Bone marrow mesenchymal stem cell-derived exosomes promote osteoblast proliferation, migration and inhibit apoptosis by regulating KLF3-AS1/miR-338-3p.

AIM: This study aimed to investigate the effect and mechanism of bone marrow mesenchymal stem cell-derived exosomes on osteoblast function. METHODS: The expression of KLF3-AS1 and miR-338-3p in serum of fracture patients was detected by qRT-PCR. Exosomes from BMSCs were isolated by ultrafast centrifugation. MC3T3-E1 cells were cultured in vitro as experimental cells. Intracellular gene expression was regulated by transfection of si-KLF3-AS1 or miR-338-3p inhibitors. MTT assay, Transwell assay and flow cytometry were used to evaluate cell viability, migration, and apoptosis. The luciferase reporter gene was used to verify the targeting relationship between KLF3-AS1 and miR-338-3p. Bioinformatics analysis was used to identify the basic functions and possible enrichment pathways of miR-338-3p target genes. RESULTS: The expressions of KLF3-AS1 and miR-338-3p in the serum of fracture patients were down-regulated and up-regulated, respectively. The expression of KLF3-AS1 was increased in MC3T3-E1 cells cultured with BMSCs-Exo, while the viability and migration ability of MC3T3-E1 cells were enhanced, and the apoptosis ability was weakened. Further analysis revealed miR-338-3p was the target gene of KLF3-AS1. The expression of miR-338-3p was downregulated in MC3T3-E1 cells cultured with BMSCs-Exo. Inhibition of miR-338-3p in MC3T3-E1 cells enhanced the viability and migration ability of MC3T3-E1 cells when cultured with BMSCs-Exo, while suppressing apoptosis. Bioinformatics analysis demonstrated that the target genes of miR-338-3p were predominantly localized at the axon's initiation site, involved in biological processes such as development and growth regulation, and mainly enriched in MAPK and ErbB signaling pathways. CONCLUSION: In vitro, BMSCs-Exo exhibits the capacity to enhance proliferation and migration while inhibiting apoptosis of MC3T3-E1 cells, potentially achieved through modulation of KLF3-AS1 and miR-338-3p expression in MC3T3-E1 cells.

A Scheduling Method of Using Multiple SAR Satellites to Observe a Large Area.

This paper presents a scheduling problem of using multiple synthetic aperture radar (SAR) satellites to observe a large irregular area (SMA). SMA is usually considered as a kind of nonlinear combinatorial optimized problem and its solution space strongly coupled with geometry grows exponentially with the increasing magnitude of SMA. It is assumed that each solution of SMA yields a profit associated with the acquired portion of the target area, and the objective of this paper is to find the optimal solution yielding the maximal profit. The SMA is solved by means of a new method composed of three successive phases, namely, grid space construction, candidate strip generation and strip selection. First, the grid space construction is proposed to discretize the irregular area into a set of points in a specific plane rectangular coordinate system and calculate the total profit of a solution of SMA. Then, the candidate strip generation is designed to produce numerous candidate strips based on the grid space of the first phase. At last, in the strip selection, the optimal schedule for all the SAR satellites is developed based on the result of the candidate strip generation. In addition, this paper proposes a normalized grid space construction algorithm, a candidate strip generation algorithm and a tabu search algorithm with variable neighborhoods for the three successive phases, respectively. To verify the effectiveness of the proposed method in this paper, we perform simulation experiments on several scenarios and compare our method with the other seven methods. Compared to the best of the other seven methods, our proposed method can improve profit by 6.38% using the same resources.

BMP-2 promotes osteogenic differentiation of mesenchymal stem cells by enhancing mitochondrial activity.

