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Background Administration of dexmedetomidine has been reported to improve inflammatory response in animals. We explored the effects of administering dexmedetomidine on the levels of C-reactive protein (CRP) and procalcitonin, and thus on inflammation, in patients with sepsis enrolled in a randomized clinical trial. Methods The DESIRE trial was a multicenter randomized clinical trial in which adult patients with sepsis were sedated with (DEX group) or without (non-DEX group) dexmedetomidine while on mechanical ventilators. As a prespecified sub-analysis, we compared CRP and procalcitonin levels during the first 14 days of treatment between the two groups. The 14-day mortality rate, albumin level, and the number of patients with disseminated intravascular coagulation (DIC) were also assessed. We used generalized linear models to estimate the differences in these outcomes between groups. We also used the Kaplan-Meier method to estimate the 14-day mortality rate and the log-rank test to assess between-group differences. Results Our study comprised 201 patients: 100 in the DEX group and 101 in the non-DEX group. CRP and procalcitonin levels were lower in the DEX vs. non-DEX group during the 14-day treatment period [CRP—range, 5.6–20.3 vs. 8.3–21.1 mg/dL ( P  = 0.03); procalcitonin—range, 1.2–37.4 vs. 1.7–52.9 ng/mL ( P  = 0.04)]. Albumin levels were higher in the DEX group (range, 2.3–2.6 g/dL) than in the non-DEX group (range, 2.1–2.7 g/dL; P  = 0.01). The percentage of patients with DIC did not significantly differ between the groups (range, 21–59% and 17–56% for the DEX and non-DEX groups, respectively; P  = 0.49). The 14-day mortality rates in the DEX and non-DEX groups were 13 and 21%, respectively ( P  = 0.16). Conclusion Sedation using dexmedetomidine reduced inflammation in patients with sepsis requiring mechanical ventilation. Trial registration ClinicalTrials.gov, NCT01760967 . Registered on 4 January 2013.

Inspired by the natural spinning process, we developed an aqueous wet spinning system using a citrate buffer with polyethylene glycol (PEG), where the citrate buffer served for ion exchange and acidification and the PEG functioned for dehydration. This biomimetic condition induced the formation of solid fibers with a core–shell structure. The PEG layer could be subsequently removed by the equipped water bath, resulting in amorphous silk fibers. Due to the amorphous state, the silk fibers could be stretched at up to 12 times the original reel speed. Eventually, the mechanical properties featured an extraordinary extension of ~100% and a toughness of ~70 MJ/m3. The crystalline state of the resultant fibers was characterized by synchrotron WAXS to determine the degree of crystallinity and orientation of the beta-sheet structure. Interestingly, the citrate buffer-mediated spinning system enabled tuning of the induction of crystallization by changing the citrate buffer concentrations and coagulation time. The current amorphous spinning of regenerated silk fibers provided in-depth insights into the green and sustainable fabrication of artificial capture-silk-like fibers with unique extensibility and toughness.Inspired by the natural spinning process, we developed an aqueous spinning system with a citrate/polyethylene glycol buffer for highly extensible silk fibers. This system enabled tuning of the induction of crystallization through the buffer conditions.

Glucocorticoids are widely used for a variety of diseases, but the prevention of glucocorticoid-induced osteoporosis is sometimes neglected. Therefore, the effectiveness of a computerized clinical decision support system (CDSS) to improve the performance rate of preventive care for glucocorticoid-induced osteoporosis was evaluated. We conducted a prospective cohort study of outpatients who used glucocorticoids for three months or longer and who met the indication for preventive care based on a guideline. The CDSS recommended bisphosphonate (BP) prescription and bone mineral density (BMD) testing based on the risk of osteoporosis. The observation period was one year (phase 1: October 2017–September 2018) before implementation and the following one year (phase 2: October 2018–September 2019) after implementation of the CDSS. Potential alerts were collected without displaying them during phase 1, and the alerts were displayed during phase 2. We measured BP prescriptions and BMD testing for long-term prescription of glucocorticoids. A total of 938 patients (phase 1, 457 patients; phase 2, 481 patients) were included, and the baseline characteristics were similar between the phases. The median age was 71 years, and men accounted for 51%. The primary disease for prescription of glucocorticoids was rheumatic disease (28%), followed by hematologic diseases (18%). The prevalence of patients who needed an alert for BP prescription (67% vs. 63%, P = 0.24) and the acceptance rate of BP prescription (16% vs. 19%, P = 0.33) were similar between the phases. The number of patients who had orders for BMD testing was significantly increased (4% vs. 24%, P < 0.001) after CDSS implementation. The number of patients who needed an alert for BMD testing was significantly decreased from 93% in phase 1 to 87% in phase 2 (P = 0.004). In conclusion, the CDSS significantly increased BMD testing in patients with a higher risk of glucocorticoid-induced osteoporosis, but did not increase BP prescription.

