Probabilistic tsunami forecasting for early warning.

Tsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types.

Burden of compensated and decompensated cirrhosis: real world data from an Italian population-based cohort study.

OBJECTIVE: To quantify the annual healthcare resource utilization, costs and mortality rate for a large cohort of Italian patients with compensated (CC) and decompensated cirrhosis (DC). PATIENTS AND METHODS: A population-based cohort study was conducted through the data-linkage of mortality for all-cause, hospitalizations and outpatient drugs and service databases of the Campania Region. All adults hospitalized with cirrhosis diagnosis (2007-2015) were grouped in CC and DC (prevalent patients) on January 1, 2016 and followed for 1-year. Incident patients with DC (2015) were also retrieved and followed from discharge date up to 1-year. Negative binomial regression was used to estimate Incidence Rate Ratios (IRRs) for predictors of all-cause hospitalizations. Costs were evaluated from the Italian National Health Service perspective and expressed in euro patient/year. RESULTS: A total of 21,433 prevalent cirrhotic patients (57.1% CC and 42.9% DC) and 1,371 incident patients with DC were identified. During a 1-year, 21.5% of prevalent patients with CC were admitted for acute events, 26.8% of those with DC and 55.4% of incident patients with DC. Ascites (IRR=1.71;95% CI: 1.37-2.14) and hepatic encephalopathy (IRR=1.35; 95% CI: 1.04-1.77) at index admission were strong predictors of hospitalizations in incident DC patients. The 1-year mortality rate was respectively 5.8% and 10.1% for prevalent patients with CC and DC and 35.6% for incident patients with DC. Direct costs amounted to 3,194€ patient/year for the prevalent CC group and 4,001€ patient/year for the DC group and 13,806 € patient/year for incident individuals with DC. CONCLUSIONS: The burden of cirrhosis dramatically differs between CC and DC patients, especially after the first decompensation episode. Ascites and hepatic encephalopathy at index admission were strong predictors of hospitalizations in incident DC patients.

Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis.

BACKGROUND AND PURPOSE: The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. METHODS: In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. RESULTS: There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. CONCLUSIONS: Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.

The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation.

Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. SUMMARY: Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.

Implementing strategies for data collection in chronic rhinosinusitis.

SUMMARY: Chronic rhinosinusitis (CRS) is a debated topic in the international rhinologic literature because of its high prevalence, heterogeneity of clinical manifestations and unpredictability of disease course. Recently, the focus in CRS research has moved to identify biological subtypes that might explain its aetiology and clinical variability. However, these analyses are still expensive and limited to scientific purposes, so that they cannot be used on a large scale in daily practice. For this reason, we wondered if it was possible to define a risk stratification for CRS patients based only on first level investigations. The heterogeneity of the disease has given us a large amount of data compelling to find an additional storage system. Herein, we present the results of our work, the RhinoBank, as we believe that it is an easy-to-use tool for those professionals dealing with CRS and an effective system to exploit in clinical research.

Hemostasis biomarkers in multiple sclerosis.

BACKGROUND AND PURPOSE: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. METHODS: In all, 138 MS patients [85 with relapsing-remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. RESULTS: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. CONCLUSIONS: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.

The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Brain abscesses in children: an Italian multicentre study.

Brain abscess is uncommon in paediatric population, but of clinical importance because of significant long-term morbidity and mortality. In this multicentre study, promoted by the Italian Society for Paediatric Infectious Diseases, we retrospectively collected patients aged 0-18 years, with a diagnosis of 'brain abscess'. Seventy-nine children were included; the median age was 8·75 years. As predisposing factor, 44 children had preceding infections. The Gram-positive cocci were mostly isolated (27 cases). Sixty (76%) children underwent a surgical intervention. Intravenous antibiotic therapy was administered in all patients, then switched to oral treatment. Clinical sequelae were recorded in 31 (39·2%) children. Twenty-one of them had a single sequela, of which, the most represented, was epilepsy in nine of them. This study focus the attention on the need to have standardized national guidelines or adequate recommendations on type and duration of antibiotic treatment.

Differential functional readthrough over homozygous nonsense mutations contributes to the bleeding phenotype in coagulation factor VII deficiency.

