natgillin/translations-raw huggingface dataset:
Derfor kan det konkluderes, at nedsat nyrefunktion ikke er et krav for Gd-aflejring, men det kan imidlertid øge mængden af Gd aflejret i hjernen. 
Therefore, it can be concluded that renal impairment is not a requirement for Gd deposition, but it may however increase the amount of Gd deposited in the brain.
Desuden anså PRAC, at det ikke er muligt at begrænse anvendelsen af intravenøse lineære GdCA'er til visse indikationer eller visse patientgrupper, idet: 
In addition, PRAC considered that it is not possible to restrict the use of intravenous linear GdCAs to certain indications or certain groups of patients as:
Der er også en bekymring for, at gadolinium-aflejringer i nogle typer væv, især knogle, kan blive frigivet på et senere tidspunkt, for eksempel under tab af knogletæthed i forbindelse med aldring eller graviditet/amning, hvilket udsætter patienter for yderligere systemisk fordeling af gadolinium. 
There is also a concern that gadolinium deposits in some tissues, particularly bone, could be released at a later stage for example during loss of bone density in aging or pregnancy/breastfeeding, exposing patients to further systemic distribution of gadolinium.
Forbedring efter gadobenatdimeglumin (MultiHance) eller dimeglumingadopentetat (Magnevist) forekom at være mere progressiv sammenlignet med gadodiamid. 
Enhancement after gadobenate dimeglumine (Multihance) or gadopentetate dimeglumine (Magnevist) appeared more progressively compared with gadodiamide.
Udformningen af en evt. fremtidig klinisk undersøgelse af langtidssikkerheden for GdCA'er hos patienter ville kræve et stort antal patienter med tilstrækkelig styrke til at påvise små bivirkninger på kognition (kognitive lidelser) eller fysiske evner (finmotoriske færdigheder). 
The design of any future clinical study to investigate the long-term safety of GdCAs in patients would require large numbers of patients to have sufficient power to detect small adverse effects on cognition (cognitive disorders) or physical abilities (fine motor skills).
Med henblik på en potentiel forskel i frekvensen af hypersensitivitetsreaktioner påpegede PRAC, at disse er kendte, sjældne reaktioner for alle GdCA'er. 
In view of a potential difference in the frequency of hypersensitivity reactions, PRAC pointed out that these are known infrequent reactions for all GdCAs.
Det kliniske fund (f.eks. Radbruch et al.), at makrocykliske midler ikke forårsager hjerne-T1-hyperintensitet, blev replikeret af andre grupper og kan derfor anses for at være underbygget. 
The clinical finding (e.g. Radbruch et al.) that macrocyclic agents do not cause brain T1 hyperintensity was replicated by other groups and can therefore be considered to be substantiated.
PRAC vurderede, at der skulle gennemføres potentielle kliniske undersøgelser for at adressere de alvorlige bekymringer for plausible neurologiske virkninger. 
PRAC considered potential clinical studies to be conducted in order to fully address the serious concerns of plausible neurological effects.
Der findes ikke stærk evidens for en reel forskel i hyppigheden af hypersensitivitetsreaktioner eller andre akutte reaktioner forbundet med GdCA'er eller for en forskel i ADR-hyppigheden med dødeligt udfald i klassen. 
There is no strong evidence of a true difference in the rate of hypersensitivity reactions or other acute reactions associated with GdCAs or of a difference in the rate of ADRs with a fatal outcome across the class.
Ud fra de foreliggende data kunne der ikke identificeres nogen specifik patientgruppe, der ikke ville opleve Gd-retention i hjernen, da både børn og voksne forventes at vise akkumulering af Gd i hjernen. 
Based on the data available, no specific patient group that would not experience Gd retention in the brain could be identified, as both children and adults are expected to show accumulation of Gd in the brain.
Dataene viser således, at lineær agenter aflejres i hjernen og opbevares dér og persisterer i op til et år eller længere. 
