Minocycline as an antibiotic has been found to have neuroprotective effect on neurodegenerative diseases. This study was aimed at determining the efficacy of minocycline adjunct to aspirin in improving neurological outcomes of ischemic stroke during 3-month follow-up. In an open-label evaluator-blinded trial, 60 patients with ischemic stroke were allocated into two groups to receive either 200 mg of oral minocycline daily for 5 days during 6-24 h following onset of signs and symptoms, or not receiving any, as control; all patients also received 100 mg of aspirin daily. Clinical assessment at baseline and on days 30, 60, and 90 was performed using National Institutes of Health Stroke Scale (NIHSS) score. Fifty-three patients (88.3%) completed the study. Females in the treatment and control groups were 53.8% and 51.9%, respectively (P = 0.884). Among all patients, NIHSS score was significantly lower in the minocycline-treated compared with control on day 90 (minocycline median 4, interquartile range 4-7, control median 7, interquartile range 5-8, P = 0.031). Among males, NIHSS was lower in minocycline-treated compared with controls on days 30, 60, and 90 (P < 0.05); however, females showed no significant differences at the same times compared with controls. No adverse outcomes including myocardial infarction, recurrent stroke, and mortality were observed in the both groups. Patients with ischemic stroke who received oral minocycline daily for 5 days had significantly better neurological outcomes on day 90 than controls. However, females showed no significant clinical improvement compared to males.

Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)—thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Background: Vitamin D has been shown to have an anticoagulant effect. A decrease in 25-hydroxyvitamin D [25(OH)D] concentration has also been associated with an increased risk of venous thromboembolism. Hence, we sought to determine the relationship between 25(OH)D levels and idiopathic lower-extremity deep vein thrombosis (DVT). Methods: In a case control study, a total of 82 participants with idiopathic lower-extremity DVT were enrolled along with 85 sex- and age-matched healthy participants as controls. The plasma 25(OH)D levels were measured in all the studied samples. Results: The participants' mean age was 47.1±12.3 years. Baseline characteristics were not significantly different between the groups. The concentration of 25(OH)D was significantly lower in the DVT group compared to that of the control group (17.9±10.3 versus 23.1±12.5 ng/mL, P=0.004). The prevalence of participants with deficient 25(OH)D levels was significantly higher in the both DVT and control groups than those with sufficient 25(OH)D levels (68.3% versus 13.4%, and 49.4% versus 28.2%, respectively, P=0.027). In a multivariate analysis, 25(OH)D levels and sex were found to be the only independent predictors of DVT (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, P=0.001 and OR 0.51, 95% CI 0.26–1.00, P=0.049, respectively). Conclusion: Low levels of 25(OH)D are associated with idiopathic lower-extremity DVT. Further investigation is needed to establish determinants and probable causative role of 25(OH)D.

Background: Cerebrolysin, a brain-derived neuropeptide, has been shown to improve the neurological outcomes of stroke, but no study has demonstrated its effect on cerebral blood flow. This study aimed to determine the cerebrolysin impact on the neurological outcomes and cerebral blood flow. Methods: In a randomized, double-blinded, placebo-controlled trial, 46 patients who had acute focal ischemic stroke were randomly assigned into two groups to receive intravenously either 30 mL of cerebrolysin diluted in normal saline daily for 10 days (n=23) or normal saline alone (n=23) adjunct to 100 mg of aspirin daily. All patients were examined using the National Institutes of Health Stroke Scale and transcranial Doppler to measure the mean flow velocity and pulsatility index (PI) of their cerebral arteries at baseline as well as on days 30, 60, and 90. Results: The patients’ mean age was 60±9.7 years, and 51.2% of patients were male. The National Institutes of Health Stroke Scale was significantly lower in the cerebrolysin group compared with the placebo group on day 60 (median 10, interquartile range 9–11, P=0.008) and day 90 (median 11, interquartile range 10–13.5, P=0.001). The median of PI in the right middle cerebral artery was significantly lower in the cerebrolysin group compared with the placebo group on days 30, 60, and 90 (P<0.05). One patient in the cerebrolysin group and two patients in the placebo group died before day 30 (4.3% versus 8.7%). Conclusion: Cerebrolysin can be useful to improve the neurological outcomes and the PI of middle cerebral artery in patients with acute focal ischemic stroke.