Self-folding RCA product into a parallel monolayer DNA nanoribbon and woven into a nano-fence structure by a short bridge strand.

The universal programmed construction of patterned periodic self-assembled nanostructures is a technical challenge in DNA origami nanotechnology but has numerous potential applications in biotechnology and biomedicine. In order to circumvent the dilemma that traditional DNA origami requires a long unusual single-stranded virus DNA as the scaffold and hundreds or even thousands of short strands as staples, we report a method for constructing periodically-self-folded rolling circle amplification products (RPs). The repeating unit is designed to have 3 intra-unit duplexes (inDP1,2,3) and 2 between-unit duplexes (buDP1,2). Based on the complementary pairing of bases, RPs each can self-fold into a periodic grid-patterned ribbon (GR) without the help of any auxiliary oligonucleotide staple. Moreover, by using only an oligonucleotide bridge strand, the GRs are connected together into the larger and denser planar nano-fence-shaped product (FP), which substantially reduces the number of DNA components compared with DNA origami and eliminates the obstacles in the practical application of DNA nanostructures. More interestingly, the FP-based DNA framework can be easily functionalized to offer spatial addressability for the precise positioning of nanoparticles and guest proteins with high spatial resolution, providing a new avenue for the future application of DNA assembled framework nanostructures in biology, material science, nanomedicine and computer science that often requires the ordered organization of functional moieties with nanometer-level and even molecular-level precision.

Multidrug-resistant bacterial infection in adult patients following cardiac surgery: clinical characteristics and risk factors.

BACKGROUND: The prevalence of infections with multidrug-resistant organism (MDRO) pose great challenges for anti-infective therapy. Previous research on MDRO infections after cardiac surgery was limited. Therefore, understanding and mastering the clinical characteristics and risk predictors of MDRO infection after cardiac surgery is of great significance for standardized management of perioperative patients. METHODS: The medical records of adult patients with MDRO infection after cardiac surgery from January 2018 to October 2021 were collected, and patients were divided into MDR infection group (n = 176) and non-MDR infection group (n = 233). Univariate and multivariate regression analysis of variables was performed to determine the risk predictors of MDRO infection. RESULTS: The incidence of MDRO infection was 8.6%. Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common, accounting for 37.3%, 23.5% and 18.0%, respectively. The main infection type were lower respiratory tract infection (LTRI = 29.0%). Univariate analysis showed that underwent coronary artery bypass graft (CABG) (P = 0.001) and secondary operation (P = 0.008), pre-infection exposure to vancomycin (P < 0.001) and linezolid (P = 0.002), combination antibiotics (P < 0.001), four antibiotics in combination (P = 0.005), glucocorticoid use (P = 0.029), preoperative hypoalbuminemia (P = 0.003) were risk factors for post-operative MDRO infection. Multivariate regression analysis showed that underwent CABG (OR = 1.228, 95%CI = 1.056∽1.427, P = 0.008), secondary operation (OR = 1.910, 95%CI = 1.131∽3.425, P = 0.015) and pre-infection exposure to linezolid (OR = 3.704, 95%CI = 1.291∽10.629, P = 0.005) were independent risk predictors for MDRO infection. The risk of MDRO infection increased with the length of stay in the ICU (P < 0.001) and the length of stay before diagnosis of infection (P = 0.003), and the difference was statistically significant. Meanwhile, the length of stay after infection (P = 0.005) and the total length of hospital stay (P < 0.001) were significantly longer in the MDRO infection group, and the all-cause mortality was numerically higher in the MDRO infection group (31.3% versus 23.2%). CONCLUSIONS: The morbidity and mortality of MDRO infection was high in adult cardiac surgery, and many risk factors influence the occurrence of MDRO infection. In the future, clinicians should focus on high-risk patients, strengthen multidisciplinary collaboration on infection prevention and control measures, reduce the morbidity and mortality of MDRO infection, and improve the prognosis of in-hospital patients.

Association between coagulation disorder scores and in-hospital mortality in ARF patients: a retrospective analysis from the MIMIC-IV database.

