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- Razavi, H., et al.
(författare)
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Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study
- 2017
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 2:5, s. 325-336
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Tidskriftsartikel (refereegranskat)abstract
- Background Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide. In the European Union (EU), treatment and cure of HCV with direct-acting antiviral therapies began in 2014. WHO targets are to achieve a 65% reduction in liver-related deaths, a 90% reduction of new viral hepatitis infections, and 90% of patients with viral hepatitis infections being diagnosed by 2030. This study assessed the prevalence of HCV in the EU and the level of intervention required to achieve WHO targets for HCV elimination. Methods We populated country Markov models for the 28 EU countries through a literature search of PubMed and Embase between Jan 1, 2000, and March 31, 2016, and a Delphi process to gain expert consensus and validate inputs. We aggregated country models to create a regional EU model. We used the EU model to forecast HCV disease progression (considering the effect of immigration) and developed a strategy to acehive WHO targets. We used weighted average sustained viral response rates and fibrosis restrictions to model the effect of current therapeutic guidelines. We used the EU model to forecast HCV disease progression (considering the effect of immigration) under current screening and therapeutic guidelines. Additionally, we back-calculated the total number of patients needing to be screened and treated to achieve WHO targets. Findings We estimated the number of viraemic HCV infections in 2015 to be 3 238 000 (95% uncertainty interval [UI] 2 106 000-3 795 000) of a total population of 509 868 000 in the EU, equating to a prevalence of viraemic HCV of 0.64% (95% UI 0.41-0.74). We estimated that 1 180 000 (95% UI 1 003 000-1 357 000) people were diagnosed with viraemia (36.4%), 150 000 (12 000-180 000) were treated (4.6% of the total infected population or 12.7% of the diagnosed population), 133 000 (106 000-160 000) were cured (4.1%), and 57 900 (43 900-67 300) were newly infected (1.8%) in 2015. Additionally, 30 400 (26 600-42 500) HCV-positive immigrants entered the EU. To achieve WHO targets, unrestricted treatment needs to increase from 150 000 patients in 2015 to 187 000 patients in 2025 and diagnosis needs to increase from 88 800 new cases annually in 2015 to 180 000 in 2025. Interpretation Given its advanced health-care infrastructure, the EU is uniquely poised to eliminate HCV; however, expansion of screening programmes is essential to increase treatment to achieve the WHO targets. A united effort, grounded in sound epidemiological evidence, will also be necessary.
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- Amin Yavari, S., et al.
(författare)
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Layer by layer coating for bio-functionalization of additively manufactured meta-biomaterials
- 2020
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Ingår i: Additive Manufacturing. - : Elsevier BV. - 2214-8604 .- 2214-7810. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing has facilitated fabrication of complex and patient-specific metallic meta-biomaterials that offer an unprecedented collection of mechanical, mass transport, and biological properties as well as a fully interconnected porous structure. However, applying meta-biomaterials for addressing unmet clinical needs in orthopedic surgery requires additional surface functionalities that should be induced through tailor-made coatings. Here, we developed multi-functional layer-by-layer coatings to simultaneously prevent implant-associated infections and stimulate bone tissue regeneration. We applied multiple layers of gelatin- and chitosan-based coatings containing either bone morphogenetic protein (BMP)-2 or vancomycin on the surface of selective laser melted porous structures made from commercial pure Titanium (CP Ti) and designed using a triply periodic minimal surface (i.e., sheet gyroid). The additive manufacturing process resulted in a porous structure and met the the design values comparatively. X-ray photoelectron spectroscopy spectra confirmed the presence and composition of the coating layers. The release profiles showed a continued release of both vancomycin and BMP-2 for 2–3 weeks. Furthermore, the developed meta-biomaterials exhibited a very strong antibacterial behavior with up to 8 orders of magnitude reduction in both planktonic and implant-adherent bacteria and no signs of biofilm formation. The osteogenic differentiation of mesenchymal stem cells was enhanced, as shown by two-fold increase in the alkaline phosphatase activity and up to four-fold increase in the mineralization of all experimental groups containing BMP-2. Eight-week subcutaneous implantation in vivo showed no signs of a foreign body response, while connective tissue ingrowth was promoted by the layer-by-layer coating. These results unequivocally confirm the superior multi-functional performance of the developed biomaterials.
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- Boosman, René J, et al.
(författare)
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Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:8, s. 1576-1584
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Tidskriftsartikel (refereegranskat)abstract
- Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.
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- Verberne, EA, et al.
(författare)
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DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:14
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Tidskriftsartikel (refereegranskat)abstract
- JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
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