We investigated the beneficial effects of midazolam against vascular endothelial growth factor (VEGF)-induced vascular leakage and its molecular mechanism of action in human retinal endothelial cells (HRECs) and the retinas of diabetic mice. Midazolam inhibited VEGF-induced elevation of intracellular Ca, generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABA) receptor antagonist flumazenil but not by the translocator protein antagonist PK11195. Midazolam also prevented VEGF-induced disassembly of adherens junctions and in vitro permeability. Intravitreal injection of midazolam prevented hyperglycemia-induced ROS generation, transglutaminase activation, and subsequent vascular leakage in the retinas of diabetic mice, and those effects were reversed by flumazenil. The roles of flumazenil were further supported by identifying GABA receptors in mouse retinas. Thus, midazolam prevents hyperglycemia-induced vascular leakage by inhibiting VEGF-induced intracellular events in the retinas of diabetic mice.-Lee, Y.-J., Kim, M., Lee, J.-Y., Jung, S.-H., Jeon, H.-Y., Lee, S.-A., Kang, S., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. The benzodiazepine anesthetic midazolam prevents hyperglycemia-induced microvascular leakage in the retinas of diabetic mice.

Background Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice. Aims To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice. Methods Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea’s nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin. Results Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA2DS2-VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54–0.71; 0.60, 0.53–0.69; and 0.71, 0.56–0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51–0.66 and 0.75, 0.60–0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69–1.04), showed a significantly lower MB risk than warfarin. Conclusions Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Background Studies have shown that the concomitant use of a vitamin K antagonist (VKA) and an antiplatelet (APL) drug increased the bleeding risk and was less effective at preventing ischemic events. This study aimed to investigate the control status of international normalized ratio (INR) and the discontinuation rate of a VKA in patients taking VKA plus an APL drug compared with those taking a VKA alone. Methods Data were extracted from the KORean Atrial Fibrillation Investigation II registry, a multicenter noninterventional prospective observational study. Nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥ 1 who newly started (within 3 months) a VKA were enrolled and followed up for 1 year. Results A total of 866 NVAF patients (mean age, 67.7 years; 60.3% men) without a bleeding history were divided into the VKA+APL (n = 229) and VKA alone (n = 637) groups. During follow‐up, mean INR level was lower in the VKA+APL group than in the VKA alone group (1.7 ± 0.8 vs 1.9 ± 0.9, P = 0.0005). INR levels were poorly controlled in both groups (66.1% and 64.7%, respectively). Patients in the VKA+APL group more frequently discontinued VKA than patients in the VKA alone group (28.8% vs 24.2%, P = 0.045). Major causes of VKA discontinuation were uncontrolled INR level and patient dissatisfaction or concerns. Conclusions The conditions of NVAF patients were inadequately controlled with VKA with or without an APL. These findings suggest that other antithrombotic treatment options are warranted in NVAF patients to achieve INR control.

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BackgroundVitamin K antagonist (VKA) to prevent thromboembolism in non-valvular atrial fibrillation (NVAF) patients has limitations such as drug interaction. This study investigated the clinical characteristics of Korean patients treated with VKA for stroke prevention and assessed quality of VKA therapy and treatment satisfaction.MethodsWe conducted a multicenter, prospective, non-interventional study. Patients with CHADS2 ≥ 1 and treated with VKA (started within the last 3 months) were enrolled from April 2013 to March 2014. Demographic and clinical features including risk factors of stroke and VKA treatment information was collected at baseline. Treatment patterns and international normalized ratio (INR) level were evaluated during follow-up. Time in therapeutic range (TTR) > 60% indicated well-controlled INR. Treatment satisfaction on the VKA use was measured by Treatment Satisfaction Questionnaire for Medication (TSQM) after 3 months of follow-up.ResultsA total of 877 patients (age, 67; male, 60%) were enrolled and followed up for one year. More than half of patients (56%) had CHADS2 ≥ 2 and 83.6% had CHA2DS2-VASc ≥ 2. A total of 852 patients had one or more INR measurement during their follow-up period. Among those patients, 25.5% discontinued VKA treatment during follow-up. Of all patients, 626 patients (73%) had poor-controlled INR (TTR < 60%) measure. Patients' treatment satisfaction measured with TSQM was 55.6 in global satisfaction domain.ConclusionINR was poorly controlled in Korean NVAF patients treated with VKA. VKA users also showed low treatment satisfaction.

