoring. Although continuous-flow microfluidics is ubiquitous, segmented-flow or droplet microfluidics offers several attractive features. Droplets can be independently manipulated and analyzed with very high throughput. Typically, microfluidics is carried out within planar networks of microchannels, namely, microfluidic chips. We propose that fibers offer an interesting alternative format with key advantages for enhanced optical coupling. Herein, we demonstrate the generation of monodisperse droplets within a uniaxial optofluidic Lab-in-a-Fiber scheme. We combine droplet microfluidics with laser-induced fluorescence (LIF) detection achieved through the development of an optical side-coupling fiber, which we term a periscope fiber. This arrangement provides stable and compact alignment. Laser-induced fluorescence offers high sensitivity and low detection limits with a rapid response time making it an attractive detection method for in situ real-time measurements. We use the well-established fluorophore, fluorescein, to characterize the Lab-in-a-Fiber device and determine the generation of ∼ 0.9 nL droplets. We present characterization data of a range of fluorescein concentrations, establishing a limit of detection (LOD) of 10 nM fluorescein. Finally, we show that the device operates within a realistic and relevant fluorescence regime by detecting reverse-transcription loop-mediated isothermal amplification (RT-LAMP) products in the context of COVID-19 diagnostics. The device represents a step towards the development of a point-of-care droplet digital RT-LAMP platform. © 2022, The Author(s).
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| 18. |
- Parker, Helen E., et al.
(författare)
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Digital detection and quantification of SARS-CoV-2 in a droplet microfluidic all-fiber device
- 2021
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Ingår i: Proceedings MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences. - : Chemical and Biological Microsystems Society. ; , s. 1047-1048
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Konferensbidrag (refereegranskat)abstract
- Silica fibers and capillaries offer opportunities for compact integration of optics with microfluidics while adding advantages such as; flexibility within a high aspect ratio format, uniaxial arrangements, and measurement-at-a-distance. Here, we describe droplet microfluidics-based nucleic acid detection of SARS-CoV-2 in a lab-in-a-fiber platform. The fiber component integrates three modules with key functions: droplet generation, incubation, and fluorescence detection. Within the scope of this work, we developed the component specifically to target the quantification of SARS-CoV-2 viral RNA through reverse-transcription loop-mediated isothermal amplification (RT-LAMP). The all-fiber component could successfully generate uniform droplets and differentiate pre-amplified positive LAMP reaction from negative sample.
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| 19. |
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| 20. |
- Parker, Helen E., et al.
(författare)
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Viral detection and quantification in a digital droplet microfluidic lab-in-a-fiber device
- 2021
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 9781510643802
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Konferensbidrag (refereegranskat)abstract
- In this work, we present the design and fabrication of a fiber device that performs digital droplet microfluidics for molecular diagnostics. A variety of fibers and capillaries were used to build three connected modules dedicated to droplet generation, incubation, and fluorescence detection which enables a uniaxial arrangement. This is in contrast to the traditional 2-dimensional lab-on-a-chip architecture. We characterize our fiber device using a fluorescein dilution series. Our observed detection limit is on the order of 10 nM fluorescein. We demonstrate our all-fiber device for the fluorescence readout after loop-mediated isothermal amplification (LAMP) of synthetic SARS-CoV-2. Our results suggest that this fiber device can successfully distinguish between positive and negative samples in molecular diagnostics. We propose that our fiber device offers benefits over microfluidic chip techniques such as easier optical integration, much simpler sample loading, and faster diagnosis with high specificity and sensitivity. Keywords: All-fiber device, microfluidics, optofluidics, loop-mediated isothermal amplification (LAMP), molecular diagnostics, SARS-CoV2.
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| 21. |
- Paulsson, Kajsa, et al.
(författare)
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Methylation of tumour suppressor gene promoters in the presence and absence of transcriptional silencing in high hyperdiploid acute lymphoblastic leukaemia
- 2009
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 144:6, s. 838-847
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Tidskriftsartikel (refereegranskat)abstract
- Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (> 50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 (IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL.
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| 22. |
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| 23. |
- Tordo, Julie, et al.
(författare)
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A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency
- 2018
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 141:7, s. 2014-2031
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.
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