Background Dexmedetomidine has been reported to improve organ dysfunction in critically ill patients. In a recent randomized controlled trial (Dexmedetomidine for Sepsis in Intensive Care Unit (ICU) Randomized Evolution [DESIRE]), we demonstrated that dexmedetomidine was associated with reduced mortality risk among patients with severe sepsis. We performed this exploratory sub-analysis to examine the mechanism underlying improved survival in patients sedated with dexmedetomidine. Methods The DESIRE trial compared a sedation strategy with and without dexmedetomidine among 201 mechanically ventilated adult patients with sepsis across eight ICUs in Japan. In the present study, we included 104 patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥ 23 (54 in the dexmedetomidine [DEX] group and 50 in the non-dexmedetomidine [non-DEX] group). Initially, we compared the changes in the sequential organ failure assessment (SOFA) scores from the baseline within 6 days after randomization between groups. Subsequently, we evaluated the variables comprising the organ component of the SOFA score that showed relevant improvement in the initial comparison. Results The mean patient age was 71.0 ± 14.1 years. There was no difference in the median APACHE II score between the two groups (29 [interquartile range (IQR), 25–31] vs. 30 [IQR, 25–33]; p = 0.35). The median SOFA score at the baseline was lower in the DEX group (9 [IQR, 7–11] vs. 11 [IQR, 9–13]; p = 0.01). While the renal SOFA subscore at the baseline was similar for both groups, it significantly decreased in the DEX group on day 4 ( p = 0.02). During the first 6 days, the urinary output was not significantly different ( p = 0.09), but serum creatinine levels were significantly lower ( p = 0.04) in the DEX group. The 28-day and in-hospital mortality rates were significantly lower in the DEX group (22% vs. 42%; p = 0.03, 28% vs. 52%; p = 0.01, respectively). Conclusion A sedation strategy with dexmedetomidine is associated with improved renal function and decrease mortality rates among patients with severe sepsis. Trial registration This trial was registered on ClinicalTrials.gov ( NCT01760967 ) on January 1, 2013.

Introduction The nature of medication errors (MEs) and the frequency of identified or intercepted MEs are not being scrutinized in daily practice in Japan. Objectives The aim of this study was to clarify the epidemiology of MEs and the risk factors for non-intercepted and unidentified MEs. Methods The Japan Adverse Drug Events (JADE) study was a prospective cohort study carried out at three tertiary-care teaching hospitals in Japan. Participants were consecutive patients ( N  = 3459) aged ≥15 years who were admitted to the study wards. MEs were identified by on-site reviews of all medical charts, self-reports, and prescription queries by pharmacists. Two independent physicians reviewed and classified all MEs and adverse drug events and determined the stages at which the MEs occurred and whether there was interception or identification of the MEs. Results A total of 514 MEs were observed among 433 patients. Sixty-four percent of MEs occurred at the ordering stage. Among these, 60 % were due to duplicate drug orders. Overall, 63 % and 45 % of MEs were not intercepted or identified during hospitalization, respectively. The independent risk factors for non-intercepted MEs were hospitalization in the surgical ward (odds ratio [OR] 2.94) and the intensive care unit (OR 3.57). MEs by resident physicians were more likely to be intercepted (OR 0.52 for non-intercepted MEs). Conclusions MEs frequently occurred and most at the ordering stage. Almost half of MEs were not intercepted or identified. Many MEs at the later stages were less likely to be intercepted and resulted in actual patient harm. Systems to improve the identification and interception of MEs should be implemented.

Aim There are few assessments of sedatives during the acute phase under sedation protocols for patients with sepsis. We aimed to compare the influence of different sedation strategies using midazolam and propofol under light sedation on clinical outcomes of ventilated patients with sepsis. Methods This study was a post‐hoc analysis of data from the dexmedetomidine for sepsis in the ICU Randomized Evaluation (DESIRE) trial. Patients were divided into propofol and midazolam groups based on continuously used drug, and sedation control between groups compared on day three. We assessed the incidence of delirium, length of ICU stay, number of ventilator‐free days within the first 28 days, and mortality after 28 days. Results The midazolam and propofol groups consisted of 51 and 66 patients, respectively. Both groups had similar characteristics, except for age and emergency surgery. The number of well‐controlled sedation patients in the propofol group on day three was significantly higher than that in the midazolam group (odds ratio [OR] 3.9, 95% CI [1.30, 11.7]). The incidence of daily coma and delirium within the initial week was different between groups and increased with midazolam administration (P = 0.0138). The number of Confusion Assessment Method for ICU‐positive patients was significantly higher in the midazolam group than in the propofol group (OR 5.71, 95% CI [2.30, 14.2]). Conclusion In patients with sepsis required mechanical ventilation, sedation with midazolam based on a light sedation protocol may be associated with inappropriate sedation during the acute phase, with increased coma and delirium as compared to propofol. The incidence of daily coma and delirium is more increase with the use of midazolam, even with protocols for light sedation management, in septic patients requiring mechanical ventilation.