OBJECTIVES: Mesenchymal stem cells (MSCs) have become seed cells and basic elements for bone regeneration and bone tissue engineering. The aim of the present study was to investigate the roles and mechanisms of bone morphogenetic protein 2 (BMP-2) on osteogenic differentiation of MSCs. METHODS: Primary MSCs were isolated from the femur and tibia bone of rats and then transfected with BMP-2 and PGC-1α adenovirus vectors. Alkaline phosphatase (ALP) activity and alizarin red staining were used to measure osteogenic differentiation of MSCs. Real-time PCR and western blot assays were performed to assess osteogenic differentiation-related proteins levels. The activities of mitochondrial respiratory chain complexes I and II and mitochondrial fluorescence intensity were used to explore mitochondria status during osteogenic differentiation of MSCs. RESULTS: We found that the ability of BMP-2 overexpressed (OE) group osteogenic differentiation was significantly improved, compared with the negative control (NC) group. The results also indicated that BMP-2 can promote the activity of mitochondria. We further used the gain- and loss-of-function approaches to demonstrate that BMP-2 promotes mitochondrial activity by up-regulating PGC-1α to promote osteogenic differentiation of MSCs. CONCLUSIONS: These results explored the important role of BMP-2 in the osteoblast differentiation of MSCs from a new perspective, providing a theoretical and experimental basis for bone defect and repair.

Intraluminal Thrombus and Outcomes of Patients With Acute Large Vessel Occlusive Stroke Undergoing Endovascular Treatment.

BACKGROUND AND PURPOSE: Intraluminal thrombus (ILT) is an emerging imaging marker in acute ischemic stroke. We aimed to investigate the association of ILT with outcomes of acute large vessel occlusion (LVO) patients receiving endovascular treatment. METHODS: Acute LVO stroke patients who underwent endovascular treatment within 24 hours, in a prospective, nationwide registry were enrolled. Pretreatment digital subtraction angiography was reviewed for the presence of ILT. The primary outcome was 90-day functional dependence (modified Rankin Scale scores, 3-6). Secondary outcomes included 24-hour LVO, 90-day death, and symptomatic intracranial hemorrhage. RESULTS: Among 711 patients enrolled, 75 (10.5%) with ILT were less likely to have 90-day functional dependence compared with those without ILT (adjusted odds ratio, 0.53 [95% CI, 0.31-0.90]; P=0.021). The same trend was found among those with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3; P=0.008) but not in those without successful reperfusion (P=0.107). Presence of ILT was also independently associated with a lower rate of 24-hour LVO (adjusted odds ratio 0.34 [95% CI, 0.13-0.89]; P=0.028). However, those with or without ILT had similar risks of symptomatic intracranial hemorrhage and 90-day death. CONCLUSIONS: Among acute LVO patients receiving endovascular treatment, pretreatment ILT-positive patients may have a better 90-day functional outcome (versus ILT-negative) but similar risk of death and symptomatic intracranial hemorrhage. The possibly favorable effect of ILT patients remained in those with successful reperfusion. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

The change index of quantitative electroencephalography for evaluating the prognosis of large hemispheric infarction.

A growing number of studies have demonstrated the role of quantitative electroencephalography in assessing brain function in neuro-intensive care units. Still, few studies have examined patients with large hemisphere infarction. Thirty patients with large hemisphere infarction were included in this preliminary study, and the patients were divided into the death group (twelve patients) and survival group (eighteen patients). Electroencephalography monitored the patients, and a computerized tomography inspection was performed. The quantitative electroencephalography of the alpha-beta/delta-theta ratio change index was calculated and used to predict the prognosis of early large hemisphere infarction patients. The relationship between three months modified Rankin Scale, and alpha-beta/delta-theta ratio change index was analyzed. The death group had negative changes for alpha-beta/delta-theta ratio change index (-0.0140 ± 0.0193), while there was an opposite trend in the survival group, the median is 0.004 (-0.0067, 0.0137). The death group's brain function decreased more severely and rapidly than the survival group (P = 0.004). The highest diagnostic value (AUC value 0.815, P < 0.001) was observed when the alpha-beta/delta-theta ratio change index dropped and exceeded -0.008. The area under the GCS curve was 0.674, but its predictive ability was low (P = 0.094). The correlation analysis result showed that the 3-month modified Rankin Scale was negatively correlated with the alpha-beta/delta-theta ratio change index (r = -0.489, P = 0.006). The alpha-beta/delta-theta ratio change index is considered an indicator for predicting the prognosis of large hemisphere infarction. Therefore, the alpha-beta/delta-theta ratio change index may be a reliable quantitative EEG parameter that predicts the early prognosis of patients with acute large hemispheric infarction.