Introduction: Acute respiratory failure (ARF) has a high mortality rate, and currently, there is no convenient risk predictor. The coagulation disorder score was proven to be a promising metric for predicting in-hospital mortality, but its role in ARF patients remains unknown. Methods: In this retrospective study, data were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients diagnosed with ARF and hospitalized for more than 2 days at their first admission were included. The coagulation disorder score was defined based on the sepsis-induced coagulopathy score and was calculated by parameters, namely, additive platelet count (PLT), international normalized ratio (INR), and activated partial thromboplastin time (APTT), based on which the participants were divided into six groups. Results: Overall, 5,284 ARF patients were enrolled. The in-hospital mortality rate was 27.9%. High levels of additive platelet score, INR score, and APTT score were significantly associated with increased mortality in ARF patients (P < 0.001). Binary logistic regression analysis showed that a higher coagulation disorder score was significantly related to the increased risk of in-hospital mortality in ARF patients (Model 2: coagulation disorder score = 6 vs. coagulation disorder score = 0: OR, 95% CI: 7.09, 4.07-12.34, P < 0.001). The AUC of the coagulation disorder score was 0.611 (P < 0.001), which was smaller than that of sequential organ failure assessment (SOFA) (De-long test P = 0.014) and simplified acute physiology score II (SAPS II) (De-long test P < 0.001) but larger than that of additive platelet count (De-long test P < 0.001), INR (De-long test P < 0.001), and APTT (De-long test P < 0.001), respectively. In subgroup analysis, we found that in-hospital mortality was markedly elevated with an increased coagulation disorder score in ARF patients. No significant interactions were observed in most subgroups. Of note, patients who did not administrate oral anticoagulant had a higher risk of in-hospital mortality than those who administrated oral anticoagulant (P for interaction = 0.024). Conclusion: This study found a significant positive association between coagulation disorder scores and in-hospital mortality. The coagulation disorder score was superior to the single indicators (additive platelet count, INR, or APTT) and inferior to SAPS II and SOFA for predicting in-hospital mortality in ARF patients.

Plasma and cerebrospinal fluid population pharmacokinetic modeling and simulation of meropenem after intravenous and intrathecal administration in postoperative neurosurgical patients.

Combined intravenous and local intrathecal administration of meropenem in patients after craniotomy is widely used to treat intracranial infections. However, the optimal dosing regimen of meropenem has not been investigated, posing a risk to treatment efficacy. We aimed to identify significant factors associated with inter-individual variability in cerebrospinal fluid (CSF) pharmacokinetics of meropenem and to evaluate potential intravenous and intrathecal meropenem dosing regimens for the treatment of patients with intracranial infections. After the diagnosis of intracranial infection, 15 patients with an indwelling drain tube received intravenous and intrathecal administration of meropenem. Blood and cerebrospinal fluid (CSF) samples were obtained at the scheduled time to measure meropenem concentration. Plasma and CSF concentration-time data were fit simultaneously using a nonlinear mixed-effects modeling approach. A 3-compartmental model was selected to characterize the in vivo behavior of meropenem. Through population modeling, multiple covariates were tested about their impact on the meropenem pharmacokinetics. Considering CSF outflow via drain tube leading to a drug loss, the drug clearance in CSF (CLCSF) was added to describe this drug loss. The covariate selection indicated that the drainage volume (mL/d) had a significant positive correlation with CLCSF. Bootstrap and visual predictive check suggested a robust and reliable pharmacokinetic model was structured. The established final population model was useful to apply with simulation to identify meropenem dosing regimens for the treatment of patients with intracranial infections. With the goal of CSF concentrations exceeding the minimum inhibitory concentration during the therapy, we created a simple to use dosage regimen table to guide clinicians with drug dosing.

Factors Influencing Norvancomycin Concentration in Plasma and Cerebrospinal Fluid in Patients After Craniotomy and Dosing Guideline: A Population Approach.

PURPOSE: Antibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood-brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing. METHODS: After craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin. Venous blood and CSF specimens were collected at a scheduled time for measuring drug concentrations. Blood and CSF data were fitted simultaneously with the use of the nonlinear fixed-effects modeling method to develop the population pharmacokinetic model. Covariate analysis was applied to select candidate factors associated with pharmacokinetic parameters. A model-based simulation was performed to find optimized regimens for different subgroups of patients. FINDINGS: A 3-compartmental model (central, peripheral, and CSF compartments) with 2 elimination pathways (drug elimination from the kidney and CSF outflow) was developed to characterize the in vivo process of norvancomycin. The covariate analysis identified that weight and drainage amount were strongly associated with the central volume and the drug clearance from CSF, respectively. Goodness-of-fit and model validation suggested that the proposed model was acceptable. A dosage regimen table was created for specific patient populations with different weights and drainage amounts to facilitate clinical application. IMPLICATIONS: We identified 2 clinical markers associated with plasma and CSF concentrations. The proposed simulation may be useful to clinicians for norvancomycin dosing in this specific population with normal kidney function.