Therefore, data shows that linear agents are deposited in the brain and are retained and persist for up to one year or longer.
Tilstedeværelse af Gd i hjernen efter sidste indgivelse af andre lineære midler, gadopentetinsyre og gadoterinsyre forblev ligeledes på samme niveau efter samme periode. 
Gd presence in the brain following the last administration of other linear agents, gadopentetic acid and gadobenic acid also remained at the same level after the same period.
• Gadolinium-akkumulering er også blevet rapporteret i en række andre væv herunder lever, nyre, muskel, hud og knogle i ikkekliniske og kliniske undersøgelser. 
• Gadolinium accumulation has also been reported in a range of other tissues including the liver, kidney, muscle, skin and bone in non-clinical and clinical studies.
Derfor skal en konklusion gående ud på, at der er betydelige og klinisk relevante forskelle med hensyn til diagnostisk ydeevne mellem to GdCA'er, understøttes af solid dokumentation fra kliniske undersøgelser herunder bevis på bedre klinisk resultat og patientadministration, hvilket mangler p.t.; indflydelsen på diagnostiske tænkning og patientadministration er ikke blevet bevist. 
Therefore, a conclusion that there are significant and clinically relevant differences in diagnostic performance between two GdCAs needs to be supported by robust evidence from clinical studies including evidence on a better clinical outcome and patient management, which is currently lacking; the impact on diagnostic thinking and patient management was not proven.
Disse konklusioner er i tråd med den udtalelse, der blev udtrykt af eksperterne på ad hocekspertmødet, nemlig at lineære og makrocykliske midler kan anvendes i flæng til billeddannelse af hjertet, og at der ikke er nogen etableret eller opfattet forskel i deres kliniske anvendelighed. 
These conclusions are in line with the opinion of the experts expressed at the ad hoc expert meeting, i.e. that linear and macrocyclic agents can be used interchangeably for cardiac imaging and that there is no established or perceived difference in their clinical utility.
CHMP konkluderede, at risikoen for NSF er forskellig for de forskellige gadolinium-holdige kontrastmidler, hvilket fører til kategorisering af GdCA'er i tre risikogrupper for NSF (høj risiko, middel risiko og lav risiko). 
The CHMP concluded that the risk of NSF is different for the different gadolinium-containing contrast agents, which lead to the categorisation of GdCAs into three risk groups for NSF (high risk, medium risk and low risk).
Med hensyn til brugen af MultiHance i den pædiatriske population blev det bemærket, at mens hepatocellulært carcinom samt metastatiske læsioner er hyppige i den voksne population, er leversygdomme hos børn mere diffuse end fokuserede, og tumorer er sjældne. 
With regards to the use of Multihance in the paediatric population, it was noted that, while hepatocellular carcinoma as well as metastatic lesions are frequent in the adult population, liver diseases in children are rather diffuse than focal and tumours are rare.
Desuden har de nylige publikationer vist, at gadolinium også akkumuleres i hjernen. 
Furthermore, recent publications have shown that gadolinium also accumulates in the brain.
Det øgede potentiale til frigivelse af gadolinium i hjernen ville være forventelig med de lineære midler, som har en lavere kinetisk og termodynamisk stabilitet og dermed er mere tilbøjelige til at frigive gadolinium i vævsmiljøet. 
The increased potential to release gadolinium in the brain would be expected with the linear agents, which have a lower kinetic and thermodynamic stability and are thus more prone to release gadolinium in the tissue environment.
PRAC bemærkede også, at der blev testes høje doser af GdCA'er (20x2,5 mmol) af McDonald et al., og undersøgelsens varighed er forholdsvis kort (f.eks. var de totale doser, der blev testet i Frenzel et al. 2017, halvdelen af McDonald et al. (10x2,5mmol), mens tidsperioden for den sidste vævsprøveudtagning i Frenzel et al. 2017 var 24 dage i stedet for 7 dage i McDonald 2017.) 
