Overview of regulatory frameworks on the national lot release of plasma-derived medicinal products in Korea.

Plasma-derived medicinal products (PDMPs) are essential in the treatment of acute and chronic life-threatening diseases. The Korea Ministry of Food and Drug Safety has conducted a national lot release (NLR) of PDMPs since 2012 based on a summary protocol review system and lot release testing. However, few studies have investigated the performance or characteristics of the NLR framework. Over the past decade, the NLR of PDMPs was approximately 1000 per year, including mainly albumins, immunoglobulins, fibrin sealant kits, and coagulation factors, among others. The NLR system for PDMPs is similar to that for vaccines, except that PDMPs are manufactured using human plasma, which requires strict safety management. This study describes the status of NLR procedures for PDMPs and outlines the regulatory requirements needed to safely manage plasma for fractionation in Korea. This study can aid national control laboratories and marketing authorization holders in developing regulatory systems that assure the availability of safe and effective PDMPs.

Promising Therapeutic Approach in Pancreatic Cancer: Metabolism-Related Genes.

Most pancreatic cancers are pancreatic ductal adenocarcinomas. This is an extremely lethal disease with poor prognosis and almost no treatment choices. Considering the profound role of the pancreas in the human body, malfunction of this organ can significantly affect quality of life. Although multiple metabolic pathways are altered in cancer cells, certain metabolic gene signatures may be critical for immunotherapy. The reprogrammed metabolism of glucose, amino acids, and lipids can nourish the tumor microenvironment (TME). Previous studies have also shown that reprogrammed metabolism influences immune responses. Tumor-infiltrating immune cells in the TME can adapt their metabolism to blunt the immune system, leading to immunosuppression and tumor progression. The identification of metabolism-related genes (MRGs) associated with immune reactions in pancreatic cancer may lead to improved treatments. This review highlights the characteristics of MRGs in pancreatic cancer and suggests that enhanced anti-cancer therapies could be used to overcome resistance to immunotherapy.

Korean clinical practice guidelines for diagnostic and procedural sedation.

Safe and effective sedation depends on various factors, such as the choice of sedatives, sedation techniques used, experience of the sedation provider, degree of sedation-related education and training, equipment and healthcare worker availability, the patient's underlying diseases, and the procedure being performed. The purpose of these evidence-based multidisciplinary clinical practice guidelines is to ensure the safety and efficacy of sedation, thereby contributing to patient safety and ultimately improving public health. These clinical practice guidelines comprise 15 key questions covering various topics related to the following: the sedation providers; medications and equipment available; appropriate patient selection; anesthesiologist referrals for high-risk patients; pre-sedation fasting; comparison of representative drugs used in adult and pediatric patients; respiratory system, cardiovascular system, and sedation depth monitoring during sedation; management of respiratory complications during pediatric sedation; and discharge criteria. The recommendations in these clinical practice guidelines were systematically developed to assist providers and patients in sedation-related decision making for diagnostic and therapeutic examinations or procedures. Depending on the characteristics of primary, secondary, and tertiary care institutions as well as the clinical needs and limitations, sedation providers at each medical institution may choose to apply the recommendations as they are, modify them appropriately, or reject them completely.

Sudden Occurrence of Pacemaker Capture Failure during Irreversible Electroporation Ablation for Prostate Cancer in Post-COVID-19 Patient: A Case Report.

Irreversible electroporation (IRE) ablation is a novel treatment option for localized prostate cancer. Here, we present a case of an abrupt and fatal arrhythmia during the IRE procedure in a prostate cancer patient with an implanted permanent pacemaker. A 78-year-old male patient with a pacemaker due to sick sinus syndrome and syncope was scheduled for IRE prostate ablation surgery under general anesthesia. He had a history of recovering from coronavirus disease 2019 (COVID-19) after having been vaccinated against it and recovered without sequalae. Pacemaker interrogation and reprogramming to asynchronous AOO mode was carried out before surgery, however, sinus pause occurred repeatedly during ablation pulse delivery. After the first sinus pause of 2.25 s there was a decrease in continuous arterial blood pressure (ABP). During the delivery of the second and third pulses, identical sinus pauses were observed due to failure to capture. However, the atrial-paced rhythm recovered instantly, and vital signs became acceptable. Although sinus pause recovered gradually, the duration thereof was increased by the delivery of more IRE pulses, with a subsequent abrupt decrease seen in blood pressure. The pacemaker was urgently reprogrammed to DOO mode, after which there were no further pacing failures and no hemodynamic adverse events. For patients with pacemakers, close cardiac monitoring in addition to the interrogation of the pacemaker during the electromagnetic interference (EMI) procedure is recommended, especially in the case of having a disease that may aggravate cardiac vulnerability, such as COVID-19.

