Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis

Objectives The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. Methods A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. Results Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. Conclusions TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.Peer reviewe

Prophecy, Policy, and Restoration : An Approach to Understanding the Composition of the Book of Hosea

Hoseabokens tillkomst är en ytterst omstridd fråga bland forskarna. I stort sett alla forskarna är eniga om att boken härstammar från Nordriket, dvs. Israel, eftersom alla geografiska namn och kult platser som nämns i boken ligger på Israels område; de flesta forskarna också anser att Hoseaboken har gått igenom en judeisk redaktionell process. Vilken roll man slutligen tillskriver redaktorerna är en omstridd fråga, samt frågan om vad som i den nuvarande Hoseaboken härstammar från den historiska profeten. Denna avhandling driver tesen att textmaterialet in Hoseaboken speglar två historiska tidsperioder, 700-talet f.Kr när profetior som ligger bakom den nuvarande formen av boken uttalades och tiden av Josias reform på 620-talet när dessa profetior omarbetades i Juda. Tesen bygger på följande premisser. För det första, Hoseabokens profetior uttalades när Assyrien utgjorde ett dödligt hot mot Israels existens. Just i sådana situationer brukade profeter in den antika Främre Orienten vara aktiva. Hoseaboken innehåller domsord till Israel, eftersom från profetens synvinkel var Israels trångmål en påföljd för Israels brutna relation till Gud. För det andra, när Hoseas profetior efter Israels fall fördes till Juda, blev de aktuella under Josias tid. Efter Israels undergång var Juda den plats där man började sammansmälta israelitiska och judeiska traditioner. Hoseas domsprofetior kunde tjäna som en varning till Juda för att inte följa Israels exempel, och därför texterna som stod till reformisternas tillfogande omarbetades för att legitimera Josias religiösa reform. Josias respekt för Hoseas profetior var också avsedd för att övertala dem som ännu levde på områden i det förra kungariket Israel att acceptera en kung av Davids släkt. ---------- Hoosean kirjan syntyhistoria on erittäin kiistanalainen aihe tutkijoiden keskuudessa. Lähes kaikki tutkijat ovat yksimielisiä siitä että kirja juontaa juurensa Pohjoisvaltakuntaan eli Israeliin, sillä kaikki maantieteelliset nimet kirjassa liittyvät Israeliin; useimmat tutkijat ovat myös sitä mieltä että kirja on käynyt läpi redaktioprossin Juudassa. Kuinka suuri rooli redaktoreilla on, on kiistelty kysymysm samoin kuin kysymys siitä mikä nykyisessä Hoosean kirjassa juontaa alkunsa historialliselta profeetalta. Tämä väitöskirja esittää että Hoosean kirjan tekstit heijastavat kahta historiallista ajanjaksoa, 700-lukua eaa jolloin kirjan nykymuodon taustalla olevat profetiat julistettiin ja Joosian reformin aikaa 620-luvulla eaa. Väite perustuu seuraaviin premisseihin. Ensinnäkin, Hoosean kirjan sisältämät profetiat julistettiin aikana jolloin Assyria muodosti kuolettavan uhan Israelin olemassaololle. Juuri sellaisissa tilanteissa profeetat muinaisessa Lähi-Idässä olivat aktiivisia. Hoosean kirja sisältää Israelille tarkoitettyja tuomioprofetiota, sillä profeetan näkemyksen mukaan israelin ahdinko aiheutui sen rikkoutuneesta suhteesta Jumalaan. Toiseksi, kun Hoosean profetiat Israelin sortumisen jälkeen päätyivät Juudaan, aktualisoituivat ne Joosian aikana. Israelin tuhon jälkeen Juuda oli se paikka jossa ruvettiin yhdistämään Israelin ja Juudan traditioita. Hoosean tuomioprofetiat psytyivät toimimaan varoituksena Juudalle siitä ettei se seuraisi Israelin esimerkkiä, ja siksi tekstit jotka olivat reformistien saatavilla muokattiin legitimoimaan Joosian reformi. Joosian arvostus Hoosean profetioita kohtaan oli myös tarkoitettu vakuuttamaan heitä jotka vielä asuivat entisen Israelin kuningaskunnan alueella jotta he hyväksyisivät Daavidin sukuun kuuluvan kuninkaan

