The pathophysiology of sepsis is characterized by a systemic inflammatory response to infection; however, the cytokine blockade that targets a specific early inflammatory mediator, such as tumor necrosis factor, has shown disappointing results in clinical trials. During sepsis, excessive endotoxins are internalized into the cytoplasm of immune cells, resulting in dysregulated pyroptotic cell death, which induces the leakage of late mediator alarmins such as HMGB1 and PTX3. As late mediators of lethal sepsis, overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE receptors, thereby amplifying inflammation during early-stage sepsis. In this study, we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide (TMR peptide) derived from the HMGB1/PTX3-receptors interacting motifs. The TMR peptide successfully attenuated HMGB1/PTX3- and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE. Moreover, we developed TMR peptide-conjugated liposomes (TMR-Lipo) to improve the peptide pharmacokinetics. In combination therapy, moderately antibiotic-loaded TMR-Lipo demonstrated a significant therapeutic effect in a mouse model of cecal ligation- and puncture-induced sepsis. The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.

Background: Post-transplant immunosuppression with calcineurin inhibitors (CNIs) is associated with kidney function impairment while mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, can be used for its renal-sparing effects. In this study, we compared the efficacy and safety of everolimus with low dose tacrolimus (EVR+Low TAC) and conventional dose tacrolimus (TAC) in liver transplantation recipients. Methods: Medical records of recipients who received liver transplantation at Seoul National University Bundang Hospital from January 1st 2009 to December 31st 2018 were retrospectively reviewed. Cohort entry date was defined as the day everolimus was initiated and tacrolimus dosage was reduced. All patients were followed up for 1 year. Indicator of efficacy was the incidence of rejection and safety was evaluated by incidence of drug adverse events including renal function. Results: Among 118 patients, there were 40 patients (33.9%) in EVR+Low TAC group. Incidence of rejection, including both biopsy proven acute rejection and clinical rejection, was similar in two groups [7.5% (n=3) vs. 6.4% (n=5), p=1.000]. Renal dysfunction was less frequent in EVR+Low TAC [17.5% (n=7) vs. 35.9% (n=28), p=0.038]. However, incidence rates of dyslipidemia, oral ulcer were more frequent in EVR+Low TAC [45.0% (n=18) vs. 21.8% (n=17), p=0.009; 15.0% (n=6) vs. 1.3% (n=1), p=0.006]. Conclusions In terms of prevention of rejection, EVR+Low TAC was as effective as TAC and had renal-sparing effect but was associated with increased risk of dyslipidemia and oral ulcer. This study demonstrates that EVR+Low TAC could be an alternative to liver transplant recipients with nephrotoxicity after administration of conventional dose tacrolimus.

Background: Post-transplant immunosuppression with calcineurin inhibitors (CNIs) is associated with kidney function impairment while mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, can be used for its renal-sparing effects. In this study, we compared the efficacy and safety of everolimus with low dose tacrolimus (EVR+Low TAC) and conventional dose tacrolimus (TAC) in liver transplantation recipients. Methods: Medical records of recipients who received liver transplantation at Seoul National University Bundang Hospital from January 1st 2009 to December 31st 2018 were retrospectively reviewed. Cohort entry date was defined as the day everolimus was initiated and tacrolimus dosage was reduced. All patients were followed up for 1 year. Indicator of efficacy was the incidence of rejection and safety was evaluated by incidence of drug adverse events including renal function. Results: Among 118 patients, there were 40 patients (33.9%) in EVR+Low TAC group. Incidence of rejection, including both biopsy proven acute rejection and clinical rejection, was similar in two groups [7.5% (n=3) vs. 6.4% (n=5), p=1.000]. Renal dysfunction was less frequent in EVR+Low TAC [17.5% (n=7) vs. 35.9% (n=28), p=0.038]. However, incidence rates of dyslipidemia, oral ulcer were more frequent in EVR+Low TAC [45.0% (n=18) vs. 21.8% (n=17), p=0.009; 15.0% (n=6) vs. 1.3% (n=1), p=0.006]. Conclusions In terms of prevention of rejection, EVR+Low TAC was as effective as TAC and had renal-sparing effect but was associated with increased risk of dyslipidemia and oral ulcer. This study demonstrates that EVR+Low TAC could be an alternative to liver transplant recipients with nephrotoxicity after administration of conventional dose tacrolimus.

