• Emotional, physical, and sexual abuse in patients visiting gynaecology clinics: a Nordic cross-sectional study

      Wijma, B; Schei, B; Swahnberg, K; Hilden, M; Offerdal, K; Pikarinen, U; Sidenius, K; Steingrimsdottir, T; Stoum, H; Halmesmäki, E (Lancet Publishing Group, 2003-06-21)
      BACKGROUND: Abuse against women causes much suffering for individuals and is a major concern for society. We aimed to estimate the prevalence of three types of abuse in patients visiting gynaecology clinics in five Nordic countries, and to assess the frequency with which gynaecologists identify abuse victims. METHODS: We did a cross-sectional, multicentre study of women attending five departments of gynaecology in Denmark, Finland, Iceland, Norway, and Sweden. We recruited 4729 patients; 3641 (77%) responded and were included in the study. Participants completed a postal questionnaire (norvold abuse questionnaire) confidentially. Primary outcome measures were prevalences of emotional, physical, and sexual abuse, and whether abused patients had told their gynaecologist about these experiences. We assessed differences between countries with Pearson's chi(2) test. FINDINGS: The ranges across the five countries of lifetime prevalence were 38-66% for physical abuse, 19-37% for emotional abuse, and 17-33% for sexual abuse. Not all abused women reported current ill-effects from the abusive experience. Most women (92-98%) had not talked to their gynaecologist about their experiences of abuse at their latest clinic visit. INTERPRETATION: Despite prevalences of emotional, physical, and sexual abuse being high in patients visiting gynaecology clinics in the Nordic countries, most victims of abuse are not identified by their gynaecologists. This lack of discussion might increase the risk of abused patients not being treated according to their needs. Gynaecologists should always consider asking their patients about abuse.
    • Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.

      Zeggini, Eleftheria; Panoutsopoulou, Kalliope; Southam, Lorraine; Rayner, Nigel W; Day-Williams, Aaron G; Lopes, Margarida C; Boraska, Vesna; Esko, Tonu; Evangelou, Evangelos; Hoffman, Albert; et al. (Elsevier Science, 2012-09-01)
      Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.
    • Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

      Smoller, JW; Craddock, N; Kendler, K; Lee, PH; Neale, BM; Nurnberger, JI; Ripke, Stephan; Santangelo, S; Sullivan, PF; Psychiatric Genomics Consortium; et al. (Elsevier Science, 2013-04-20)
      Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.
    • Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.

      Nalls, M A; Plagnol, V; Sveinbjornsdottir, S; International Parkinson Disease Genomics Consortium (Lancet Publishing Group, 2011-02)
      BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk. INTERPRETATION: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies.
    • Knee replacement.

      Carr, Andrew J; Robertsson, Otto; Graves, Stephen; Price, Andrew J; Arden, Nigel K; Judge, Andrew; Beard, David J; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (2012-04-07)
      Knee-replacement surgery is frequently done and highly successful. It relieves pain and improves knee function in people with advanced arthritis of the joint. The most common indication for the procedure is osteoarthritis. We review the epidemiology of and risk factors for knee replacement. Because replacement is increasingly considered for patients younger than 55 years, improved decision making about whether a patient should undergo the procedure is needed. We discuss assessment of surgery outcomes based on data for revision surgery from national joint-replacement registries and on patient-reported outcome measures. Widespread surveillance of existing implants is urgently needed alongside the carefully monitored introduction of new implant designs. Developments for the future are improved delivery of care and training for surgeons and clinical teams. In an increasingly ageing society, the demand for knee-replacement surgery will probably rise further, and we predict future trends. We also emphasise the need for new strategies to treat early-stage osteoarthritis, which will ultimately reduce the demand for joint-replacement surgery.
    • Linkage to BRCA2 region in hereditary male breast cancer.

      Thorlacius, S; Tryggvadottir, L; Olafsdottir, G H; Jonasson, J G; Ogmundsdottir, H M; Tulinius, H; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Reykjavik, Iceland. (Lancet Publishing Group, 1995-08-26)
      Breast cancer is rare in men, and family history of the disease is a risk factor. The recently discovered BRCA2 gene on chromosome 13q is thought to account for some families with increased risk of breast cancer, including male breast cancer. We describe a family with multiple cases of male breast cancer but, interestingly, no increase in female breast cancer. Linkage to the BRCA2 region is demonstrated and all the affected men share the same haplotype for the BCRA2 markers and loss of the other alleles in their tumours.
    • Mortality after surgery in Europe: a 7 day cohort study.

      Pearse, Rupert M; Moreno, Rui P; Bauer, Peter; Pelosi, Paolo; Metnitz, Philipp; Spies, Claudia; Vallet, Benoit; Vincent, Jean-Louis; Hoeft, Andreas; Rhodes, Andrew; et al. (Elsevier Science, 2012-09-22)
      Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe. We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ(2) and Fisher's exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p<0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries. We included 46,539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9-3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0-3·0] for Iceland to 21·5% [16·9-26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19-1·05; p=0·06] for Finland to 6·92 [2·37-20·27; p=0·0004] for Poland). The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.
    • Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S)

