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| 2. |
- Macchi, Chiara, et al.
(författare)
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Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9 - The Role of STAT3
- 2020
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Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 190:11, s. 2226-2236
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Tidskriftsartikel (refereegranskat)abstract
- In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of signal transducer and activator of transcript 3 (STAT3). In HepG2 cells, leptin and resistin upregulated PCSK9 gene and protein expression as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knock-down of STAT3 did not affect the expression of leptin and resistin receptors as well as that of PCSK9. The analysis of human PCSK9 promoter region showed that the two adipokines raise PCSK9 promoter activity via the involvement of sterol regulatory element motif. In healthy male, a positive association between circulating leptin and PCSK9 levels was found only when BMI was < 25 kg/m2. In conclusion, our study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
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| 3. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 4. |
- Sharrack, Basil, et al.
(författare)
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Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
- 2020
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Ingår i: Bone Marrow Transplantation. - : Springer Nature. - 0268-3369 .- 1476-5365. ; 55:2, s. 283-306
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Tidskriftsartikel (refereegranskat)abstract
- These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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| 5. |
- Arnott, Shelley E., et al.
(författare)
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Widespread variation in salt tolerance within freshwater zooplankton species reduces the predictability of community-level salt tolerance
- 2023
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Ingår i: Limnology and Oceanography Letters. - : John Wiley & Sons. - 2378-2242. ; 8:1, s. 8-18
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Tidskriftsartikel (refereegranskat)abstract
- The salinization of freshwaters is a global threat to aquatic biodiversity. We quantified variation in chloride (Cl-) tolerance of 19 freshwater zooplankton species in four countries to answer three questions: (1) How much variation in Cl- tolerance is present among populations? (2) What factors predict intraspecific variation in Cl- tolerance? (3) Must we account for intraspecific variation to accurately predict community Cl- tolerance? We conducted field mesocosm experiments at 16 sites and compiled acute LC(50)s from published laboratory studies. We found high variation in LC(50)s for Cl- tolerance in multiple species, which, in the experiment, was only explained by zooplankton community composition. Variation in species-LC50 was high enough that at 45% of lakes, community response was not predictable based on species tolerances measured at other sites. This suggests that water quality guidelines should be based on multiple populations and communities to account for large intraspecific variation in Cl- tolerance.
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| 6. |
- Batura, Neha, et al.
(författare)
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Collecting and analysing cost data for complex public health trials : reflections on practice
- 2014
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Ingår i: Global Health Action. - : CoAction Publishing. - 1654-9716 .- 1654-9880. ; 7, s. 23257-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Current guidelines for the conduct of cost-effectiveness analysis (CEA) are mainly applicable to facility-based interventions in high-income settings. Differences in the unit of analysis and the high cost of data collection can make these guidelines challenging to follow within public health trials in low- and middle- income settings.OBJECTIVE: This paper reflects on the challenges experienced within our own work and proposes solutions that may be useful to others attempting to collect, analyse, and compare cost data between public health research sites in low- and middle- income countries.DESIGN: We describe the generally accepted methods (norms) for collecting and analysing cost data in a single-site trial from the provider perspective. We then describe our own experience applying these methods within eight comparable cluster randomised, controlled, trials. We describe the strategies used to maximise adherence to the norm, highlight ways in which we deviated from the norm, and reflect on the learning and limitations that resulted.RESULTS: When the expenses incurred by a number of small research sites are used to estimate the cost-effectiveness of delivering an intervention on a national scale, then deciding which expenses constitute 'start-up' costs will be a nontrivial decision that may differ among sites. Similarly, the decision to include or exclude research or monitoring and evaluation costs can have a significant impact on the findings. We separated out research costs and argued that monitoring and evaluation costs should be reported as part of the total trial cost. The human resource constraints that we experienced are also likely to be common to other trials. As we did not have an economist in each site, we collaborated with key personnel at each site who were trained to use a standardised cost collection tool. This approach both accommodated our resource constraints and served as a knowledge sharing and capacity building process within the research teams.CONCLUSIONS: Given the practical reality of conducting randomised, controlled trials of public health interventions in low- and middle- income countries, it is not always possible to adhere to prescribed guidelines for the analysis of cost effectiveness. Compromises are frequently required as researchers seek a pragmatic balance between rigor and feasibility. There is no single solution to this tension but researchers are encouraged to be mindful of the limitations that accompany compromise, whilst being reassured that meaningful analyses can still be conducted with the resulting data.
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| 7. |
- Biswas, Dhruva, et al.
(författare)
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A clonal expression biomarker associates with lung cancer mortality
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25:10, s. 1540-1548
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Tidskriftsartikel (refereegranskat)abstract
- An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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| 8. |
- Chiatti, Carlos, et al.