Background: Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used in post-transplantation maintenance therapy. The drug has a narrow therapeutic range and requires periodic therapeutic drug monitoring. Although many studies have reported the effects of intrapatient variability of tacrolimus on survival, rejection, and complications in renal transplant recipients, very few studies have reported these effects in liver transplant recipients. The purpose of this study was to evaluate the effect of intrapatient variability of tacrolimus on clinical outcomes after liver transplantation. Methods: Intrapatient variability was calculated using individual, averaged tacrolimus concentrations. Patients were divided into two groups according to their median variability value:high-variability and low-variability groups. The rate of deviation from the therapeutic range, incidence of acute rejection, posttransplant diabetes, incidence of infection, and estimated glomerular filtration rate (eGFR) after transplantation were compared between the groups. Results: Of the total patients (n=82), the high-variability group (n=41) exhibited significantly greater deviation from the therapeutic range (65.92% vs. 56.84%; p<0.001). There was no significant difference in acute rejection or posttransplantation diabetes incidence or eGFR; however, the number of infection in the first 6 months was significantly lower in the low-variability group (0.4 vs. 0.9 times; p=0.039). Multiple linear regression analysis showed that the number of infection significantly increased as intrapatient variability increased (p=0.015). Conclusion High intrapatient variability in tacrolimus concentrations was strongly associated with an increased frequency of deviation from the suggested therapeutic range and an increased number of infection.

Background: Prevention of osteoporosis and bone fracture is one of the important issues for liver transplant recipients because a long history of liver disease and lifelong use of immunosuppressants, including corticosteroids, may cause these diseases. In this study, we aimed to analyze liver recipient bone status, 10-year fracture risk, and medication history. Methods: The electronic medical records of adult patients aged >40 years who received liver transplantation at Seoul National University Bundang Hospital between January 2009 and June 2017 were reviewed retrospectively. On the basis of their bone mineral density and fracture history, their fracture risks were analyzed using the Korean fracture risk assessment tool. Results: A total of 57 liver transplant recipients were treated with corticosteroids during a mean of 8.8 months after transplantation. 30 patients (52.6%) showed bone metabolism dysfunction such as osteopenia or osteoporosis. The 10-year femoral fracture risk was 2.1%, and dual-energy X-ray absorptiometry monitoring was performed, including right before liver transplantation every 27.5±19.2 months. The mean femoral bone mineral density decreased by −7.2%±7.3%. Four patients (7.0%) had a fracture after liver transplantation. Osteoporotic fracture occurred in 3 patients with osteoporosis (25.0%). Among the osteopenia patients with moderate fracture risk who were not treated with bisphosphonate, 1 patient (12.5%) had a history of bone fracture after liver transplantation. Conclusions Considering the deterioration of bone density and moderate fracture risk, medication for osteoporosis should be prescribed to liver transplant recipients with regular monitoring of bone density after transplantation.