Cortical Microinfarcts Associated With Worse Outcomes in Patients With Acute Ischemic Stroke Receiving Endovascular Treatment.

BACKGROUND AND PURPOSE: We aimed to evaluate the impact of cortical microinfarcts (CMIs) on functional outcome after endovascular treatment in patients with acute ischemic stroke. METHODS: In a multicenter registration study for RESCUE-RE (a registration study for Critical Care of Acute Ischemic Stroke After Recanalization), eligible patients with large vessel occlusion stroke receiving endovascular treatment, who had undergone 3T magnetic resonance imaging on admission or within 24 hours after endovascular treatment were analyzed. We evaluated the presence and numbers of CMIs with assessment of axial T1, T2-weighted images, and fluid-attenuated inversion recovery images. The primary outcome was functional dependence or death defined as modified Rankin Scale scores of 3 to 6 at 90 days. Secondary outcomes included early neurological improvement, any intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality. We investigated the independent associations of CMIs with the outcomes using multivariable logistic regression in overall patients and in subgroups. RESULTS: Among 414 patients (enrolled from July 2018 to May 2019) included in the analyses, 96 (23.2%) patients had at least one CMI (maximum 6). Patients with CMI(s) were more likely to be functionally dependent or dead at 90 days, compared with those without (55.2% versus 37.4%; P<0.01). In multivariable logistic regression analyses, presence of CMI(s) (adjusted odds ratio, 1.78 [95% CI, 1.04-3.07]; P=0.04) and multiple CMIs (CMIs ≥2; adjusted odds ratio, 7.41 [95% CI, 2.48-22.17]; P<0.001) were independently, significantly associated with the primary outcome. There was no significant difference between subgroups in the associations between CMI presence and the primary outcome. CONCLUSIONS: Acute large vessel occlusion stroke patients receiving endovascular treatment with CMI(s) were more likely to have a poor functional outcome at 90 days, independent of patients' characteristics. Such associations may be dose-dependent. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

Multiplicity issues for platform trials with a shared control arm.

This paper provides in-depth discussion about different types of error generated in platform trials with a common control arm, and how they compare to the ones arisen from standard independent trials. We provide our views on some of the popular "myths" associated with such design, under the frequentist framework. It is found that platform trial generally performs quite well in terms of type I error rate, false discovery rate, and power. In most cases, these operating characteristics of a platform trial are comparable to or even better than running individual trials.

Implementation of a Phase Synchronization Scheme Based on Pulsed Signal at Carrier Frequency for Bistatic SAR.

Phase synchronization is one of the key technical challenges and prerequisites for the bistatic synthetic aperture radar (SAR) system, which can form a single-pass interferometry system to perform topographic mapping. In this paper, an advanced phase synchronization scheme based on a pulsed signal at carrier frequency is proposed for a bistatic SAR system and it is verified by a ground validation system. In the proposed phase synchronization scheme, the pulsed signal at carrier frequency is used for phase synchronization link, and it is exchanged by virtue of a time slot between radar signals. The feasibility of the scheme is proven by theoretical analysis of various factors affecting the performance of phase synchronization, and the reliability of the scheme is verified by the test results of the ground validation system.

Circulating miR-22-5p and miR-122-5p are promising novel biomarkers for diagnosis of acute myocardial infarction.

BACKGROUND/AIMS: This study sought to evaluate the potential of circulating microRNAs (miRNAs) as novel indicators for acute myocardial infarction (AMI). METHODS: Plasma samples were collected from each participant, and total RNA was extracted. Quantitative real-time polymerase chain reaction were used to investigate the expression of circulating miRNAs. We measured circulating levels of six individual miRNAs, which are known to be relevant to AMI, in the plasma samples from 66 AMI patients and 70 non-AMI healthy comparisons. RESULTS: Five small RNAs were specifically expressed in AMI patients, plasma miR-122-5p levels is significantly elevated (p < 0.0001) in AMI patients, while plasma miR-22-5p ( p < 0.05) levels were significantly decreased. In addition, significant correlations between miR-22-5p and miR-122-5p ( R = 0.773), miR-122-5p and creatine kinase isoenzyme (CK-MB; R = 0.6296) were detected. Further, receiver operating characteristic (ROC) analysis indicated that miR-22-5p showed considerable diagnostic efficiency for predicting AMI (area under the curve [AUC] = 0.975). Combining miR-22-5p and miR-122-5p in a panel increased the sensitivity (98.6%) of distinguishing between patients with AMI and healthy comparisons. CONCLUSION: Circulating miR-22-5p and miR-122-5p could be considered promising novel diagnostic biomarkers for AMI.

