Staatliche Gründungsfinanzierung: Stand der Forschung und offene Fragen

Der Beitrag gibt einen Überblick über den Stand der Forschung zur staatlichen Gründungsfinanzierung, speziell in Deutschland. Dabei steht die Frage im Vordergrund, ob eine öffentliche Gründungsfinanzierung aus wirtschaftspolitischer Sicht zu rechtfertigen ist. Konkret werden vier Forschungsfragen untersucht. Die erste Frage lautet, ob Unternehmensgründungen für eine Wirtschaft überhaupt Nutzen stiften. Die zweite Frage lautet, ob auf dem Markt der Finanzierung von Gründungsunternehmen Unvollkommenheiten bzw. Marktversagen feststellbar sind. Die dritte Frage lautet, ob staatliche Maßnahmen der Gründungsfinanzierung einzelwirtschaftlich effektiv sind, dass sich also geförderte Unternehmen als erfolgreicher erweisen als nicht geförderte. Die vierte Frage lautet, ob eine staatliche Gründungsfinanzierung die angestrebten wirtschaftspolitischen Ziele zu den niedrigstmöglichen Kosten erreicht, also effizient ist. Die Antworten sind durchweg negativ und zeigen, dass die bisherige Forschung keine ausreichende Rechtfertigung für eine staatliche Gründungsfinanzierung bieten kann.

Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes

Background Prognostic models have been developed for patients infected with HIV-1 who start combination antiretroviral therapy (ART) in high-income countries, but not for patients in sub-Saharan Africa. We developed two prognostic models to estimate the probability of death in patients starting ART in sub-Saharan Africa. Methods We analysed data for adult patients who started ART in four scale-up programmes in Côte d'Ivoire, South Africa, and Malawi from 2004 to 2007. Patients lost to follow-up in the first year were excluded. We used Weibull survival models to construct two prognostic models: one with CD4 cell count, clinical stage, bodyweight, age, and sex (CD4 count model); and one that replaced CD4 cell count with total lymphocyte count and severity of anaemia (total lymphocyte and haemoglobin model), because CD4 cell count is not routinely measured in many African ART programmes. Death from all causes in the first year of ART was the primary outcome. Findings 912 (8·2%) of 11 153 patients died in the first year of ART. 822 patients were lost to follow-up and not included in the main analysis; 10 331 patients were analysed. Mortality was strongly associated with high baseline CD4 cell count (≥200 cells per μL vs <25; adjusted hazard ratio 0·21, 95% CI 0·17–0·27), WHO clinical stage (stages III–IV vs I–II; 3·45, 2·43–4·90), bodyweight (≥60 kg vs <45 kg; 0·23, 0·18–0·30), and anaemia status (none vs severe: 0·27, 0·20–0·36). Other independent risk factors for mortality were low total lymphocyte count, advanced age, and male sex. Probability of death at 1 year ranged from 0·9% (95% CI 0·6–1·4) to 52·5% (43·8–61·7) with the CD4 model, and from 0·9% (0·5–1·4) to 59·6% (48·2–71·4) with the total lymphocyte and haemoglobin model. Both models accurately predict early mortality in patients starting ART in sub-Saharan Africa compared with observed data. Interpretation Prognostic models should be used to counsel patients, plan health services, and predict outcomes for patients with HIV-1 infection in sub-Saharan Africa.

[Acute myocardial infarction: importance of the networking in the initial management]

Early reperfusion with prompt re-establishment of coronary blood flow improves survival in patients suffering from acute ST-elevation myocardial infarction (STEMI). Leaving systemic thrombolysis for primary percutaneous coronary intervention (PCI) is justified by clinical results in favor of PCI. Nevertheless, primary PCI necessitates additional transfer time and requires an efficient territorial networking. The present article summarizes the up-to-dated management of patients with acute STEMI and/or overt cardiogenic shock.

Combined use of pulsed arterial spin-labeling and susceptibility-weighted imaging in stroke at 3T

Background and Purpose: In acute stroke it is no longer sufficient to detect simply ischemia, but also to try to evaluate reperfusion/recanalization status and predict eventual hemorrhagic transformation. Arterial spin labeling (ASL) perfusion may have advantages over contrast-enhanced perfusion-weighted imaging (cePWI), and susceptibility weighted imaging (SWI) has an intrinsic sensitivity to paramagnetic effects in addition to its ability to detect small areas of bleeding and hemorrhage. We want to determine here if their combined use in acute stroke and stroke follow-up at 3T could bring new insight into the diagnosis and prognosis of stroke leading to eventual improved patient management. Methods: We prospectively examined 41 patients admitted for acute stroke (NIHSS >1). Early imaging was performed between 1 h and 2 weeks. The imaging protocol included ASL, cePWI, SWI, T2 and diffusion tensor imaging (DTI), in addition to standard stroke protocol. Results: We saw four kinds of imaging patterns based on ASL and SWI: patients with either hypoperfusion and hyperperfusion on ASL with or without changes on SWI. Hyperperfusion was observed on ASL in 12/41 cases, with hyperperfusion status that was not evident on conventional cePWI images. Signs of hemorrhage or blood-brain barrier breakdown were visible on SWI in 15/41 cases, not always resulting in poor outcome (2/15 were scored mRS = 0–6). Early SWI changes, together with hypoperfusion, were associated with the occurrence of hemorrhage. Hyperperfusion on ASL, even when associated with hemorrhage detected on SWI, resulted in good outcome. Hyperperfusion predicted a better outcome than hypoperfusion (p = 0.0148). Conclusions: ASL is able to detect acute-stage hyperperfusion corresponding to luxury perfusion previously reported by PET studies. The presence of hyperperfusion on ASL-type perfusion seems indicative of reperfusion/collateral flow that is protective of hemorrhagic transformation and a marker of favorable tissue outcome. The combination of hypoperfusion and changes on SWI seems on the other hand to predict hemorrhage and/or poor outcome.

