Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Sonotrombolisis; Endovascular; Cambio de equilibrio clínicoSonothrombolysis; Endovascular; Equipoise shiftSonotrombolisis; Endovascular; Canvi d'equilibri clínicBackground: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Gene expression differences between stroke-associated and asymptomatic carotid plaques

Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p &lt; 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Estimated GFR and the Effect of Intensive Blood Pressure Lowering after Acute Intracerebral Hemorrhage

Background: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. Study Design: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP 90, 60-90, and <60 mL/min/1.73 m2, respectively). Outcomes: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. Results: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P = 0.5 for homogeneity). Limitations: Generalizability issues arising from a clinical trial population. Conclusions: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs

Food webs under changing biodiversity - Top-down control

Report on effects of changing predation pressure on benthic and pelagic specie

Sensitivity of soil phosphorus tests in predicting the potential risk of phosphorus loss from pasture soil

The objective of this study was to examine the effects of urine and dung additions on the phosphorus (P) chemistry of pasture land and to compare the sensitivity of two soil extraction methods in assessing the P-loading risk. In a field experiment, urine and dung were added to soil in amounts corresponding to single excrement portions and the soil samples, taken at certain intervals, were analysed for pHH2O, acid ammonium acetate extractable P (PAc) and water extractable total P (TPw), and molybdate reactive P (MRPw). Urine additions immediately increased soil pH and MRPw, but no such response was observed in PAc extraction due to the low pH (4.65) of the extractant enhancing the resorption of P. The PAc responded to the dunginduced increase in soil total P similarly as did Pw, which suggests that both tests can serve to detect areas of high P concentration. However, water extraction was a more sensitive method for estimating short-term changes in P solubility. In pasture soils, the risk of P loss increases as a result of the interaction of urination and high P concentration in the topsoil resulting from continuous dung excretion.;Maan fysikaalisten ja kemiallisten olosuhteiden muutoksetsekä muutokset maan fosforitilassa voivat edistää fosforin (P) huuhtoutumista maasta ja sitä kautta myös vesistöjen rehevöitymistä. Tutkimuksen tarkoituksena oli selvittää sonta- ja virtsalisäysten vaikutusta laidunmaan fosforitilaan sekä verrata kahden uuttotestin, vesiuuton ja happaman ammoniumasetaattiuuton, herkkyyttä muutosten seurannassa. Aineisto kerättiin MTT:n Maaningan tutkimusasemalla sijainneesta kenttäkokeesta. Sontaa ja virtsaa levitettiin koeruuduille keskimääräistä kertaeritystä vastaavat määrät ja koeruuduista (virtsa, sonta ja kontrolli) otettiin 02 cm ja 210 cm syvyyksiltä maanäytteet tietyin aikavälein. Maanäytteistä määritettiin pHH2O, vesiliukoinen kokonaisfosfori (TPw) ja epäorgaaninen fosfori (MRPw) sekä viljavuusanalyysin fosfori (PAc), jota Suomessa käytetään fosforilannoitustarpeen ennustamiseen. Eri käsittelyjen vaikutukset olivat pääasiassa havaittavissa vain maan pintakerroksessa (02 cm). Virtsa nosti maan pH:ta välittömästi lisäyksen jälkeen ja MRPw:n pitoisuudet seurailivat kiinteästi pH:n muutoksia maassa. Vastaavaa nousua ei juurikaan ollut havaittavissa PAc:n pitoisuudessa. Tämä johtuu viljavuusuuttoliuoksen (hapan ammoniumasetaatti) alhaisesta pH:sta (4,65), joka edistää fosforin pidättymistä maahan. Molemmat testit reagoivat samalla tavoin sontalisäyksen aiheuttamaan maan kokonaisfosforipitoisuuden kasvuun. Tulosten mukaan vesiuutto on viljavuusanalyysin uuttoa herkempi menetelmä tarkasteltaessa lyhyen ajan muutoksia maan helppoliukoisen fosforin pitoisuuksissa. Laidunmailla virtsan aiheuttama pH:n nousu lisää liukoisen fosforin määrää, mikä yhdessä sontalisäysten aiheuttaman pintamaan fosforipitoisuuden nousun kanssa kasvattaa fosforin huuhtoutumisriskiä

Extractability of slurry and fertilizer phosphorus in soil after repeated freezing

The potential effects of freezing on phosphorus (P) chemistry in Finnish soils are not well known. We studied the effects of multiple freeze-thaw cycles on soil P chemistry in a laboratory incubation experiment with one organic and one mineral surface soil. The soils were incubated at +5°C or at alternating +5/20°C temperatures for 24 weeks, either without amendment or amended with pig slurry or with commercial compound fertilizer (NPK 2039). After incubation, the soils were analyzed for water-soluble reactive and unreactive P, and acid ammonium acetate soluble P (PAAA). Freezing and thawing of soils during the incubation had no significant effect on any of the water-soluble P fractions or PAAA. The outcome was most likely a consequence of the good P status of the soils, which masked the gentle effects of freezing. According to these results, the time of soil sampling (fall vs. spring) has no effect on P test results on soils with a good P status. Concentrations of soluble P after incubation were roughly twice as high in the slurry treatments than in the fertilizer treatments, demonstrating potentially better long-term availability of slurry P.

Dissolved organic matter in the Baltic Sea

Several factors highlight the importance of dissolved organic matter (DOM) in coastal ecosystems such as the Baltic Sea: 1) DOM is the main energy source for heterotrophic bacteria in surface waters, thus contributing to the productivity and trophic state of bodies of water. 2) DOM functions as a nutrient source: in the Baltic Sea, more than one-fourth of the bioavailable nutrients can occur in the dissolved organic form in riverine inputs and in surface water during summer. Thus, DOM also supports primary production, both directly (osmotrophy) and indirectly (via remineralization). 3) Flocculation and subsequent deposition of terrestrial DOM within river estuaries may contribute to production and oxygen consumption in coastal sediments. 4) Chromophoric DOM, which is one of the major absorbers of light entering the Baltic Sea, contributes highly to water color, thus affecting the photosynthetic depth as well as recreational value of the Baltic Sea. Despite its large-scale importance to the Baltic Sea ecosystem, DOM has been of minor interest compared with inorganic nutrient loadings. Information on the concentrations and dynamics of DOM in the Baltic Sea has accumulated since the late 1990s, but it is still sporadic. This review provides a coherent view of the current understanding of DOM dynamics in the Baltic Sea.201