Background: Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used in post-transplantation maintenance therapy. The drug has a narrow therapeutic range and requires periodic therapeutic drug monitoring. Although many studies have reported the effects of intrapatient variability of tacrolimus on survival, rejection, and complications in renal transplant recipients, very few studies have reported these effects in liver transplant recipients. The purpose of this study was to evaluate the effect of intrapatient variability of tacrolimus on clinical outcomes after liver transplantation. Methods: Intrapatient variability was calculated using individual, averaged tacrolimus concentrations. Patients were divided into two groups according to their median variability value:high-variability and low-variability groups. The rate of deviation from the therapeutic range, incidence of acute rejection, posttransplant diabetes, incidence of infection, and estimated glomerular filtration rate (eGFR) after transplantation were compared between the groups. Results: Of the total patients (n=82), the high-variability group (n=41) exhibited significantly greater deviation from the therapeutic range (65.92% vs. 56.84%; p<0.001). There was no significant difference in acute rejection or posttransplantation diabetes incidence or eGFR; however, the number of infection in the first 6 months was significantly lower in the low-variability group (0.4 vs. 0.9 times; p=0.039). Multiple linear regression analysis showed that the number of infection significantly increased as intrapatient variability increased (p=0.015). Conclusion High intrapatient variability in tacrolimus concentrations was strongly associated with an increased frequency of deviation from the suggested therapeutic range and an increased number of infection.

Background: Prevention of osteoporosis and bone fracture is one of the important issues for liver transplant recipients because a long history of liver disease and lifelong use of immunosuppressants, including corticosteroids, may cause these diseases. In this study, we aimed to analyze liver recipient bone status, 10-year fracture risk, and medication history. Methods: The electronic medical records of adult patients aged >40 years who received liver transplantation at Seoul National University Bundang Hospital between January 2009 and June 2017 were reviewed retrospectively. On the basis of their bone mineral density and fracture history, their fracture risks were analyzed using the Korean fracture risk assessment tool. Results: A total of 57 liver transplant recipients were treated with corticosteroids during a mean of 8.8 months after transplantation. 30 patients (52.6%) showed bone metabolism dysfunction such as osteopenia or osteoporosis. The 10-year femoral fracture risk was 2.1%, and dual-energy X-ray absorptiometry monitoring was performed, including right before liver transplantation every 27.5±19.2 months. The mean femoral bone mineral density decreased by −7.2%±7.3%. Four patients (7.0%) had a fracture after liver transplantation. Osteoporotic fracture occurred in 3 patients with osteoporosis (25.0%). Among the osteopenia patients with moderate fracture risk who were not treated with bisphosphonate, 1 patient (12.5%) had a history of bone fracture after liver transplantation. Conclusions Considering the deterioration of bone density and moderate fracture risk, medication for osteoporosis should be prescribed to liver transplant recipients with regular monitoring of bone density after transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) patients need parenteral nutrition because of nausea, vomiting, and mucositis caused by conditioning regimens. The demand for glutamine increases during the HSCT period. We evaluated the effects of glutamine-containing parenteral nutrition on the clinical outcomes of HSCT patients. METHODS: In this retrospective analysis, we reviewed HSCT patients from Seoul National University from August 2013 to July 2017. Depending on their glutamine supplementation status, 91 patients were divided into 2 groups: glutamine group (N=44) and non-glutamine group (N=47). We analyzed the rate of weight change, infection (clinically/microbiologically documented), complications (duration of mucositis and neutropenia, acute graft versus host disease), and 100-days mortality in each group. RESULTS: Regarding the clinical characteristics of the patients, there were no significant differences between the 2 groups except that there was a larger proportion of myeloablative conditioning regimen in the glutamine group (P=0.005). In the glutamine group, the average number of days of glutamine use, parenteral nutrition, and mucositis was 7.6±1.4, 14.6±9.9, and 13.3±9.5, respectively. Furthermore, multivariate analysis revealed odds ratios of 0.37 (95% CI, 0.14–0.96; P=0.042) and 0.08 (95% CI, 0.01–0.98; P=0.048) for clinically documented infection and 100-days mortality, respectively, in the glutamine group. CONCLUSION: Results showed that the glutamine group had less clinically documented infection and 100-days mortality than the non-glutamine group, but the other outcomes did not show significant differences. The extended duration of glutamine supplementation according to the period of total parenteral nutrition and mucositis should be considered.
Adult ; Glutamine ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; Humans ; Mortality ; Mucositis ; Multivariate Analysis ; Nausea ; Neutropenia ; Odds Ratio ; Parenteral Nutrition ; Parenteral Nutrition, Total ; Retrospective Studies ; Seoul ; Transplants ; Vomiting