Essentials Potentially null homozygous Factor(F)7 nonsense mutations are associated to variable bleeding symptoms. Readthrough of p.Ser112X (life-threatening) and p.Cys132X (moderate) stop codons was investigated. Readthrough-mediated insertion of wild-type or tolerated residues produce functional proteins. Functional readthrough over homozygous F7 nonsense mutations contributes to the bleeding phenotype. SUMMARY: Background Whereas the rare homozygous nonsense mutations causing factor (F)VII deficiency may predict null conditions that are almost completely incompatible with life, they are associated with appreciable differences in hemorrhagic symptoms. The misrecognition of premature stop codons (readthrough) may account for variable levels of functional full-length proteins. Objectives To experimentally evaluate the basal and drug-induced levels of FVII resulting from the homozygous p.Cys132X and p.Ser112X nonsense mutations that are associated with moderate (132X) or life-threatening (112X) symptoms, and that are predicted to undergo readthrough with (132X) or without (112X) production of wild-type FVII. Methods We transiently expressed recombinant FVII (rFVII) nonsense and missense variants in human embryonic kidney 293 cells, and evaluated secreted FVII protein and functional levels by ELISA, activated FX generation, and coagulation assays. Results The levels of functional FVII produced by p.Cys132X and p.Ser112X mutants (rFVII-132X, 1.1% ± 0.2% of wild-type rFVII; rFVII-112X, 0.5% ± 0.1% of wild-type rFVII) were compatible with the occurrence of spontaneous readthrough, which was magnified by the addition of G418 - up to 12% of the wild-type value for the rFVII-132X nonsense variant. The predicted missense variants arising from readthrough abolished (rFVII-132Trp/Arg) or reduced (rFVII-112Trp/Cys/Arg, 22-45% of wild-type levels) secretion and function. These data suggest that the appreciable rescue of p.Cys132X function was driven by reinsertion of the wild-type residue, whereas the minimal p.Ser112X function was explained by missense changes permitting FVII secretion and function. Conclusions The extent of functional readthrough might explain differences in the bleeding phenotype of patients homozygous for F7 nonsense mutations, and prevent null conditions even for the most readthrough-unfavorable mutations.

Recommendations for authors of manuscripts reporting inhibitor cases developed in previously treated patients with hemophilia: communication from the SSC of the ISTH.

Aim The scope of this recommendation is to provide guidance for reporting of inhibitor cases in previously treated patients (PTPs) with hemophilia A. This guidance is intended to improve transparency and completeness of reporting of observed events; it does not cover planning, executing or analyzing original studies aimed at the assessment of inhibitor rates. Recommendation We recommend that for each case of inhibitor development reported in a published paper, a paragraph or a table is included in the main publication reporting as a minimum the underlined data fields in Table . We recommend transparent reporting when any of the suggested information is not available. We recommend that particular care is used in reporting the timeline of events by clearly identifying a reference time-point. We suggest that journals in the field adopt this guidance as instructions for the authors and as a guide for reviewers. Conclusion Development of inhibitors in PTPs is a very rare event. Standardized reporting of inhibitor characteristics will contribute to generating a body of evidence otherwise not available. Case by case reporting of the recommended data elements may shed light on the natural history and risk factors of inhibitor development in PTPs and be useful for tailoring care in similar future cases.

Septal flip flap for anterior skull base reconstruction after endoscopic resection of sinonasal cancers: preliminary outcomes.

Over the past decade surgery for sinonasal malignancies encroaching into the anterior skull base (ASB) has evolved from open craniofacial resection to the use of minimally invasive transnasal endoscopic approaches. Using these techniques, ASB reconstruction is most often performed in a multilayer fashion with autologous free grafts (fascia lata or iliotibial tract) which leads to the production of abundant nasal crusting in the postoperative months and discomfort for patients. In carefully selected cases, we propose harvesting a flap from the contralateral nasal septum based on the septal branches of the anterior and posterior ethmoidal arteries (Septal Flip Flap, SFF), which can be rotated to resurface the ASB defect. The exclusion criteria for using the SFF were as follows: cases where the tumour extended to both ethmoid complexes; cases where there was nasal septum or planum spheno-ethmoidalis involvement by the disease; cases of sinonasal malignant tumour with multifocal histology. In our tertiary care referral centre, skull base reconstruction using the SFF was performed in four patients; one was affected by ethmoidal teratocarcinosarcoma, one by persistence of sinonasal undifferentiated carcinoma after radio-chemotherapy, another by olfactory cleft esthesioneuroblastoma and the fourth by ethmoidal squamous cell carcinoma. Successful skull base reconstruction was obtained in all four cases without any intra- or post-operative complications. Post-operatively, nasal crusting was significantly reduced with faster healing of the surgical cavity. No recurrences of disease have been observed after a mean follow-up of 15 months. The SFF can be considered as a safe and effective technique for ASB reconstruction with high success rates similar to those obtained with other pedicled flaps. This flap also ensured a faster healing process with reduction of nasal crusting and improvement in the quality of life of patients in the postoperative period. This technique appears to be a safe and effective option for ASB reconstruction after endonasal resection of sinonasal malignancies in selected cases. Larger case series with a longer follow-up are needed to validate the preliminary results obtained with such an innovative and promising surgical technique.

Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study.

BACKGROUND: Plasma concentration of activated factor VII (FVIIa)-antithrombin (AT) complex has been proposed as an indicator of intravascular exposure of tissue factor. OBJECTIVES: The aims of this observational study were to evaluate (i) FVIIa-AT plasma concentration in subjects with or without coronary artery disease (CAD) and (ii) its association with mortality in a prospective cohort of patients with CAD. METHODS: FVIIa-AT levels were measured by elisa in 686 subjects with (n = 546) or without (n = 140) angiographically proven CAD. Subjects with acute coronary syndromes and those taking anticoagulant drugs at the time of enrollment were excluded. CAD patients were followed for total and cardiovascular mortality. RESULTS: There was no difference in FVIIa-AT levels between CAD (84.8 with 95% confidence interval [CI] 80.6-88.2 pmol L(-1) ) and CAD-free subjects (83.9 with 95% CI 76.7-92.8 pmol L(-1) ). Within the CAD population, during a 64-month median follow-up, patients with FVIIa-AT levels higher than the median value at baseline (≥ 79 pmol L(-1) ) had a two-fold greater risk of both total and cardiovascular mortality. Results were confirmed after adjustment for sex, age, the other predictors of mortality (hazard ratio for total mortality: 2.05 with 95% CI 1.22-3.45, hazard ratio for cardiovascular mortality 1.94 with 95% CI 1.01-3.73, with a slight improvement of C-statistic over traditional risk factors), FVIIa levels, drug therapy at discharge, and even patients using all the usual medications for CAD treatment. High FVIIa-AT levels also correlated with increased thrombin generation. CONCLUSIONS: This preliminary study suggests that plasma concentration of FVIIa-AT is a thrombophilic marker of total and cardiovascular mortality risk in patients with clinically stable CAD.

Recommendations for the diagnosis of pediatric tuberculosis.

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease.

Evidence for localized moment picture in Mn-based Heusler compounds.

X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD) were used to probe the electronic structure and magnetic moment of Mn in Heusler compounds with different crystallographic structure. The results were compared with theoretical calculations of the magnetic and electronic properties, and it was found that in full and half Heusler alloys, Mn is metallic on both sublattices. The magnetic moment is large and localized when octahedrally coordinated by the main group element, consistent with previous theoretical work, and reduced when the main group coordination is tetrahedral. The magnetic and electronic properties of Mn in full and half Heusler compounds are strongly dependent on the structure and sublattice, a fact that can be exploited to design new materials.

The carboxyl-terminal region is NOT essential for secreted and functional levels of coagulation factor X.

BACKGROUND: The homologous coagulation factor X (FX), VII (FVII), IX (FIX) and protein C (PC) display striking differences in the carboxyl-terminus, with that of FX being the most extended. This region is essential for FVII, FIX and PC secretion. OBJECTIVES: To provide experimental evidence for the role of the FX carboxyl-terminus. METHODS: Recombinant FX (rFX) variants were expressed in multiple eukaryotic cell systems. Protein and activity levels were evaluated by ELISA, coagulant and amidolytic assays. RESULTS AND DISCUSSION: Expression of a panel of progressively truncated rFX variants in HEK293 cells revealed that the deletion of up to 21 residues in the carboxyl-terminus did not significantly affect secreted protein levels, as confirmed in HepG2 and BHK21 cells. In contrast, chimeric rFX-FVII variants with swapped terminal residues showed severely reduced levels. The truncated rFX variants revealed normal amidolytic activity, suggesting an intact active site. Intriguingly, these variants, which included that resembling the activated FXß form once cleaved, also displayed remarkable or normal pro-coagulant capacity in PT- and aPTT-based assays. This supports the hypothesis that subjects with nonsense mutations in the FX carboxyl-terminus, so far never identified, would be asymptomatic. CONCLUSIONS: For the first time we demonstrate that the FX carboxyl-terminal region downstream of residue K467 is not essential for secretion and provides a modest contribution to pro-coagulant properties. These findings, which might suggest an involvement of the carboxyl-terminal region in the divergence of the homologous FX, FVII, FIX and PC, help to interpret the mutational pattern of FX deficiency.

Asymmetric processing of mutant factor X Arg386Cys reveals differences between intrinsic and extrinsic pathway activation.

Alterations in coagulation factor X (FX) activation, mediated by the extrinsic VIIa/tissue factor (FVIIa/TF) or the intrinsic factor IXa/factor VIIIa (FIXa/FVIIIa) complexes, can result in hemorrhagic/prothrombotic tendencies. However, the molecular determinants involved in substrate recognition by these enzymes are poorly defined. Here, we investigated the role of arginine 386 (chymotrypsin numbering c202), a surface-exposed residue on the FX catalytic domain. The naturally occurring FX386Cys mutant and FX386Ala variant were characterized. Despite the unpaired cysteine, recombinant (r)FX386Cys was efficiently secreted (88.6±21.3% of rFXwt) and possessed normal clearance in mice. rFX386Cys was also normally activated by FVIIa/TF and displayed intact amidolytic activity. In contrast, rFX386Cys activation by the FIXa/FVIIIa complex was 4.5-fold reduced, which was driven by a decrease in the kcat (1.6∗10(-4) s(-1) vs 5.8∗10(-4) s(-1), rFXwt). The virtually unaltered Km (70.6 nM vs 55.6nM, rFXwt) suggested no major alterations in the FX substrate exosite. Functional assays in plasma supplemented with rFX386Cys indicated a remarkable reduction in the thrombin generation rate and thus in coagulation efficiency. Consistently, the rFX386Ala variant displayed similar biochemical features suggesting that global changes at position 386 impact the intrinsic pathway activation. These data indicate that the FXArg386 is involved in FIXa/FVIIIa-mediated FX activation and help in elucidating the bleeding tendency associated with the FX386Cys in a rare FX deficiency case. Taking advantage of the unpaired cysteine, the rFX386Cys mutant may be efficiently targeted by thiol-specific ligands and represent a valuable tool to study FX structure-function relationships both in vitro and in vivo.

An engineered U1 small nuclear RNA rescues splicing defective coagulation F7 gene expression in mice.

BACKGROUND: The ability of the spliceosomal small nuclear RNA U1 (U1snRNA) to rescue pre-mRNA splicing impaired by mutations makes it an attractive therapeutic molecule. Coagulation factor deficiencies due to splicing mutations are relatively frequent and could therefore benefit from this strategy. However, the effects of U1snRNAs in vivo remain unknown. OBJECTIVES: To assess the rescue of the F7 c.859+5G>A splicing mutation (FVII+5A), causing severe human factor VII (hFVII) deficiency, by the modified U1snRNA+5a (U1+5a) in a murine model. METHODS: Mice expressing the human F7 c.859+5G>A mutant were generated following liver-directed expression by plasmid or recombinant adeno-associated viral (AAV) vector administration. The rescue of the splice-site defective pre-mRNA by U1+5a was monitored in liver and plasma through hFVII-specific assays. RESULTS: Injection of plasmids encoding the U1+5a rescued plasma hFVII levels, which increased from undetectable to ~8.5% of those obtained with the wild-type hFVII plasmid control. To assess long-term effects, mice were injected with low and high doses of two AAV vectors encoding the FVII+5A splice site mutant as template to be corrected by U1+5a. This strategy resulted in hFVII plasma levels of 3.9 ± 0.8 or 23.3 ± 5.1 ng mL⁻¹ in a dose-dependent manner, corresponding in patients to circulating FVII levels of ~1-4.5% of normal. Moreover, in both experimental models, we also detected correctly spliced hFVII transcripts and hFVII-positive cells in liver cells. CONCLUSIONS: Here we provide the first in vivo proof of-principle of the rescue of the expression of a splicing-defective F7 mutant by U1snRNAs, thus highlighting their therapeutic potential in coagulation disorders.