Electron transfer properties of NADH: Ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON)

AbstractWe report the electron transfer properties of the NADH: ubiquinone oxidoreductase complex of the respiratory chain (Complex I) in mitochondria of cells derived from LHON patients with two different mutations in mitochondrial DNA (mtDNA). The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I. TheNDI/3460 mutation exhibits 80% reduction in rotenone-sensitive and ubiquinone-dependent electron transfer activity, whereas the proximal NADH dehydrogenase activity of the Complex is unaffected. This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone. In contrast, theND4/11778 mutation had no effect on electron transfer activity of the Complex in inner mitochondrial membrane preparations: alsoKm for NADH and NADH dehydrogenase activity were unaffected. However, in isolated mitochondria with theND4 mutation, the rate of oxidation of NAD-linked substrates, but not of succinate, was significantly decreased. This suggests that the ND4 subunit might be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I, which may result in fast (‘solid state’) electron transfer from the former to the latter

mtDNA Variation in the South African Kung and Khwe—and Their Genetic Relationships to Other African Populations

The mtDNA variation of 74 Khoisan-speaking individuals (Kung and Khwe) from Schmidtsdrift, in the Northern Cape Province of South Africa, was examined by high-resolution RFLP analysis and control region (CR) sequencing. The resulting data were combined with published RFLP haplotype and CR sequence data from sub-Saharan African populations and then were subjected to phylogenetic analysis to deduce the evolutionary relationships among them. More than 77% of the Kung and Khwe mtDNA samples were found to belong to the major mtDNA lineage, macrohaplogroup L* (defined by a HpaI site at nucleotide position 3592), which is prevalent in sub-Saharan African populations. Additional sets of RFLPs subdivided macrohaplogroup L* into two extended haplogroups—L1 and L2—both of which appeared in the Kung and Khwe. Besides revealing the significant substructure of macrohaplogroup L* in African populations, these data showed that the Biaka Pygmies have one of the most ancient RFLP sublineages observed in African mtDNA and, thus, that they could represent one of the oldest human populations. In addition, the Kung exhibited a set of related haplotypes that were positioned closest to the root of the human mtDNA phylogeny, suggesting that they, too, represent one of the most ancient African populations. Comparison of Kung and Khwe CR sequences with those from other African populations confirmed the genetic association of the Kung with other Khoisan-speaking peoples, whereas the Khwe were more closely linked to non–Khoisan-speaking (Bantu) populations. Finally, the overall sequence divergence of 214 African RFLP haplotypes defined in both this and an earlier study was 0.364%, giving an estimated age, for all African mtDNAs, of 125,500–165,500 years before the present, a date that is concordant with all previous estimates derived from mtDNA and other genetic data, for the time of origin of modern humans in Africa

A Rare Mitochondrial DNA Haplotype Observed in Koreans

The haplogroup affiliations of Korean mitochondrial DNAs (mtDNAs) were determined by restriction analysis. Out of the 101 mtDNAs analyzed, 91 (90%) belonged to Asian-specific haplogroups M, C, D, G, A, B, and F. Haplogroup E was not detected among the Korean mtDNAs. Three mtDNAs represented an unusual mtDNA haplotype characterized by simultaneous presence of E and G haplogroup-specific polymorphisms. To characterize this haplotype in more detail, we sequenced the hypervariable segment I (HVSI) from these mtDNAs as well as from those from selected individuals representing each haplogroup. Sequence data were further used to compare Korean mtDNAs with mtDNAs from other Asian populations. The observed rare haplotype was also found among Japanese, which suggests that it is one of the ancestral lineages originally peopling Japan