OBJECTIVESThere have been epidemiological studies of adverse events (AEs) among general patients but those of patients cared by cardiologist are not well scrutinized. We investigated the occurrence of AEs and medical errors (MEs) among adult patients with cardiology in Japan. METHODSWe conducted a cross-sectional study of adult outpatients at a Japanese teaching hospital from February through November 2006. We measured AE and ME incidents from patient report, which were verified by medical records, laboratory data, incident reports, and prescription queries. Two independent physicians reviewed the incidents to determine whether they were AEs or MEs and to assess severity and symptoms. RESULTSWe identified 144 AEs and 30 MEs (16.3 and 3.9 per 100 patients, respectively). Of the 144 AEs, 99 were solely adverse drug events (ADEs), 20 were solely non-ADEs, and the remaining 25 were both causes. The most frequent symptoms of ADEs were skin and allergic reactions due to medication. The most frequent symptoms of non-ADEs were bleeding due to therapeutic interventions. Among AEs, 12% was life threatening. Life-threatening AEs were 25% of non-ADEs and 5% of ADEs (P = 0.0003). Among the 30 MEs, 21MEs (70%) were associated with drugs. CONCLUSIONSAdverse events were common among cardiology patients. Adverse drug events were the most frequent AEs, and non-ADEs were more critical than ADEs. Such data should be recognized among practicing physicians to improve the patientsʼ outcomes.

Background Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. We planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs. Methods/design The GRACE-VAP trial is a multicentre, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical response rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days and adverse events. Patients are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and an anti-MRSA agent is administered. A total sample size of 200 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable patients. Discussion The GRACE-VAP trial is expected to reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotic selection strategy in patients with VAP. Trial registration Clinicaltrials.gov, NCT03506113 . Registered on 29 March 2018. University Hospital Medical Information Network, UMIN000031933. Registered on 26 March 2018.

Aim There are no definitive data to determine whether age influences the effects of dexmedetomidine (DEX) treatment. Thus, we investigated whether older age was associated with more favorable sedative action by DEX in sepsis patients who required mechanical ventilation. Methods This study involved a post‐hoc analysis of data from the Dexmedetomidine for Sepsis in the ICU Randomized Evaluation (DESIRE) trial. The patients were categorized based on median age into elderly and younger groups. The two groups were then compared during the first 7 days after ventilation based on proportion of patients with well‐controlled sedation (Richmond Agitation–Sedation Scale score between −3 and +1), days free from delirium (based on the Confusion Assessment Method for ICU), and days free from coma (Richmond Agitation–Sedation Scale score between −4 and −5). Results One hundred and one patients were assigned to the elderly group and 100 patients were assigned to the younger group. In the elderly group, 50 patients received DEX treatment and 51 patients received non‐DEX treatment, with the DEX arm having significantly better‐controlled sedation (range, 14–52% versus 16–27%; P = 0.01). In the younger group, 50 patients received DEX treatment and 50 patients received non‐DEX treatment, with no significant difference in the proportions of well‐controlled sedation (range, 20–64% versus 24–60%; P = 0.73). There were no significant differences in the numbers of days free from delirium or coma between the groups. Conclusion In elderly sepsis patients who require ventilation, dexmedetomidine could be more effective than other sedative agents for achieving proper sedation. Dexmedetomidine is more effective than other sedative agents for proper sedation in septic elderly patients requiring mechanical ventilation.

Background Use of high-dose norepinephrine is thought to have an immunosuppressive action that increases mortality. This study aimed to evaluate the correlation between norepinephrine dosage and prognosis of patients with septic shock. Methods This study was a nested cohort of the DExmedetomidine for Sepsis in Intensive Care Unit Randomized Evaluation (DESIRE) trial. We evaluated 112 patients with septic shock and an initial Sequential Organ Failure Assessment Cardiovascular (SOFA-C) category score > 2 and initial lactate level > 2 mmol/L. We divided the patients into two groups according to the norepinephrine dosage administered over the initial 7 days: high dose (≥ 416 μg/kg/week) (H group, n  = 56) and low dose (< 416 μg/kg/week) (L group, n  = 56). The primary outcome of interest was 28-day mortality. Secondary outcomes were ventilator-free days, initial 24-h infusion volume, initial 24- to 48-h infusion volume, and the need for renal replacement therapy. For comparisons between the H group and L group, we used the chi-square test or Fisher’s exact test for categorical variables and the t test or Wilcoxon rank sum test for continuous variables. For time-to-event outcomes, Cox proportional hazards models were used. Kaplan-Meier survival curves were created for graphical representation. Results Patient characteristics appeared to be similar between the two groups except for the SOFA-C score and fibrinogen degradation product level. The cumulative incidence of death at 28 days was 29.9% (16 patients) in the L group and 29.7% (15 patients) in the H group ( p  = 0.99). The median number of 28-day ventilator-free days was 20 (0, 25) in the L group and 16 (0, 22) in the H group ( p  < 0.05). Initial infusion volume at 0–24 h in the H group was significantly higher than that in the L group ( p  = 0.004). Infusion volume at 24–48 h in the H group was also significantly higher than that in the L group ( p  = 0.03). Conclusions No statistically significant difference was observed in 28-day mortality between patients with septic shock treated with high-dose norepinephrine compared with those treated with low-dose norepinephrine. However, the number of ventilator-free days in the L group was higher than that in the H group. Trial registration clinicaltrials.gov Identifier: NCT01760967 Date of trial registration: January 4, 2013.