The PRAC also noted that high GdCAs doses were tested (20x2.5 mmol) by McDonald et al., and the study duration is comparably short (e.g. the total doses tested in Frenzel et al 2017 was half that of McDonald et al (10x2.5mmol), while the time period to the last tissue sampling in Frenzel et al 2017 was 24 days instead of 7 days in McDonald 2017.)
PRAC bemærkede også, at det tværtimod ikke var muligt at identificere en specifik patientgruppe for NSF (nyreinsufficiens og patienter i den perioperative levertransplantationsperiode), ligesom undgåelse af brug i disse populationer synes at have minimeret risikoen for NSF. 
The PRAC also noted that in contrast, for NSF a specific patient group (renal insufficiency and patients in the perioperative liver transplantation period) could be identified, and avoidance of use in these populations appears to have minimised the risk of NSF.
Yderligere undersøgelser har forsøgt at karakterisere og kvantificere mængden af aflejret gadolinium i hjernen. 
Further studies have tried to characterise and quantify the amount of deposition of gadolinium in the brain.
Den væsentligste udskillelsesvej for GdCA'er er renal, og langvarig elimineringstid på grund af alvorligt nedsat nyrefunktion kan teoretisk øge potentialet for akkumulering i hjernevæv. 
The major route of excretion for GdCAs is renal, and prolonged elimination time due to severely impaired renal function could theoretically increase the potential for accumulation in brain tissue.
Et rotteforsøg bekræftede ligeledes, at et dosisafhængigt niveau af Gd i hjernen for lineære midler sandsynligvis var relateret til kumulativ dosering snarere end en enkelt stor eller gentagne små doseringssystemer. 
A rat study also confirmed the finding that dose-dependent level of Gd in the brain for linear agents was likely to be related to cumulative dose rather than a single large or repeat small dose regimens.
• PRAC overvejede muligheder for risikominimeringsforanstaltninger. 
• PRAC considered options for risk minimisation measures.
Men lineære midler bevares og persisterer i op til et år eller længere. 
However linear agents are retained and persist for up to one year or longer.
Nedsat nyrefunktion er også kendt for at øge langtidsretentionen af Gd hos rotter i overensstemmelse med GdCA'ers evne til at frigive Gd in vivo. 
Renal impairment is also known to increase the long term retention of Gd in rats in line with the propensity of GdCAs to release Gd in vivo.
Perfusionsbilleddannelse i MRI udføres typisk både i hvile og under farmakologisk stress (for eksempel med adenosin eller dipyridamol) og anvender en dynamisk billeddannelsesteknik, hvor signalintensitet i myocardium evalueres under passagen af kontrastmidlet bolus. 
Perfusion imaging in MRI is typically performed both at rest and during pharmacological stress (for example, with adenosine or dipyridamole), and utilizes a dynamic imaging technique in which signal intensity in the myocardium is evaluated during the passage of the contrast bolus.
I betragtning af det meget lave potentiale for retention af gadolinium i væv, deres stabilitet og lave risiko for dechelatering, fastholdt PRAC sin anbefaling om, at fordelene ved makrocykliske agenter opvejer risiciene. 
In view of the very low potential for retention of gadolinium in tissues, their stability and low risk of dechelation, PRAC maintained its recommendation that the benefits of macrocyclic agents outweigh their risks.
PRAC konkluderede da, at på grundlag af de foreliggende data kan MultiHance fortsat anvendes i pædiatriske patienter til forsinket fasebilleddannelse af leveren. 
The PRAC concluded that based on the available data Multihance can continue to be used in paediatric patients for delayed phase liver imaging.
Makrocykliske GdCA'er har et meget lavt potentiale for retention af gadolinium i væv, er meget stabile og har en lav risiko for dechelatering. 
Macrocyclic GdCAs have a very low potential for retention of gadolinium in tissues, are very stable and have a low risk of dechelation.
