Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Evaluation of stroke thrombectomy including patients where IV thrombolysis is contraindicated or has failed: a randomized trial of two novel thrombectomy devices.

BACKGROUND: Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices - ERIC (a retriever device) and SOFIA (a distal access catheter) - used alone or in combination depending on operator preference. METHODS: Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. RESULTS: Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). CONCLUSIONS: Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

High-viscosity injector-based pink-beam serial crystallography of microcrystals at a synchrotron radiation source.

Since the first successful serial crystallography (SX) experiment at a synchrotron radiation source, the popularity of this approach has continued to grow showing that third-generation synchrotrons can be viable alternatives to scarce X-ray free-electron laser sources. Synchrotron radiation flux may be increased ∼100 times by a moderate increase in the bandwidth ('pink beam' conditions) at some cost to data analysis complexity. Here, we report the first high-viscosity injector-based pink-beam SX experiments. The structures of proteinase K (PK) and A2A adenosine receptor (A2AAR) were determined to resolutions of 1.8 and 4.2 Šusing 4 and 24 consecutive 100 ps X-ray pulse exposures, respectively. Strong PK data were processed using existing Laue approaches, while weaker A2AAR data required an alternative data-processing strategy. This demonstration of the feasibility presents new opportunities for time-resolved experiments with microcrystals to study structural changes in real time at pink-beam synchrotron beamlines worldwide.

Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation.

Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX) is severely limited by the scarcity of X-ray free-electron laser (XFEL) sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX). As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS), are reported. Microcrystals (5-20 µm) of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A2A adenosine receptor (A2AAR), the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP) or a high-molecular-weight poly(ethylene oxide) (PEO; molecular weight 8 000 000) were delivered to the beam using a high-viscosity injector. In-house data-reduction (hit-finding) software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A2AAR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A2AAR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 Šresolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5-20 µm crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the planned APS-U upgrade will increase the intensity by two orders of magnitude. These developments will enable structure determination from smaller and/or weakly diffracting microcrystals.

Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder.

OBJECTIVE: Treatment-resistant depression (TRD) imposes substantial cost from the perspective of employers. The objective of this study was to assess direct healthcare costs and indirect (disability and medical-related absenteeism) costs associated with TRD compared with non-treatment-resistant major depressive disorder (MDD). METHODS: Employees with one or more inpatient, or two or more outpatient/other MDD diagnoses (ICD-9-CM: 296.2x, 296.3x) from 2004 through 2007, ages 18-63 years, were selected from a claims database. Employees who initiated a third antidepressant following two antidepressant treatments of adequate dose and duration or who met published TRD criteria were classified as TRD likely (N = 2312). The index date was the date of the first antidepressant, starting 1/1/2004. The control group was an age- and sex-matched cohort of employees with MDD but without TRD. All had continuous eligibility during the 6-month pre-index (baseline) and 24-month post-index (study) period. McNemar tests were used to compare baseline comorbidities. Wilcoxon signed-rank tests were used to compare costs from employer perspective. RESULTS: TRD-likely employees were on average 48 years old, and 64.8% were women. Compared with MDD controls, TRD-likely employees had significantly higher rates of mental-health disorders, chronic pain, fibromyalgia, and higher Charlson Comorbidity Index. Average direct 2-year costs were significantly higher for TRD-likely employees ($22,784) compared with MDD controls ($11,733), p < 0.0001. Average indirect costs were also higher among TRD-likely employees ($12,765) compared with MDD controls ($6885), p < 0.0001. LIMITATIONS: Limitations of claims data related to accuracy of diagnosis coding and lack of clinical information apply to this study. CONCLUSIONS: Based on comorbidities and healthcare resources used, patients with TRD appeared to represent a clinically complex subgroup of individuals with MDD. TRD was associated with significant cost burden.

Glipizide matrix transdermal systems for diabetes mellitus: preparation, in vitro and preclinical studies.

The aim of the present investigation was to prepare glipizide matrix transdermal systems using the combinations of ethyl cellulose/polyvinylpyrrolidone and Eudragit RL-100/Eudragit RS-100. The systems were evaluated for various in vitro (drug content, drug permeation, scanning electron microscopy and drug-polymer interactions) and in vivo (acute and long-term hypoglycemic activity, biochemical and histopathological studies, skin irritation and pharmacokinetic studies in mice) parameters. Drug content of the patches was found to be more than 98%. Variations in drug permeation profiles were observed among various formulations. The scanning electron microscopy of the patches showed the formation of pores on the surface after in vitro permeation studies. The drug-polymer interaction results suggested no interaction between drug and polymers. The in vivo results revealed that the patches successfully prevented the severe hypoglycemia in the initial hours and they were also effective on chronic application. The transdermal route exhibited negligible skin irritation and produced better improvement with all the tested in vivo parameters compared to oral administration.