Osteoporosis is a common problem, especially among postmenopausal women. Postmenopausal women with osteoporosis have major risk factors for osteoporotic fractures. The abuse of epidural steroid injections (ESIs) or the misunderstanding of their proper use could cause osteoporotic fractures. Therefore, we aimed to investigate whether ESIs are associated with osteoporotic fractures in postmenopausal women with low back pain and osteoporosis. Furthermore, we aimed to provide evidence on whether ESIs could be used in postmenopausal women with osteoporosis who are at high risk for osteoporotic fractures. We reviewed the medical records of postmenopausal women with osteoporosis but no fractures. A total of 172 postmenopausal women were divided into 2 groups. Group 1 comprised patients receiving medications and Group 2 comprised patients receiving ESIs. All participants received medications for treating osteoporosis. Each patient's age, bone mineral density, body mass index, medical history, and status with respect to smoking, drinking, physical activity, and exercise were obtained using a questionnaire and medical records. The mean total number of ESIs was 6.2, and the mean cumulative administered dose of glucocorticoids (dexamethasone) was 31 mg. The incidences of fractures in the medication and ESI groups were 22% and 24%, respectively, in the thoracolumbar spine, and 2% and 5%, respectively, in the hip joint. There was no significant difference in the incidences of osteoporotic fractures at the thoraco-lumbar spine and hip joint in postmenopausal women with osteoporosis between those who received ESIs (a mean of 6.2 ESIs, a cumulative dexamethasone dose of 31 mg) and those who did not, with both groups taking anti-osteoporotic medications for low back pain. Our data suggest that ESI treatment using a mean of 6.2 ESIs to deliver a maximum cumulative dexamethasone dose of 31 mg could be safely used in postmenopausal women with osteoporosis, without any significant impact on the their risk for osteoporotic fractures.

Background: The GlideScope® videolaryngoscope (GVL) is widely used in patients with difficult airways and provides a good glottic view. However, the acute angle of the blade can make insertion and advancement of an endotracheal tube (ETT) more difficult than direct laryngoscopy, and the use of a stylet is recommended. This randomized controlled trial compared Parker Flex-It™ stylet (PFS) with GlideRite® rigid stylet (GRS) to facilitate intubation with the GVL in simulated difficult intubations. Methods: Fifty-four patients were randomly allocated to undergo GVL intubation using either GRS (GRS group) or PFS (PFS group). The total intubation time (TIT), 100-mm visual analog scale (VAS) for ease of intubation, success rate at the first attempt, use of laryngeal manipulation, tube advancement rate by assistant, and complications were recorded. Results: There was no significant difference between the GRS and PFS groups regarding TIT (50.3 ± 12.0 s in the GRS group and 57.8 ± 18.8 s in the PFS group, P = 0.108). However, intubation was more difficult in the PFS group than in the GRS group according to VAS score (P = 0.011). Cases in which the ETT was advanced from the stylet by an assistant, were more frequent in the GRS group than in the PFS group (P = 0.002). The overall incidence of possible complications was not significantly different. Conclusions: In patients with a simulated difficult airway, there was no difference in TIT using either the PFS or GRS. However, endotracheal intubation with PFS is more difficult to perform than GRS.

The incidence of osteoporosis and diabetes mellitus (DM) is known to increase with aging. DM is associated with osteoporotic fractures and decreased bone mineral metabolism. However, no studies have compared the effects of DM on the changes in bone mineral density (BMD) and osteoporotic fracture after epidural steroid injections (ESIs). The present study aimed to analyze the relationship between ESI and BMD changes in elderly women with and without DM. The medical records of elderly women who underwent ESI were retrospectively analyzed. All patients had radiographic and BMD assessments performed before and after receiving lumbar ESIs. A total of 172 patients were divided into two groups according to the presence of DM. The duration of BMD monitoring was 16.1 and 16.8 months in the non-DM and DM groups, respectively. The mean total number of ESIs was 3.4 and 3.2, and the mean cumulative administered dose of glucocorticoids (dexamethasone) was 17 and 16 mg in the non-DM and DM groups, respectively. There were no significant differences between baseline and posttreatment BMD in the lumbar spine, total femur, and femoral neck region in either group. The incidence of osteoporotic fractures at the hip joint and thoracolumbar spine was not significantly different in both groups. ESIs could be used without concerns regarding osteoporosis and fractures in elderly women with DM if low doses of glucocorticoids are used.