Scheduled versus Pro Re Nata Dosing in the VIEW Trials

PURPOSE To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

Ms. Praed. 107 - Quaestiones in Sententiarum Petri Lombardi libros quattuor

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Haupt-Nachweisung des Grundsteuer-Sollaufkommens in den westlichen Provinzen pro 1849 : in Folge des Grundsteuergesetzes vom 21ten Januar 1839

Welsch (Projektbearbeiter): Vorgesehene Verwendung der veranschlagten Grundsteuereinnahmen des Jahres 1849 in den preußischen Provinzen Rheinprovinz und Westfalen (nach Regierungsbezirken)

Denkschrift die zur Aufbringung des außerordentlichen Staats-Haushalts-Bedarfs erforderlichen Mittel betreffend: Etat pro 1848: Die Bemerkungen über die Finanzlage des Staats und über die Nothwendigkeit der Beschaffung außerordentlicher Hülfsmittel ...

Welsch (Projektbearbeiter): Rechenschaftslegung der Finanzministers Hansemann (Ministerium Auerswald - Hansemann) über die finanzielle Lage des preußischen Staates: aufgrund der zu erwartenden bedeutenden Einnahmeausfälle (geschätzte 8 Millionen Taler) bei gleichzeitigen Mehrausgaben (geschätzte 22,5 Millionen Taler) mußten dem Staatsschatz 13 Millionen Taler entnommen werden. Da sich jedoch trotz alledem noch eine Haushaltslücke von 15 Millionen Talern ergibt, sind Steuererhöhungen unumgänglich. Samt beigefügtem Gutachten des Vereinigten Landtages vom 8. April 1848

Antisemitismus im Mittelalter : ein Wort pro domo

Raphael Strauß

Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis

BACKGROUND During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells. METHODS The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10. RESULTS Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups. CONCLUSIONS Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Pro und contra

Julius Brutzkus

Economic Reforms and Pro-Poor Growth: Lessons for Africa and other Developing Regions and Economies in Transition

The paper discusses the meaning and measurement of pro-poor growth and also reviews evidence of pro-poor growth (or the lack of it) in a large cross-section of countries and time periods. The emerging story is that many episodes of growth are not pro-poor and also that although economic reforms have had positive effects in those countries that have been steadfast in implementing market reforms, the overall impact on growth has been small for many countries and in most cases not pro-poor. I present a general theory of pro-poor growth that includes ten principles that should be incorporated in all economic reforms that seek to generate pro-poor growth. These principles highlight the importance of understanding the poor, their economic activities, capabilities, constraints that impede their participation in markets and also an appreciation of linkages within sectors and regions. It is argued that pro-poor reforms cannot have the intended impact unless there are significant changes in the institutions of governance. Finally, the principles presented underscore the fact that pro-poor growth policies cannot be sustained without workable partnerships between markets and states in the ever changing and complex processes of social and economic development.

Pro confessione : (ein Brief)

Herman Glenn