Derudover er lave koncentrationer af lineære gadoliniummidler såvel som makrocykliske midler blevet påvist i ikkekliniske og kliniske undersøgelser via massespektrometri. 
In addition, low concentrations of linear gadolinium agents as well as macrocyclic agents were detected in non-clinical and clinical studies via mass spectrometry.
Gentagne toksicitetsundersøgelser for gadodiamid har vist, at de absolutte, lave niveauer af gadolinium i hjernen blev observeret 1 uge efter dosering. 
Repeat toxicity studies for gadodiamide showed that the absolute low levels of gadolinium in the brain were observed at 1 week post-dosing.
PRAC fastholdt også sine konklusioner om, at fordelene ved den intra-artikulære præsentation af det lineære GdCA, Magnevist, opvejer risiciene (med forbehold af ændringer i produktinformationen), da de indgives i meget lave doser og med lav risiko for vævsakkumulering. 
PRAC also maintained its conclusions that benefits of the intra-articular presentation of the linear GdCA Magnevist outweigh their risks (subject to changes to the product information) as they are administered at very low doses and present a low risk of tissue accumulation.
De hjerneopløselige fraktioner fra dyr, der modtog lineære midler, indeholdt en andel af makromolekyler; gadolinium-bundne makromolekyler blev ikke påvist i hjernen hos dyr, der havde modtaget makrocykliske midler. 
The brain soluble fractions from animals receiving linear agents contained a proportion of macromolecules; gadolinium-bound macromolecules were not detected in the brain of animals that received macrocyclic agents.
• Gadolinium er blevet målt i hjernen, både indirekte gennem undersøgelser der viser stigende signal-intensitet, og direkte gennem undersøgelser, der måler gadoliniumkoncentrationer med massespektrometri, herunder metoder der tillader lokalisering i hjernen (LA-ICP-MS) og separation af Gd-arter (GPC -MS). 
• Gadolinium has been measured in the brain, both indirectly by studies showing signal intensity increases, and directly by studies measuring gadolinium concentrations with mass spectrometry, including methods that allow localisation in the brain (LA-ICP-MS) and separation of Gd species (GPC-MS).
I en tidligere indbringelse i henhold til artikel 31 i direktiv 2001/83/EF, som blev afsluttet i 2010, konkluderede Udvalget for Lægemidler til Mennesker (CHMP), at brugen af GdCA'er var forbundet med risikoen for nefrogen systemisk fibrose (NSF), et alvorligt og livstruende syndrom, der involverer fibrose af huden, leddene og de indre organer hos patienter med nedsat nyrefunktion. 
In a previous referral under Article 31 of Directive 20010/83/EC finalised in 2010, the Committee for Medicinal Products for Human Use (CHMP) concluded that the use of GdCAs was associated with the risk of nephrogenic systemic fibrosis (NSF), a serious and life-threatening syndrome involving fibrosis of the skin, joints and internal organs in patients with renal impairment.
De indgives i lave koncentrationer, ca. 200 gange lavere end den intravenøse brug GdCAlægemidler, og potentialet for patienter for modtagelse af store antal gentagne eksponeringer er mindre for MR-artrografi-indikationen end for indikationerne for det intravenøse lægemiddel. 
They are administered at low concentrations, approximately 200-fold lower than the intravenous use GdCA products, and the potential for patients to receive large numbers of repeated exposures is less for the MR arthrography indication than for the indications for the intravenous product.
• den forsinkede fase, der beror på selektiv optagelse af en GdCA ved fungerende hepatocytter, hvilket resulterer i forbedring og visualisering af den normale hepatiske parenkym og samtidig forbedring af afbildningen og påvisningen af læsioner, såsom cyster og hepatocellulære carcinomer. 
• the delayed phase that relies on selective uptake of a GdCA by functioning hepatocytes, which results in enhancement and visualisation of the normal hepatic parenchyma while improving the delineation and detection of lesions such as cysts and hepatocellular carcinomas.