      Strandberg, Timo E; Pyörälä, Kalevi; Cook, Thomas J; Wilhelmsen, Lars; Faergeman, Ole; Thorgeirsson, Gudmundur; Pedersen, Terje R; Kjekshus, John (Lancet Publishing Group, 2004-08-28)
      BACKGROUND: The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5-6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial. METHODS: 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5.5-8.0 mmol/L, and serum triglycerides 2.5 mmol/L or lower. The double-blind period lasted for a median of 5.4 years (range for survivors 4.9-6.3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10.4 years (range for survivors 9.9-11.3). Analysis was by intention to treat. FINDINGS: 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10.4-year follow-up (relative risk 0.85 [95% CI 0.74-0.97], p=0.02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0.76 [0.64-0.90], p=0.0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0.81 [0.60-1.08], p=0.14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0.88 [0.73-1.05], p=0.15). Incidence of any specific type of cancer did not rise in the simvastatin group. INTERPRETATION: Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.
    • Mutation in cystatin C gene causes hereditary brain haemorrhage

      Palsdottir, A; Abrahamson, M; Thorsteinsson, L; Arnason, A; Olafsson, I; Grubb, A; Jensson, O; National Hospital, University of Iceland, Reykjavik. (Lancet Publishing Group, 1988-09-10)
      Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder in which a cysteine proteinase inhibitor, cystatin C, is deposited as amyloid fibrils in the cerebral arteries of patients and leads to massive brain haemorrhage and death in young adults. A full length cystatin C cDNA probe revealed a mutation in the codon for leucine at position 68 which abolishes an Alu I restriction site in the cystatin C gene of HCCAA patients. The Alu I marker has been used to show that this mutation is transmitted only in affected members of all eight families investigated, and that the mutated cystatin C gene causes HCCAA.
    • Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

      Voight, Benjamin F; Peloso, Gina M; Orho-Melander, Marju; Frikke-Schmidt, Ruth; Barbalic, Maja; Jensen, Majken K; Hindy, George; Hólm, Hilma; Ding, Eric L; Johnson, Toby; et al. (Elsevier Science, 2012-08-11)
      High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
    • Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

      Sever, Peter S; Dahlöf, Björn; Poulter, Neil R; Wedel, Hans; Beevers, Gareth; Caulfield, Mark; Collins, Rory; Kjeldsen, Sverre E; Kristinsson, Arni; McInnes, Gordon T; et al. (Elsevier, 2003-04-05)
      BACKGROUND: The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. METHODS: Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. FINDINGS: Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. INTERPRETATION: The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.
    • Prevention of diabetic retinopathy

      Einarsdottir, Anna B; Stefansson, Einar; University of Iceland and Landspitali, National Hospital, 101 Reykjavík, Iceland. einarste@landspitali.is (Lancet Publishing Group, 2009-04-18)
      No Abstract
    • Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

      Williams, Nigel M; Zaharieva, Irina; Martin, Andrew; Langley, Kate; Mantripragada, Kiran; Fossdal, Ragnheidur; Stefansson, Hreinn; Stefansson, Kari; Magnusson, Pall; Gudmundsson, Olafur O; et al. (Lancet Publishing Group, 2010-10-23)
      BACKGROUND: Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. METHODS: We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls. FINDINGS: Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10(-5)). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10(-6)), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). INTERPRETATION: Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. FUNDING: Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.
    • Smoking cessation, lung function, and weight gain: a follow-up study

      Chinn, Susan; Jarvis, Deborah; Melotti, Roberto; Luczynska, Christina; Ackermann-Liebrich, Ursula; Antó, Josep M; Cerveri, Isa; de Marco, Roberto; Gislason, Thorarinn; Heinrich, Joachim; et al. (2005-05-01)
      BACKGROUND: Only one population-based study in one country has reported effects of smoking cessation and weight change on lung function, and none has reported the net effect. We estimated the net benefit of smoking cessation, and the independent effects of smoking and weight change on change in ventilatory lung function in the international European Community Respiratory Health Survey. METHODS: 6654 participants in 27 centres had lung function measured in 1991-93, when aged 20-44 years, and in 1998-2002. Smoking information was obtained from detailed questionnaires. Changes in lung function were analysed by change in smoking and weight, adjusted for age and height, in men and women separately and together with interaction terms. FINDINGS: Compared with those who had never smoked, decline in FEV1 was lower in male sustained quitters (mean difference 5.4 mL per year, 95% CI 1.7 to 9.1) and those who quit between surveys (2.5 mL, -1.9 to 7.0), and greater in smokers (-4.8 mL, -7.9 to -1.6). In women, estimates were 1.3 mL per year (-1.5 to 4.1), 2.8 mL (-0.8 to 6.3) and -5.1 mL (-7.5 to -2.8), respectively. These sex differences were not significant. FEV1 changed by -11.5 mL (-13.3 to -9.6) per kg weight gained in men, and by -3.7 mL per kg (-5.0 to -2.5) in women, which diminished the benefit of quitting by 38% in men, and by 17% in women. INTERPRETATION: Smoking cessation is beneficial for lung function, but maximum benefit needs control of weight gain, especially in men.
    • Supplement and stimulation for stunted children

      Thorsdottir, Inga (Elsevier, 2005-11-19)
    • Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.

      Jungebluth, Philipp; Alici, Evren; Baiguera, Silvia; Le Blanc, Katarina; Blomberg, Pontus; Bozóky, Béla; Crowley, Claire; Einarsson, Oskar; Grinnemo, Karl-Henrik; Gudbjartsson, Tomas; et al. (Lancet Publishing Group, 2011-12-10)
      BACKGROUND: Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. METHODS: A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 μg/kg) and epoetin beta (40,000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. FINDINGS: We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. INTERPRETATION: Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome