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Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.
Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).
Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.
Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.
Trial registry: ClinicalTrials.gov identifier: NCT03426657.
This paper provides an overview of current research on a hybrid and robust parsing architecture for the morphological, syntactic and semantic annotation of German text corpora. The novel contribution of this research lies not in the individual parsing modules, each of which relies on state-of-the-art algorithms and techniques. Rather what is new about the present approach is the combination of these modules into a single architecture. This combination provides a means to significantly optimize the performance of each component, resulting in an increased accuracy of annotation.
Short tandem repeat (STR) Loci sind ideale Marker für gerichtliche und abstammungs genetische DNAUntersuchungen. Sie bestehen aus sich wiederholenden 26 bp langen Einheiten und sind über das gesamte menschliche Genom verteilt. Aufgrund ihrer geringen Allellängen (100600 bp) lassen sich STRs leicht mit Hilfe der Polymerasekettenreaktion (PCR) amplifizieren. In der vorliegenden Arbeit sind fünf STRPolymorphismen der Loci D11S488, D18S51, D19S246, HUMFIBRA (FGA) und HUMVWFA31/A auf ihre Populationsgenetik und Sequenzstruktur hin untersucht worden. Die Daten wurden anhand genomischer DNA von 100 gesunden, unverwandten kaukasischen Blutspendern aus der Region Hessen gewonnen. Über ein 6 %iges denaturierendes Polyacrylamidgel wurden die PCRProdukte aufgetrennt und unter Gebrauch fluoreszenzmarkierter Primer mit einem 373A DNASequenzer analysiert. Der Locus D11S488 ist durch eine zusammengesetzte Repeatregion (compound repeat) von AAAG und GAAG Blöcken gekennzeichnet. Mit einer Variationsmöglichkeit an vier unter schiedlichen Positionen kam es zum Auftreten von Mikroheterogenitäten in Allelen gleicher Länge. 29 verschiedene Allele wurden gefunden, die basierend auf ihrer Gesamtrepeatanzahl (YAAG) 2641 (242 bp302 bp), in 15 Allelklassen gruppiert wurden. Bei D19S246 (TGTA und TCTA) liegt ebenfalls ein compound repeat vor. Mikroheterogenitäten führten in 11 Allelgruppen (182230 bp) zu 17 unterschiedlichen Allelen. Der Locus D18S51 (AGAA) ist ein STRPolymorphismus mit einer einfachen Repeatstruktur (simple repeat). 12 unter schiedliche Allele wurden beobachtet, die alle einen regelmäßigen Tetranukleotidrepeat aufwiesen. Die Allelspanne reichte von Allel 11 mit 278 bp bis Allel 22 mit 322 bp. Ebenfalls ein einfacher Repeat bestimmt das HUMFIBRA System (TCTT). Eines der beobachteten 10 Allele differierte allerdings um nur 2 bp. Zusammen mit dem compound repeat HUMVWFA31/A (8 Allele) sind alle untersuchten Marker multiplexfähig. Ein ausgeprägter Polymorphismus der individuellen Loci, die dem HardyWeinberg Equilibrium folgen, sowie eine Übereinstimmungswahrscheinlichkeit (pM) der Merkmale zwischen unverwandten Personen von 3 x 10 7 machen eine Analyse dieser fünf TetranukleotidMarker zu einer sinnvollen Ergänzung in der Bearbeitung abstammungs genetischer Fragestellungen.
A measurement of the transverse momentum spectra of jets in Pb-Pb collisions at sNN−−−√=2.76 TeV is reported. Jets are reconstructed from charged particles using the anti-kT jet algorithm with jet resolution parameters R of 0.2 and 0.3 in pseudo-rapidity |η|<0.5. The transverse momentum pT of charged particles is measured down to 0.15 GeV/c which gives access to the low pT fragments of the jet. Jets found in heavy-ion collisions are corrected event-by-event for average background density and on an inclusive basis (via unfolding) for residual background fluctuations and detector effects. A strong suppression of jet production in central events with respect to peripheral events is observed. The suppression is found to be similar to the suppression of charged hadrons, which suggests that substantial energy is radiated at angles larger than the jet resolution parameter R=0.3 considered in the analysis. The fragmentation bias introduced by selecting jets with a high pT leading particle, which rejects jets with a soft fragmentation pattern, has a similar effect on the jet yield for central and peripheral events. The ratio of jet spectra with R=0.2 and R=0.3 is found to be similar in Pb-Pb and simulated PYTHIA pp events, indicating no strong broadening of the radial jet structure in the reconstructed jets with R<0.3.
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 < pT,assoc < pT,trig < 5.0 GeV/c is examined, to include correlations induced by jets originating from low momentum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range |η| < 0.9. The near-side long-range pseudorapidity correlations observed in high-multiplicity p–Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton–parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p–Pb collisions. Further, the number scales only in the intermediate multiplicity region with the number of binary nucleon–nucleon collisions estimated with a Glauber Monte-Carlo simulation.
Large-scale genetic census of an elusive carnivore, the European wildcat (Felis s. silvestris)
(2016)
The European wildcat, Felis silvestris silvestris, serves as a prominent target species for the reconnection of central European forest habitats. Monitoring of this species, however, appears difficult due to its elusive behaviour and the ease of confusion with domestic cats. Recently, evidence for multiple wildcat occurrences outside its known distribution has accumulated in several areas across Central Europe, questioning the validity of available distribution data for this species. Our aim was to assess the fine-scale distribution and genetic status of the wildcat in its central European distribution range. We compiled and analysed genetic samples from roadkills and hundreds of recent hair-trapping surveys and applied phylogenetic and genetic clustering methods to discriminate wild and domestic cats and identify population subdivision. 2220 individuals were confirmed as either wildcat (n = 1792) or domestic cat (n = 342), and the remaining 86 (3.9 %) were identified as hybrids between the two. Remarkably, genetic distinction of domestic cats, wildcats and their hybrids was only possible when taking into account the presence of two highly distinct genetic lineages of wildcats, with a suture zone in central Germany. 44 % of the individual wildcats where sampled outside the previously published distribution. Our analyses confirm a relatively continuous spatial presence of wildcats across large parts of the study area in contrast to previous analyses indicating a highly fragmented distribution. Our results suggest that wildcat conservation and management should take advantage of the higher than previously assumed dispersal potential of wildcats, which may use wildlife corridors very efficiently.
Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous.
Freeze-out radii extracted from three-pion cumulants in pp, p–Pb and Pb–Pb collisions at the LHC
(2014)
In high-energy collisions, the spatio-temporal size of the particle production region can be measured using the Bose–Einstein correlations of identical bosons at low relative momentum. The source radii are typically extracted using two-pion correlations, and characterize the system at the last stage of interaction, called kinetic freeze-out. In low-multiplicity collisions, unlike in high-multiplicity collisions, two-pion correlations are substantially altered by background correlations, e.g. mini-jets. Such correlations can be suppressed using three-pion cumulant correlations. We present the first measurements of the size of the system at freeze-out extracted from three-pion cumulant correlations in pp, p–Pb and Pb–Pb collisions at the LHC with ALICE. At similar multiplicity, the invariant radii extracted in p–Pb collisions are found to be 5–15% larger than those in pp, while those in Pb–Pb are 35–55% larger than those in p–Pb. Our measurements disfavor models which incorporate substantially stronger collective expansion in p–Pb as compared to pp collisions at similar multiplicity.
We report on the measurement of the inclusive Υ (1S) production in Pb–Pb collisions at √sNN = 2.76 TeV carried out at forward rapidity (2.5 < y < 4) and down to zero transverse momentum using its μ+μ−decay channel with the ALICE detector at the Large Hadron Collider. A strong suppression of the inclusive Υ (1S) yield is observed with respect to pp collisions scaled by the number of independent nucleon–nucleon collisions. The nuclear modification factor, for events in the 0–90% centrality range, amounts to 0.30 ± 0.05(stat) ± 0.04(syst). The observed Υ (1S) suppression tends to increase with the centrality of the collision and seems more pronounced than in corresponding mid-rapidity measurements. Our results are compared with model calculations, which are found to underestimate the measured suppression and fail to reproduce its rapidity dependence.
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
The transverse momentum (pT) spectrum and nuclear modification factor (RAA) of reconstructed jets in 0–10% and 10–30% central Pb–Pb collisions at √sNN = 2.76 TeV were measured. Jets were reconstructed using the anti-kT jet algorithm with a resolution parameter of R = 0.2 from charged and neutral particles, utilizing the ALICE tracking detectors and Electromagnetic Calorimeter (EMCal). The jet pT spectra are reported in the pseudorapidity interval of |ηjet| < 0.5 for 40 < pT, jet < 120 GeV/c in 0–10% and for 30 < pT, jet < 100 GeV/c in 10–30% collisions. Reconstructed jets were required to contain a leading charged particle with pT > 5 GeV/c to suppress jets constructed from the combinatorial background in Pb–Pb collisions. The leading charged particle requirement applied to jet spectra both in pp and Pb–Pb collisions had a negligible effect on the RAA. The nuclear modification factor RAA was found to be 0.28 ± 0.04 in 0–10% and 0.35 ± 0.04 in 10–30% collisions, independent of pT, jet within the uncertainties of the measurement. The observed suppression is in fair agreement with expectations from two model calculations with different approaches to jet quenching.
We have performed the first measurement of the coherent ψ(2S) photo production cross section in ultraperipheral Pb–Pb collisions at the LHC. This charmonium excited state is reconstructed via the ψ(2S) → l +l − and ψ(2S) → J/ψπ+π− decays, where the J/ψ decays into two leptons. The analysis is based on an event sample corresponding to an integrated luminosity of about 22 μb−1. The cross section for coherent ψ(2S) production in the rapidity interval −0.9 < y < 0.9 is dσcoh ψ(2S)/dy = 0.83±0.19 stat+syst mb. The ψ(2S) to J/ψ coherent cross section ratio is 0.34+0.08 −0.07(stat + syst). The obtained results are compared to predictions from theoretical models.
A measurement of dijet correlations in p–Pb collisions at √sNN = 5.02 TeV with the ALICE detector is presented. Jets are reconstructed from charged particles measured in the central tracking detectors and neutral energy deposited in the electromagnetic calorimeter. The transverse momentum of the full jet (clustered from charged and neutral constituents) and charged jet (clustered from charged particles only) is corrected event-by-event for the contribution of the underlying event, while corrections for underlying event fluctuations and finite detector resolution are applied on an inclusive basis. A projection of the dijet transverse momentum, kTy = pch+ne T,jet sin(ϕdijet) with ϕdijet the azimuthal angle between a full and charged jet and pch+ne T,jet the transverse momentum of the full jet, is used to study nuclear matter effects in p–Pb collisions. This observable is sensitive to the acoplanarity of dijet production and its potential modification in p–Pb collisions with respect to pp collisions. Measurements of the dijet kTy as a function of the transverse momentum of the full and recoil charged jet, and the event multiplicity are presented. No significant modification of kTy due to nuclear matter effects in p–Pb collisions with respect to the event multiplicity or a PYTHIA8 reference is observed.
The measurement of the mass differences for systems bound by the strong force has reached a very high precision with protons and anti-protons1,2. The extension of such measurement from (anti-)baryons to (anti-)nuclei allows one to probe any difference in the interactions between nucleons and anti-nucleons encoded in the (anti-)nuclei masses. This force is a remnant of the underlying strong interaction among quarks and gluons and can be described by effective theories3, but cannot yet be directly derived from quantum chromodynamics. Here we report a measurement of the difference between the ratios of the mass and charge of deuterons (d) and anti-deuterons (), and 3He and nuclei carried out with the ALICE (A Large Ion Collider Experiment)4 detector in Pb–Pb collisions at a centre-of-mass energy per nucleon pair of 2.76 TeV. Our direct measurement of the mass-over-charge differences confirms CPT invariance to an unprecedented precision in the sector of light nuclei5,6. This fundamental symmetry of nature, which exchanges particles with anti-particles, implies that all physics laws are the same under the simultaneous reversal of charge(s) (charge conjugation C), reflection of spatial coordinates (parity transformation P) and time inversion (T).
The ALICE Collaboration at the LHC reports measurement of the inclusive production cross section of electrons from semi-leptonic decays of beauty hadrons with rapidity |y| < 0.8 and transverse momentum 1 < pT < 10 GeV/c, in pp collisions at √s = 2.76 TeV. Electrons not originating from semi-electronic decay of beauty hadrons are suppressed using the impact parameter of the corresponding tracks. The production cross section of beauty decay electrons is compared to the result obtained with an alternative method which uses the distribution of the azimuthal angle between heavy-flavour decay electrons and charged hadrons. Perturbative QCD predictions agree with the measured cross section within the experimental and theoretical uncertainties. The integrated visible cross section, σb→e = 3.47 ± 0.40(stat) +1.12 −1.33(sys) ± 0.07(norm) μb, was extrapolated to full phase space using Fixed Order plus Next-to-Leading Log (FONLL) calculations to obtain the total bb production ¯ cross section, σbb¯ = 130 ± 15.1(stat) +42.1 −49.8(sys) +3.4 −3.1(extr) ± 2.5(norm) ± 4.4(BR) μb.
Background and Aims: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4–0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15–30% of patients report no risk factors and ALT levels can be normal in up to 20–30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively.
Methods: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA.
Results: The overall HCV seroprevalence was 2.6% (95% CI: 2.4–2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5–1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously.
Conclusions: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.