Delayed Adverse Events after Procedural Sedation in Pediatric Patients with Hematologic Malignancies.

Background and objectives: Procedural sedation for bone marrow examination (BME) and intrathecal chemotherapy (ITC) is necessary for pediatric patients with hematological malignancies. There has been no report on adverse events after discharge from the recovery room. This retrospective study evaluated the types and incidences of delayed adverse events among pediatric patients scheduled for BME or ITC under deep sedation in a single center for 3 years. Materials and Methods: The patients were divided into two groups: inpatients (group I) and outpatients (group O). All patients were managed during the procedures and the recovery period. In total, 10 adverse events were assessed; these occurred 2 h (T1, acute), 12 h (T2, early), and 24 h (T3, delayed) after the procedure. The duration of each adverse event was also recorded and was classified as 2 h (D1), 12 h (D2), or 24 h (D3). The data of 263 patients (147 inpatients and 116 outpatients) who met the inclusion criteria were analyzed. Results: The overall incidence of adverse events was statistically significant difference: 48.3% in group I and 33.6% in group O (p = 0.011). The rates of adverse events at T1 and T2 were significantly different between groups I and O (42.8% vs. 11.2% and 7.5% vs. 20.7%, respectively) (p < 0.001). The adverse events were mostly of D1 or D2 duration in both groups. Patients with a higher proportion of ketamine in a propofol−ketamine mixture had a significantly higher proportion of adverse events at T1 (34.6%), as compared with those with a mixture with a lower proportion of ketamine (21.1%) or propofol alone (17.9%) (p = 0.012). Conclusions: The most common adverse events were dizziness or headache; typically, they did not last longer than 12 h. The propofol-ketamine combination with a higher proportion of ketamine seems to produce more adverse events within 2 h after the procedure. Nevertheless, all sedative types appear safe to use without additional management.

Is There a Difference between Perineural Dexamethasone with Single-Shot Interscalene Block (SSIB) and Interscalene Indwelling Catheter Analgesia (IICA) for Early Pain after Arthroscopic Rotator Cuff Repair? A Pilot Study.

Interscalene block is applied to control acute postoperative pain after arthroscopic rotator cuff repair (ARCR), typically with single-shot interscalene block (SSIB) or continuous interscalene indwelling catheter analgesia (IICA), and dexamethasone (Dex) for extending the analgesic effect. This study investigated whether perineural Dex can extend the postoperative analgesic effect of SSIB to match that of IICA. A total of 130 patients were recruited and divided into two groups (Group D, SSIB with perineural Dex, n = 94; Group C, IICA, n = 36). The surgical and anesthetic processes were identical except for the method of nerve block. Pain was measured by a visual analog scale (VAS) at 6, 12, 24, and 48 h after ARCR. The number of each and the total analgesics used and adverse effects were compared. The duration of ARCR was longer in group D. The VAS score was higher in group C 6 h after ARCR, but there was no difference at other time points. More postoperative analgesics were administered to group C, and there was no difference in the number of adverse effects. In conclusion, combining perineural Dex with SSIB can reduce rebound hyperalgesia after 6 h and extend the duration of the analgesic effect to that of IICA. Therefore, IICA could be substituted with SSIB and Dex between at 6 and 48 h after ARCR.

Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial.

OBJECTIVE: Osteoarthritis (OA) patients who undergo staged bilateral total knee arthroplasty (TKA) feel postoperative hyperalgesia in the second operated knee compared with the first knee. Ketamine is an important drug for central temporal summation and inhibition of secondary mechanical hyperalgesia. This study investigated whether central sensitization has a significant effect on hyperalgesia after consecutive operations. METHODS: Seventy-one of 80 OA patients were randomly allocated to the ketamine or saline group. A bolus of ketamine (group K) or saline (group C) (0.5 mg/kg) was injected before induction and at an infusion rate of 3 µg/kg/minute during surgery. A visual analog scale (VAS) was used to assess resting and moving pain and opioid consumption on postoperative days 1, 2, and 3. RESULTS: The difference in the VAS score between stages 1 and 2 (DV2-V1) was higher in the ketamine compared with the saline group. DV2-V1 for movement between the two groups was not inferior for all periods. Ketamine did not show a large analgesic effect on second-operated knee hyperalgesia in staged bilateral TKAs. CONCLUSIONS: We could not confirm that hyperalgesia was only related to central sensitization with low-dose ketamine. Other factors might be also associated with the hyperexcitability of nociceptive stimuli.Clinical Research Information Service (CRIS) trial registry no: KCT0001481.

Analgesic Effect of Low Dose Nefopam Hydrochloride after Arthroscopic Rotator Cuff Repair: A Randomized Controlled Trial.