Circulating miR-26a-1, miR-146a and miR-199a-1 are potential candidate biomarkers for acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) was considered to be one of the major causes of morbidity and mortality worldwide. In order to manage the acute myocardial infarction outbreaks, accurate biomarkers for risk prediction are needed. Circulating microRNAs (miRNAs) may act as diagnostic and prognostic biomarkers for cardiovascular events. METHODS: This study aimed to determine the possibility of circulating miRNAs used as biomarkers for AMI and their dynamic expression levels before and after percutaneous coronary intervention (PCI) in patients. Circulating miR-26a-1, miR-27a, miR-30d, miR-146a, miR-199a-1 and miR-423 were selected and validated in 31 AMI patients and 27 matched controls by quantitative real-time PCR (qPCR). RESULTS: The expression levels of plasma miR-26a-1, miR-146a and miR-199a-1 were significantly increased in AMI patients. Receiver operating characteristic (ROC) analysis indicated that miR-26a-1, miR-146a and miR-199a-1 showed considerable diagnostic efficiency for predicting AMI. Furthermore, we demonstrated that the combination of miR-26a-1, miR-146a and miR-199a-1 facilitated AMI diagnosis. CONCLUSIONS: Our findings suggest that circulating miR-26a-1, miR-146a and miR-199a-1 have the potential to be used as biomarkers for AMI diagnosis.

Power and sample size for dose-finding studies with survival endpoints under model uncertainty.

Multiple comparison procedures combined with modeling techniques (MCP-Mod) (Bretz et al., 2005) is an efficient and robust statistical methodology for the model-based design and analysis of dose-finding studies with an unknown dose-response model. With this approach, multiple comparison methods are used to identify statistically significant contrasts corresponding to a set of candidate dose-response models, and the best model is then used to estimate the target dose. Power and sample size calculations for this methodology require knowledge of the covariance matrix for the estimators of the (placebo-adjusted) mean responses among the dose groups. In this article, we consider survival endpoints and derive an analytic form of the covariance matrix for the estimators of the log hazard ratios as a function of the total number of events in the study. We then use this closed-form expression of the covariance matrix to derive the power and sample size formulas. We discuss practical considerations in the application of these formulas. In addition, we provide an illustration with a motivating example on chronic obstructive pulmonary disease. Finally, we demonstrate through simulation studies that the proposed formulas are accurate enough for practical use.

KCNQ1OT1, HIF1A-AS2 and APOA1-AS are promising novel biomarkers for diagnosis of coronary artery disease.

This study aimed to evaluate the potential of long noncoding RNAs (lncRNAs) as biomarkers for coronary artery disease (CAD). We measured the levels of three atherosclerosis- or cardiac-related lncRNAs in peripheral blood monocyte cells (PBMCs) from 20 CAD patients and 20 non-CAD control participants using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) methods. We found that the levels of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1), hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) and apolipoprotein A-1 antisense RNA (APOA1-AS) were significantly increased in CAD patients (KCNQ1OT1 increased by 2.38-fold, P = 0.00042; HIF1A-AS2 increased by 2.00-fold, P = 0.0001; APOA1-AS increased by 4.52-fold, P = 0.000048). The area under the ROC curve was 0.865 for KCNQ1OT1, 0.852 for HIF1A-AS2, and 0.967 for APOA1-AS. Furthermore, the combination of lncRNAs resulted in a much higher AUC value of 0.990 for the prediction of CAD. Spearman's correlation analysis showed that APOA1-AS was positively correlated with NT-proBNP, CKMB, MYO and HsTnT, whereas HIF1A-AS2 was correlated with NT-proBNP and HsTnT. Hence, the elevation of KCNQ1OT1, HIF1A-AS2 and APOA1-AS predicts CAD and these molecules may be considered as novel biomarkers of CAD.

Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials. METHODS: Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments. RESULTS: The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies. CONCLUSIONS: A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo. TRIAL REGISTRATION: NCT00144339 .

Tiotropium might improve survival in subjects with COPD at high risk of mortality.

BACKGROUND: Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD. METHODS: The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George's Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up. RESULTS: Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75-1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters. CONCLUSIONS: Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients.

Historical feature pattern extraction based network attack situation sensing algorithm.

The situation sequence contains a series of complicated and multivariate random trends, which are very sudden, uncertain, and difficult to recognize and describe its principle by traditional algorithms. To solve the above questions, estimating parameters of super long situation sequence is essential, but very difficult, so this paper proposes a situation prediction method based on historical feature pattern extraction (HFPE). First, HFPE algorithm seeks similar indications from the history situation sequence recorded and weighs the link intensity between occurred indication and subsequent effect. Then it calculates the probability that a certain effect reappears according to the current indication and makes a prediction after weighting. Meanwhile, HFPE method gives an evolution algorithm to derive the prediction deviation from the views of pattern and accuracy. This algorithm can continuously promote the adaptability of HFPE through gradual fine-tuning. The method preserves the rules in sequence at its best, does not need data preprocessing, and can track and adapt to the variation of situation sequence continuously.

Review of yeast culture concerning the interactions between gut microbiota and young ruminant animals.

Microorganisms inhabit the gastrointestinal tract of ruminants and regulate body metabolism by maintaining intestinal health. The state of gastrointestinal health is influenced not only by the macro-level factors of optimal development and the physiological structure integrity but also by the delicate equilibrium between the intestinal flora and immune status at the micro-level. Abrupt weaning in young ruminants causes incomplete development of the intestinal tract resulting in an unstable and unformed microbiota. Abrupt weaning also induced damages to the microecological homeostasis of the intestinal tract, resulting in the intestinal infections and diseases, such as diarrhea. Recently, nutritional and functional yeast culture has been researched to tackle these problems. Herein, we summarized current known interactions between intestinal microorganisms and the body of young ruminants, then we discussed the regulatory effects of using yeast culture as a feed supplement. Yeast culture is a microecological preparation that contains yeast, enriched with yeast metabolites and other nutrient-active components, including ß-glucan, mannan, digestive enzymes, amino acids, minerals, vitamins, and some other unknown growth factors. It stimulates the proliferation of intestinal mucosal epithelial cells and the reproduction of intestinal microorganisms by providing special nutrient substrates to support the intestinal function. Additionally, the ß-glucan and mannan effectively stimulate intestinal mucosal immunity, promote immune response, activate macrophages, and increase acid phosphatase levels, thereby improving the body's resistance to several disease. The incorporation of yeast culture into young ruminants' diet significantly alleviated the damage caused by weaning stress to the gastrointestinal tract which also acts an effective strategy to promote the balance of intestinal flora, development of intestinal tissue, and establishment of mucosal immune system. Our review provides a theoretical basis for the application of yeast culture in the diet of young ruminants.

Immunometabolism and immune response regulate macrophage function in atherosclerosis.

Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in maintaining inflammatory response, promoting plaque development, and facilitating thrombosis. Increasing studies indicate that metabolic reprogramming and immune response mediate macrophage functional changes in all stages of atherosclerosis. In this review article, we explain how metabolic changes in glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid synthesis, fatty acid oxidation, and cholesterol metabolism regulate macrophage function in atherosclerosis. We discuss how immune response to oxidized lipids regulate macrophage function in atherosclerosis. Additionally, we explore how abnormal metabolism leads to macrophage mitochondrial dysfunction in atherosclerosis.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Efficacy of tiotropium in COPD patients with FEV1 ≥ 60% participating in the UPLIFT® trial.

GOLD stage II COPD encompasses patients with FEV1 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV1 <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted from UPLIFT®. Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT® cohort, 1,210 (632 tiotropium, 578 control) had baseline post-bronchodilator FEV1 ≥60% predicted (range 60-78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post-bronchodilator FEV1 decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV1 and FVC improvements for tiotropium versus control were 87-127 mL and 139-186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropium-control) were 2.0-3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of ≥4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 [0.71, 0.96]) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 [0.45, 0.96]). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV1 ≥60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339).