Interictal arterial spin-labeling MRI perfusion in intractable epilepsy

INTRODUCTION: Magnetic resonance imaging (MRI) is required for the investigation of surgically intractable epilepsy. In addition to the standard MRI techniques, perfusion sequences can be added to improve visualization of underlying pathological changes. Arterial spin-labeling (ASL) MRI perfusion does not require contrast administration and, for this reason, may have advantages in these patients. METHODS: We report here on 16 patients with epilepsy who underwent MRI of the brain with ASL and positron emission tomography (PET). RESULTS: Despite a slightly reduced resolution with ASL, we found a correlation between ASL, PET and electrophysiological data, with hypoperfusion on ASL that corresponded with hypoperfusion on interictal PET. CONCLUSION: Given the correlation between ASL and PET and electrophysiology, perfusion with ASL could become part of the standard work-up in patients with epilepsy.

Estimating loss to follow-up in HIV-infected patients on antiretroviral therapy: the effect of the competing risk of death in Zambia and Switzerland

Background Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. Methods and Findings HIV-infected patients aged ≥18 years who started ART 2004–2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. Conclusions In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings.

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

Theta burst TMS increases cerebral blood flow in the primary motor cortex during motor performance as assessed by arterial spin labeling (ASL)

Theta burst stimulation (TBS) is a novel variant of repetitive transcranial magnetic stimulation (rTMS), which induces changes in neuronal excitability persisting up to 1h. When elicited in the primary motor cortex, such physiological modulations might also have an impact on motor behavior. In the present study, we applied TBS in combination with pseudo continuous arterial spin labeling (pCASL) in order to address the question of whether TBS effects are measurable by means of changes in physiological parameters such as cerebral blood flow (CBF) and if TBS-induced plasticity can modify motor behavior. Twelve right-handed healthy subjects were stimulated using an inhibitory TBS protocol at subthreshold stimulation intensity targeted over the right motor cortex. The control condition consisted of within-subject Sham treatment in a crossover design. PCASL was performed before (pre TBS/pre Sham) and immediately after treatment (post TBS/post Sham). During the pCASL runs, the subjects performed a sequential fingertapping task with the left hand at individual maximum speed. There was a significant increase of CBF in the primary motor cortex after TBS, but not after Sham. It is assumed that inhibitory TBS induced a "local virtual lesion" which leads to the mobilization of more neuronal resources. There was no TBS-specific modulation in motor behavior, which might indicate that acute changes in brain plasticity caused by TBS are immediately compensated. This compensatory reaction seems to be observable at the metabolic, but not at the behavioral level.

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

OBJECTIVE: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy. DESIGN: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003. METHODS: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. RESULTS: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone. CONCLUSION: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.

Sendai virus RNA polymerase scanning for mRNA start sites at gene junctions

Mini-genomes expressing two reporter genes and a variable gene junction were used to study Sendai virus RNA polymerase (RdRp) scanning for the mRNA start signal of the downstream gene (gs2). We found that RdRp could scan the template efficiently as long as the initiating uridylate of gs2 (3' UCCCnnUUUC) was preceded by the conserved intergenic region (3' GAA) and the last 3 uridylates of the upstream gene end signal (ge1; 3' AUUCUUUUU). The end of the leader sequence (3' CUAAAA, which precedes gs1) could also be used for gene2 expression, but this sequence was considerably less efficient. Increasing the distance between ge1 and gs2 (up to 200 nt) led to the progressive loss of gene2 expression, in which half of gene2 expression was lost for each 70 nucleotides of intervening sequence. Beyond 200 nt, gene2 expression was lost more slowly. Our results suggest that there may be two populations of RdRp that scan at gene junctions, which can be distinguished by the efficiency with which they can scan the genome template for gs.

MRI follow-up of TNF-dependent differential progression of atherosclerotic wall-thickening in mouse aortic arch from early to advanced stages

OBJECTIVES: An optimized, longitudinal in vivo magnetic resonance vessel wall-imaging protocol was evaluated regarding its capability of detecting differences in the time-dependent atherosclerotic lesion progression in the aortic arch between ApoE(-/-) and double-deficient ApoE(-/-)/TNF(-/-) mice at comparatively early plaque development stages. MATERIALS AND METHODS: Seven ApoE(-/-) and seven ApoE(-/-)/TNF(-/-) female mice underwent MRI at 11.75 teslas at four stages up to 26 weeks of age. A double-gated spin-echo MRI sequence was used with careful perpendicular slice positioning to visualize the vessel wall of the ascending aortic arch. RESULTS: Wall-thickness progression measured with MRI was significant at 11 weeks of age in ApoE(-/-) mice, but only at 26 weeks in ApoE(-/-)/TNF(-/-) mice. A significant correlation was found between MRI wall-thickness and lesion area determined on histology. CONCLUSION: MRI was shown to be sensitive enough to reveal subtle genetically-induced differences in lesion progression at ages earlier than 25 weeks.

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II)

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

CD4+ T-cell count increase in HIV-1-infected patients with suppressed viral load within 1 year after start of antiretroviral therapy

BACKGROUND: CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). METHODS: Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included (n=1816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2-3 and years 4-5 of suppression. Multiple median regression adjusted for repeated CD4+ T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. RESULTS: Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/microl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/microl at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+ T-cell increases compared with stavudine. CONCLUSIONS: In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.