Med hensyn til påstanden om, at der stort set ikke frigives Gd fra gadodiamid i kroppen, bemærkede PRAC, at ved 37°C i humant serum dissocieres Gd hurtigt fra dets chelatdanner in vitro (Frenzel et al. 2008). 
With regards to the claim that virtually no Gd becomes liberated from gadodiamide in the body, PRAC noted that at 37°C in human serum Gd rapidly dissociates from its chelator in vitro (Frenzel et al. 2008).
De foreliggende data fra mennesker understøtter en konklusion om, at mens nedsat nyrefunktion ikke er en nødvendig forudsætning for stigende signal-hyperintensitet i hjernen, så reducerer nedsat nyrefunktion omfanget af hjerneakkumulering og signal-hyperintensitet. 
The available data in humans support a conclusion that while impaired renal function is not a necessary precondition for signal hyperintensity increases in the brain, impaired renal function does increase the extent of brain accumulation and signal hyperintensity.
Eksperterne udtalte også, at det er sandsynligt, at der kan være negative kliniske konsekvenser forbundet med gadolinium-retention i hjernen. 
The experts also stated that it is plausible that adverse clinical consequences could be associated with gadolinium retention in the brain.
Elimineringen af GdCA'er derfor nedsat hos patienter med nedsat nyrefunktion. 
Elimination of GdCAs is therefore reduced in patient with renal dysfunction.
Kontrastmidler (GdCA'er), som indeholder gadolinium, er komplekser af paramagnetisk gadolinium (III) med forskellige typer organisk chelatdannere. 
Gadolinium containing contrast agents (GdCAs) are complexes of paramagnetic gadolinium (III) with different types of organic chelators.
Indehaverne af markedsføringstilladelse fremlagde flere forslag til risikominimeringsforanstaltninger med hensyn til akkumulering og retention af GDCA i hjernen hos patienter, der eksponeres for disse midler under diagnostiske procedurer: 
The MAHs provided several proposals for risk minimization measures with regards the accumulation and retention of GdCA in the brain of patients exposed to these agents during diagnostic procedures:
Det er rimeligt at antage, at gadolinium kan dechelatere fra lineære GdCA'er og binde sig til makromolekyler i den menneskelige hjerne på samme måde, som det er blevet observeret i gnaverhjerner. 
It is reasonable to suppose that gadolinium can de-chelate from linear GdCAs and bind to macromolecules in human brains similarly as what is observed in rodent brains.
• Foruden NSF er der også evidens for, at andre skadelige resultater er forbundet med eksponering for lineære GdCA'er, især gadolinium-associerede hudplaques. 
• In addition to NSF, there is also evidence that other harmful outcomes are associated with exposure to linear GdCAs, in particular gadolinium-associated skin plaques.
• Den begrænsede brug af lineære GdCA'er vil stadig efterlade patienter i den resterende population eksponeret for risikoen for skade, uden at kende den sikre tærskelværdi for retention i hjernen og andet kropsvæv til dechelateret gadolinium. 
• The restriction of the use of linear GdCAs will still leave patients in the remaining population exposed to the risk of harm, without knowing safe threshold level for retention in the brain and other tissues of the body to dechelated gadolinium.
En in vitro-undersøgelse i rotteneuroner rapporterede om gadolinium-induceret cytotoksicitet via oxidativ skade. 
An in vitro study in rat neurons reported gadolinium-induced cytotoxicity via oxidative injury.
En gruppe af eksperter (herunder patientrepræsentanten) støttede PRAC's anbefaling (dvs. suspendering af lineære midler ud over Primovist® og intra-artikulær Magnevist) og dens rationale, med undtagelse af suspenderingen af MultiHance til billeddannelse af leveren i fravær af makrocykliske midler for denne indikation og manglende tilgængelighed af Primovist® i en medlemsstat. 