(författare)
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Migrant care work for elderly households in Italy
- 2013
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Ingår i: Ageing in the Mediterranean. - Bristol : Policy Press. - 9781447301066 ; , s. 235-256
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This paper aims at pointing out the need for a more equitable, internationally driven approach to solve elder care staff shortages, on the background of the implications deriving from the widespread phenomenon of employing migrant care workers in the Italian elder care sector. The paper describes at first how this form of care provision has become so popular in this country to face the long term care needs characterising its ageing population. Main reasons are identified, on the one hand, in the decreasing availability of informal care, due to the increasing female participation in the labor market, a longer working life and a reduction in the support provided by social networks. On the “formal” side, a major role has been played also by the lack of appropriate long term care services, such as residential and public home care, as well as by a chronic shortage of nursing staff and a shorter length of hospital stays. The traditionally “cash-oriented” profile of the Italian welfare system – more based on cash-for-care measures rather than in-kind services – has ended up with perpetuating familistic tendencies stimulating the employment of foreign migrant care workers, often on a live-in, undeclared basis. The paper’s conclusions focus on the analysis of the main opportunities and challenges raised by this phenomenon, trying to catch all involved parties’ perspectives: the older care recipients’ families; the migrant care workers; the receiving and the sending societies. This approach allows to identify core advantages of this solution in the possibility to increase ageing in place opportunities (thus reducing institutionalisation rates) and to provide a more personalised home care at reasonable costs. On the other hand, drawbacks can occur in terms of low quality of care, risk of widespread undeclared labour conditions, possible exploitation of foreign migrants and abuse of older people, as well as “brain and care drain” effects in sending countries. A more neutral, internationally driven governance is therefore suggested in order to minimize these risks and promote equitable solutions to solve care provision shortages in some countries without “plundering the future” of other nations.
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| 9. |
- Fortino, Vittorio, et al.
(författare)
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Machine-learning-driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:52, s. 33474-33485
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Tidskriftsartikel (refereegranskat)abstract
- Contact dermatitis tremendously impacts the quality of life of suffering patients. Currently, diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits; however, distinguishing the clinical phenotype of irritant and allergic contact dermatitis remains challenging. Employing integrative transcriptomic analysis and machine-learning approaches, we aimed to decipher disease-related signature genes to find suitable sets of biomarkers. A total of 89 positive patch-test reaction biopsies against four contact allergens and two irritants were analyzed via microarray. Coexpression network analysis and Random Forest classification were used to discover potential biomarkers and selected biomarker models were validated in an independent patient group. Differential gene-expression analysis identified major gene-expression changes depending on the stimulus. Random Forest classification identified CD47, BATF, FASLG, RGS16, SYNPO, SELE, PTPN7, WARS, PRC1, EXO1, RRM2, PBK, RAD54L, KIFC1, SPC25, PKMYT, HISTH1A, TPX2, DLGAP5, TPX2, CH25H, and IL37 as potential biomarkers to distinguish allergic and irritant contact dermatitis in human skin. Validation experiments and prediction performances on external testing datasets demonstrated potential applicability of the identified biomarker models in the clinic. Capitalizing on this knowledge, novel diagnostic tools can be developed to guide clinical diagnosis of contact allergies.
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| 10. |
- Genet, Nadine, et al.
(författare)
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Home care in Europe : a systematic literature review
- 2011
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Ingår i: BMC Health Services Research. - : BMC. - 1472-6963. ; 11:207
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Forskningsöversikt (refereegranskat)abstract
- Background: Health and social services provided at home are becoming increasingly important. Hence, there is a need for information on home care in Europe. The objective of this literature review was to respond to this need, by systematically describing what has been reported on home care in Europe in the scientific literature over the past decade. Methods: A systematic literature search was performed for papers on home care published in English, using the following data bases: Cinahl, the Cochrane Library, Embase, Medline, PsycINFO, Sociological Abstracts, Social Services Abstracts, and Social Care Online. Studies were only included if they complied with the definition of home care, were published between January 1998 and October 2009, and dealt with at least one of the 31 specified countries. Clinical interventions, instrument developments, local projects and reviews were excluded. The data extracted included: the characteristics of the study and aspects of home care ‘policy & regulation’, 'financing', ‘organisation & service delivery’, and ‘clients & informal carers’. Results: Seventy-four out of 5,133 potentially relevant studies met the inclusion criteria, providing information on 18 countries. Many focused on the characteristics of home care recipients and on the organisation of home care. Geographical inequalities, market forces, quality and integration of services were also among the issues frequently discussed. Conclusions: It can be concluded that home care systems appeared to differ not just between but also within countries. The papers included, however, provided only a limited picture of home care. Many studies only focused on one aspect of the home care system and international comparative studies were rare. Furthermore, little information emerged on home care financing and on home care in general in Eastern Europe. This review clearly shows the need for more scientific publications on home care, especially papers comparing countries. A comprehensive and more complete insight into the state of home care in Europe requires gathering of information using a uniform framework and methodology.
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