Intraventricular administration of tigecycline for the treatment of multidrug-resistant bacterial meningitis after craniotomy: a case report.

BACKGROUND: Intracranial infections, especially multidrug-resistant (MDR) bacterial meningitis, are one of the most severe complications after craniotomy and may greatly impact patient outcomes. CASE PRESENTATION: We report a case of severe MDR Klebsiella pneumonia meningitis after craniotomy that was treated with three different dosages of tigecycline (Pfizer, New York, NY, U.S.A.)via a combined intravenous (IV) and intracerebroventricular (ICV) administration. Here, we discuss the pharmacokinetics (PK) of a combined IV and ICV tigecycline administration for a patient with an intracranial infection after craniotomy. CONCLUSION: In the present case, three different dosages of tigecycline were administered: 49 mg IV plus 1 mg ICV q12 h, 45 mg IV plus 5 mg ICV q12 h, 40 mg IV plus 10 mg ICV q12 h. The combined IV and ICV administration might improve CSF tigecycline concentrations, and in this case, the methods of administration were safe and effective.

The Prophylactic Use of Remifentanil for Delayed Extubation After Elective Intracranial Operations: a Prospective, Randomized, Double-Blinded Trial.

BACKGROUND: Endotracheal extubation is a painful and stressful procedure. The authors hypothesized that the prophylactic use of remifentanil would attenuate the pain intensity and stress responses resulting from extubation in neurosurgical patients. MATERIALS AND METHODS: In this prospective, randomized, double-blinded, controlled trial, 160 patients with planned delay extubation after elective intracranial operation were randomized 1:1 to receive either remifentanil or normal saline (control) before their extubation. The dose regime of remifentanil was a bolus of 0.5 µg/kg over 1 minute, followed by a continuous infusion of 0.05 µg/kg/min for 20 minutes. The primary outcome was the incidence of severe pain during the periextubation period. Secondary outcomes included changes in the pain intensity and vital signs, failing to pass an extubation evaluation after the study drug infusion, severe adverse events, postextubation complications, and clinical outcomes. RESULTS: Two patients in the remifentanil group did not pass the extubation evaluation. The incidence of severe pain during the periextubation period was significantly lower in the remifentanil group compared with the control group (25.0% vs. 41.3%, P=0.029). Compared with the control group, the visual analog scale in the remifentanil group was significantly lower after the bolus of remifentanil (12±18 vs. 25±27, P=0.001) and immediately after extubation (19±25 vs. 34±30, P=0.001). There were no significant differences in the vital signs immediately after extubation between the 2 groups (P>0.05). CONCLUSIONS: The prophylactic use of remifentanil decreases the incidence of severe pain. Our preliminary findings merit a larger trial to clarify the effect of the prophylactic use of remifentanil on clinical outcomes and adverse events.

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients and the Application in Dosing Recommendation.

Our previous study indicates that cerebrospinal fluid (CSF) albumin level is a determinant of CSF vancomycin concentration for postoperative neurosurgical patients. We aimed to develop an improved vancomycin population pharmacokinetic model with incorporation of more covariates, and to provide dosing guidance for clinicians. Vancomycin was administered intravenously to 20 patients with external ventricular drains after neurosurgical operation. Blood and CSF were collected and vancomycin concentrations were measured by HPLC. A separate CSF compartment was considered, and was linked to the central compartment by a first-order process (QCSF). The clearance of the CSF compartment (ClCSF) was used to characterize vancomycin elimination from CSF through external ventricular drain. Nonlinear mixed-effects modeling approach was used to develop the model. The CSF albumin level (mg/dL) was the covariate influencing QCSF: QCSF=0.0049+0.000021×(CSF albumin-279). The effect of body weight (BW, kg) was significant on central volume (VC): VC=27.84+0.96×(BW-69). All parameters were estimated with an acceptable precision (relative standard error: RSE% < 30.26). The performance of the final model was acceptable with our previous dataset. A simple to use dosage regimen table was created to guide clinicians with vancomycin dosing. This model incorporates variables of both CSF albumin and BW, which offers improvements to the previous pharmacokinetics model.

[The value of a tool for evaluation of pain in patients undergone craniotomy].