PURPOSE: Enteral nutrition is recommended in critically ill patients. On the other hand, the recommendation of nutritional support is limited and often controversial in critically ill patients in the prone position. Therefore, this study evaluated the clinical outcomes of nutritional support in critically ill patients in the prone position. METHODS: A retrospective evaluation of the electronic medical records was conducted, including adult patients who were in the medical intensive care unit (ICU) in the prone position in Seoul National University Bundang Hospital from May 1, 2015 to June 30, 2017. The patients' characteristics, nutritional support status while they were in the prone position, mortality in ICU and during hospitalization, ICU length of stay, mechanical ventilation days, and complications, such as ventilator associated pneumonia (VAP) and vomiting were collected. RESULTS: In total, 100 patients were included. Of these, 12 received enteral nutrition and parenteral nutrition and 88 received only parenteral nutrition. The groups were similar in terms of age, sex, number of comorbidity, weight, PaO₂/FiO₂, hours of prone position, Simplified Acute Physiology Score II (SAPS II), Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, and Sequential Organ Failure Assessment (SOFA) score. No differences were observed in ICU mortality (75.0% vs. 46.6%; P=0.065), hospital mortality (83.3% vs. 58.0%; P=0.081), ICU length of stay (22.2±14.6 vs. 18.2±21.2; P=0.128) and mechanical ventilation days (19.3±14.8 vs. 14.5±19.1; P=0.098). In addition, there were no differences in the possible complications of the prone position, such as VAP (8.3% vs. 4.5%; P=0.480) and vomiting (8.3% vs. 1.1%; P=0.227). CONCLUSION: No significant differences in the clinical outcomes were observed. Further studies will be needed to confirm the way of nutrition support while in the prone position.
Adult ; Comorbidity ; Critical Illness* ; Electronic Health Records ; Enteral Nutrition ; Hand ; Hospital Mortality ; Hospitalization ; Humans ; Intensive Care Units ; Length of Stay ; Mortality ; Nutritional Support ; Parenteral Nutrition ; Physiology ; Pneumonia, Ventilator-Associated ; Prone Position* ; Respiration, Artificial ; Retrospective Studies ; Seoul ; Vomiting

BACKGROUND: The role of clinical pharmacists in medication therapy to improve clinical and economic outcomes has been reported in the literature. This study was conducted to analyze the changes in details of medication interventions before and after the introduction of clinical pharmacists into the care of neurocritical care unit (NCU) patients, and to evaluate the economic effects of clinical pharmacists by calculating the avoidance cost. METHODS: A retrospective study was conducted reviewing the electronic medical records from June 2013 to May 2014 (before), and from June 2016 to May 2017 (after). We calculated the number and rates of intervention, the acceptance rates of it, and also reviewed the list of interventions. We calculated avoidance cost if there was no intervention. RESULTS: The monthly mean number of interventions increased from 8.0 (±5.7) to 31.7 (±12.8) (P < 0.001) and the frequency of intervention also increased from 0.8% to 1.6% (P=0.003). The most frequently provided pharmacist intervention was nutritional support before introduction of clinical pharmacists and discussions on the medication plan after. The number of classified interventions was 14 before introduction of clinical pharmacist services and 33 after. The calculated cost avoidance associated with a clinical pharmacists' integration was 77,990,615 won per year. CONCLUSION: Introduction of clinicals pharmacist into the NCU was associated with increased intervention rates and expanded types of clinical interventions. The cost avoidance achieved by the pharmacists' interventions can be further explored to evaluate if similar expansions of pharmacists' services achieve similar results in other settings.
Costs and Cost Analysis ; Electronic Health Records ; Humans ; Intensive Care Units ; Medication Reconciliation ; Nutritional Support ; Pharmacists ; Retrospective Studies