One group of experts (including the patient representative) supported the PRAC recommendation (i.e. suspension of linear agents besides Primovist and intraarticular Magnevist) and its rationale, with the exception of the suspension of Multihance for liver imaging in absence of macrocyclic agents for this indication and lack of availability of Primovist in one Member State.
Gadobensyre gennemgår hepatisk optagelse. 
Gadobenic acid undergoes hepatic uptake.
PRAC's konklusioner for begrundelserne for revurdering 
PRAC conclusions on grounds for re-examination
• Desuden blev der påvist tætte aflejringer i forskellige væv efter indgivelse af GdCA via transmissionselektronmikroskopi (TEM), der blev betragtet som Gd-aflejringer. 
• Furthermore, dense deposits in various tissues were detected after GdCA administration by Transmission electron microscopy (TEM), which were regarded as Gd deposits.
Varighed af gadolinium-retention i hjernen 
Duration of gadolinium retention in the brain
Kun en forbigående stigning i T1-signalintensitet og gadoliniumkoncentration (målt ved ICP-MS1 og således uden skelnen til den molekylære Gd-form) blev observeret med makrocykliske midler. 
Only a transient increase in T1signal intensity and gadolinium concentration (measured by ICP-MS1, thus not distinguishing the molecular form of Gd) was observed with macrocyclic agents.
Dataene synes at antyde, at makrocykliske agenter også aflejres i hjernen, men viser kun en forbigående stigning i Gd og gennemgår tidlig udvaskning. 
Data appears to suggest that macrocyclic agents are also deposited in the brain but show only a transient increase in Gd and undergo early washout.
• Undersøgelsesresultaterne fra undersøgelsen på Mayo Clinic Study of Aging (MCSA) (McDonald et al. 2017, manuskript under udarbejdelse), er begrænset til små prøver, relativt kort opfølgning med hensyn til potentielle langtidsvirkninger, manglende diskussion af sensitiviteten af de påtænkte endepunkter vedrørende påvisning af potentielle skadelige virkninger, mangel på detaljerede oplysninger om statistiske metoder og disses robusthed, og at de generelt er for begrænsede til at give forsikring med hensyn til sikkerheden af brugen af GdCA'er. 
• the study results from the Mayo Clinic Study of Ageing (MCSA) study (McDonald et al. 2017, manuscript in preparation), are limited by small sample sizes, relatively short follow-up with regard to potential long-term effects, lack of discussion of sensitivity of the envisaged endpoints regarding detection of potential adverse effects, lack of full detailed information on statistical methods and their robustness and that they are overall too limited to provide reassurance about the safety of usage of GdCAs.
Mens akkumulering i form af T1w-signalintensitet øges, og gadolinium målt i hjernen (sandsynligvis i form af intakt GdCA-molekyle) er blevet set på kort sigt med disse midler, er der ikke blevet observeret langvarig persistens i hjernen. 
While accumulation in terms of T1w signal intensity increases and gadolinium measured in the brain (likely in the form of intact GdCA molecule) has been seen in the short term with these agents, long-term persistence in the brain was not be observed.
I henhold til artikel 116 i direktiv 2001/83/EF anbefaler CHMP derfor suspendering af markedsføringstilladelserne for intravenøse lægemidler, der indeholder gadodiamid, gadopentetinsyre og gadoversetamid. 
Therefore, pursuant to Article 116 of Directive 2001/83/EC, the CHMP recommends the suspension of the marketing authorisations for intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide.
En anden undersøgelse viste, at indgivelse af de lineære GdCA'er, gadodiamid og gadobensyre, direkte ind i cerebrospinalvæsken (CSF) resulterede i øget signalintensitet i DCN i rotter op til 5 uger efter indgivelse. 
Another study showed that administration of the linear GdCAs gadodiamide and gadobenic acid directly into the cerebrospinal fluid (CSF) resulted in increased signal intensity in the DCN in rats up to 5 weeks after administration.