OBJECTIVE: To determine the optimal cut-off value of critical-care pain observation tool (CPOT) in assessing degree of pain in patients undergone craniotomy, and to determine the sensitivity and specificity of CPOT with this cut-off value. METHODS: A prospective observational study was conducted in Beijing Tiantan Hospital. A total of 118 patients admitted to intensive care unit (ICU) after craniotomy was consecutively enrolled during August 2014 to August 2015. CPOT and visual analogue scale (VAS) were used to assess the pain before, during and 20 minutes after the removal of central venous catheters, and the difference was compared between two scores at three time points. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values for evaluation of the sensitivity and specificity of CPOT. Patients' complaint of pain was considered the "gold-standard". RESULTS: CPOT values (inter-quartile range) before, during and after the procedure were 0 (0-3), 0 (0-6) and 0 (0-2), respectively; while VAS values were 4 (1, 6), 3 (1, 6) and 4 (1, 6), respectively. CPOT value during the procedure was significantly higher than CPOT values before and after the procedure (both P < 0.01). When the optimal cut-off value of CPOT was 1, CPOT showed the highest Youden index before, during and after the procedure (1.183, 1.515, and 1.438, respectively), and showed high specificity (all 100%) and low sensitivity (18.3% and 43.8%, respectively) when assessing the pain before and after the removal of the catheter. The sensitivity and the specificity were high when assessing the pain during the procedure, the sensitivity was 69.4%, and the specificity was 82.1%. When the optimal cut-off value of VAS was 2 before and during the procedure, and was 4 after the procedure, VAS showed the highest Youden index, 1.568, 1.452, and 1.509, respectively. VAS demonstrated high sensitivity and specificity before, during and after the procedure (sensitivity was 97.2%, 95.2% and 75.0%, respectively; specificity was 59.6%, 50.0% and 75.9%, respectively). The area under ROC curve (AUC) of CPOT before, during and after the procedure were 0.592 [95% confidence interval (95%CI) = 0.490-0.693], 0.778 (95%CI = 0.693-0.863) and 0.719 (95%CI = 0.627-0.811), respectively; the AUC of VAS before, during and after the procedure were 0.846 (95%CI = 0.771-0.920), 0.767 (95%CI = 0.681-0.854) and 0.838 (95%CI = 0.767-0.909), respectively. The AUC of VAS before and after the procedure was significantly higher than the AUC of CPOT (P < 0.001 and P = 0.006), while there was no significant difference between the AUC of VAS and CPOT during the procedure (P = 0.826). CONCLUSIONS: CPOT can be used to assess the pain during painful procedure, and it shows high accuracy, but with poor evaluation effect on pain in rest.

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients.

Neurosurgical procedures may damage the blood-brain barrier to allow more vancomycin distribution into the cerebrospinal fluid (CSF) from blood after intravenous administration. However, a large intersubject variability in CSF vancomycin concentration was observed. We aimed to develop a population pharmacokinetic model to guide vancomycin dosing in patients after neurosurgical operation. Blood and CSF samples were collected and determined from postoperative neurosurgical patients after vancomycin administration. A three-compartment (central, peripheral, and CSF) model was proposed to characterize the pharmacokinetics of vancomycin. A nonlinear mixed-effects modeling approach was applied to fit the blood and CSF data simultaneously. The covariate analysis found that the CSF albumin level was strongly associated with the clearance between central and CSF compartment. Visual predictive check indicated that the proposed population pharmacokinetic model agrees well with the observed vancomycin concentrations. Individualized vancomycin dosage regimens could be developed for postoperative neurosurgical patients with different CSF albumin levels through model simulations. The CSF albumin level is a determinant of CSF vancomycin concentration.

Drug concentrations in the serum and cerebrospinal fluid of patients treated with cefoperazone/sulbactam after craniotomy.

BACKGROUND: To identify changes in cefoperazone/sulbactam penetration into cerebrospinal fluid (CSF) after craniotomy and to investigate preliminarily whether cefoperazone/sulbactam CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation. METHODS: Neurosurgical patients with an indwelling ventricular drainage pipe who received prophylactic cefoperazone/sulbactam for the treatment of intracranial infection were received a cefoperazone/sulbactam 2:1, 3.0-g infusion for 3 hours every 6 hours for 24 h. Venous blood and CSF specimens were collected to determine cefoperazone/sulbactam concentrations. RESULTS: The cefoperazone and sulbactam concentrations in serum were highest at the second hour (237.54 ± 336.72 mg/L and 66.52 ± 80.38 mg/L, respectively) and then decreased. The cefoperazone and sulbactam concentrations in CSF were highest at the 4th hour (39.22 ± 75.55 mg/L and 6.24 ± 8.35 mg/L, respectively) and then decreased. CSF penetration measured by the ratio of peak concentrations (CSF/serum) was 8.6% ± 7.2% for cefoperazone and 13.5% ± 11.9% for sulbactam, CSF penetration measured by the ratio of trough concentrations (CSF/serum) was 13.4% ± 5.3% for cefoperazone and 106.5% ± 87.5% for sulbactam. CSF penetration represented by the ratio of area under the curve (AUC) of CSF and serum was 14.5% for cefoperazone and 22.6% for sulbactam. Neurosurgical impairment of the blood-brain barrier may improve the CSF penetration of these drugs, but it is difficult to reach the MIC90 of resistant bacteria. If single intravenous administration time was extended to 3 hours, the serum concentrations of drugs were able to meet the PK/PD standard (T> MIC%> 50%) for treating common, highly resistant bacteria. CONCLUSIONS: The CSF penetration of cefoperazone/sulbactam may be enhanced after neurosurgical impairment of the blood-brain barrier. This study is a pilot research of cefoperazone/sulbactam using in neurosurgical individuals, However, it needs to be confirmed by further large-scale studies.

Short-term use of remifentanil during endotracheal extubation for prophylactic analgesia in neurosurgical patients after craniotomy (SURE after Craniotomy Study): a study protocol and statistical analysis plan for a randomised controlled trial.

INTRODUCTION: Acute pain is common during the endotracheal extubation period, and is related to complications and adverse outcomes. Patients with delayed extubation after craniotomy are vulnerable to pain and complications of extubation. However, pain control during extubation is still inadequate. Remifentanil, a new opioid with rapid onset and short duration of action, provides adequate analgesia during procedures with minimal effect of respiratory depression. METHODS AND ANALYSIS: The study is a prospective, randomised, double-blinded, controlled parallel-group design. Patients with delayed extubation after intracranial surgery are screened daily. Adult patients ready for extubation are enrolled and assigned randomly to one of the two treatment study groups, labelled as the 'Remi group' or 'Saline group'. Patients in the Remi group receive an intravenous bolus dose of remifentanil 0.5 µg/kg over 60 s followed by a continuous infusion 0.05 µg/kg/min for 20 min. Patients in the Saline group receive an intravenous infusion of 0.9% sodium chloride at a volume and rate equal to that of remifentanil. Pain intensity is measured by the visual analogue scale (VAS) pain score. Adverse events during drug infusion are documented and reported. Patients will be followed up until hospital discharge, death or 60 days after the trial intervention on a first come, first served basis. Details of the incidence of reintubation and reoperation within 72 h after extubation, length of stay in the intensive care unit and hospital and mortality are collected. The primary end point is the incidence of severe pain (defined as a VAS pain score more than 5 cm) during the periextubation period (defined as the period of time from immediately before extubation to 20 min after extubation). ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board (IRB) of the Beijing Tiantan Hospital, Capital Medical University. The study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials (NCT): ChiCTR-PRC-13003879.

A Retrospective Study on the Incidence of Seizures among Neurosurgical Patients Who Treated with Imipenem/Cilastatin or Meropenem.

OBJECTIVE: We sought to evaluate the safety of imipenem and meropenem in the treatment of infections in neurosurgical patients. METHODS: An observational retrospective study was conducted of consecutive cases treated with imipenem from Sept. 2007 to Sept. 2009 and meropenem within 1 year from Sept. 2008 in Beijing Tiantan Hospital, China. Data including the dosage and duration of the drug use, occurrence of seizures and mortality outcome was collected from the electronic pharmacy records. The incidence of epilepsy, epileptic standardized morbidity rate (SMR) were reported. Attention was paid to the relationship between the use of imipenem/meropenem and the incidence of epilepsy. RESULTS: The imipenem patients within two years amounted to 71, with mean age 45.9±20.2 years, male to female ratio 46/25. The incidence of epilepsy was 11.3% (8 cases). Among them, 1 case occurred during treatment (1/633, 1.6/1000 patient-days), and the remaining 7 cases occurred before treatment (7/2819, 2.5/1000 patient-days), with the standardized incidence rate 0.64, 95% CI (0.08-5.18).The meropenem patients within one year amounted to 92, mean age 45.1±19.4 years, male to female ratio 51/41. The incidence of epilepsy was 6.5% (6 cases). 2 occurred during treatment (2/582, 2.0/1000 patients-hospital days) and 4 before treatment (4/2047, 3.4/1000 patients-inpatient days), standardized incidence rate 1.76, 95% CI (0.32-9.63). CONCLUSION: Despite many other epileptogenic factors, imipenem or meropenem did not increase the risk of seizures in neurosurgical patients. There was not further risk for patients with pre-existing seizures or creatinine clearance abnormalities when dosed appropriate.