Arthroscopic rotator cuff repair causes acute postoperative hyperalgesia. Multimodal analgesia is preferable to opioid-based intravenous patient-controlled analgesia (IV-PCA) due to postoperative nausea and vomiting (PONV). We evaluated the effect of nefopam as a postoperative non-opioid analgesic after shoulder surgeries. A total of 180 adult patients were enrolled for arthroscopic rotator cuff repair. They were randomly assigned to nefopam (N) or control (C) groups and each group was reclassified according to the interscalene block (B) into NB, CB and NX, CX. Nefopam was applied at a constant dose intravenously during recovery. Pain scores were measured with a Visual Analogue Scale (VAS) before (T0), immediately after (T1), 30 min (T2) and 12 h (T3), 24 h (T4) and 48 h (T5) after surgery. There was no significant difference in demographic data. The overall VAS scores did not differ with regard to nefopam use, except for the NB group at T4 in intention to treat (ITT) analysis (p < 0.05). PONV occurred more frequently in the N group than in the C group (p < 0.05). Neither individual nor all risk factors were associated with PONV occurrence (p > 0.10). In conclusion, nefopam alone did not show a definite decrease in postoperative pain. It instead increased PONV regardless of risk factors.

CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22.

The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82-RUNX1-Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis.

Interscalene brachial plexus bolus block versus patient-controlled interscalene indwelling catheter analgesia for the first 48 hours after arthroscopic rotator cuff repair.

BACKGROUND: We sought to compare the efficacy of interscalene brachial plexus bolus blockade (IBPBB) and patient-controlled interscalene indwelling catheter analgesia (PCIA) for postoperative pain management within 48 hours postoperatively in patients undergoing arthroscopic rotator cuff repairs (ARCR). METHODS: Patients undergoing ARCR were randomized into 3 groups by postoperative analgesia method. The IBPBB group received a mixed solution of 16 mL of 0.75% ropivacaine and 4 mL of 2% lidocaine as a bolus postoperatively. The PCIA group received a 10-mL bolus solution of 0.75% ropivacaine (4 mL) and 5% dextrose water (6 mL) just after the operation and continuous infusion of this solution. The control received only meperidine as needed, 12.5 mg, intravenously. Visual analog scale (VAS) pain scores were evaluated for the first 48 hours postoperatively. RESULTS: For the first 2 hours postoperatively, VAS scores in the IBPBB group were significantly lower than in the PCIA group and control group, but at 12 and 24 hours postoperatively, VAS scores of the IBPBB group were significantly higher than the PCIA group (P < .05). At 48 hours postoperatively, there was no significant difference in VAS scores among the 3 groups (P = .169). The method of analgesia was the only factor affecting pain scores at 24 hours postoperatively (P < .05). CONCLUSIONS: IBPBB provided effective immediate postoperative analgesia until 6 hours postoperatively. Especially until postoperative 2 hours, the VAS pain score was less than 1 point in the IBPBB group; however, there was significant rebound pain at 12 hours after surgery. During the first 24 hours postoperatively, PCIA reduced postoperative pain without rebound pain. Surgeons should choose methods for control of postoperative pain considering the advantages and disadvantages of each analgesic method.

The effect of humidified heated breathing circuit on core body temperature in perioperative hypothermia during thyroid surgery.

Purpose: During general anesthesia, human body easily reaches a hypothermic state, which is mainly caused by heat redistribution. Most studies suggested that humidified heated breathing circuits (HHBC) have little influence on maintenance of the core temperature during early phase of anesthesia. This study was aimed at examining heat preservation effect with HHBC in case of undergoing surgery with less exposure of surgical fields and short surgical duration. Methods: Patients aged 19 to 70 yr - old, ASA-PS I or II who were scheduled for elective thyroidectomy were assigned and divided to the group using HHBC (G1) and the group using conventional circuit (G2) by random allocation. During operation, core, skin, and room temperatures were measured every 5minutes by specific thermometer. Results: G1 was decreased by a lesser extent than G2 in core temperature, apparently higher at 30 and 60 minutes after induction. Skin and room temperatures showed no differences between the two groups (p>0.05). Consequently, we confirmed HHBC efficiently prevented a decrease in core temperature during early period in small operation which has difficulty in preparing warming devices or environments were not usually considered. Conclusions: This study showed that HHBC influences heat redistribution in early period of operation and can lessen the magnitude of the decrease in core body temperature. Therefore, it can be applied efficiently for other active warming devices in mild hypothermia.

Femoral Nerve Block versus Adductor Canal Block for Analgesia after Total Knee Arthroplasty.

Inadequate pain management after total knee arthroplasty (TKA) impedes recovery, increases the risk of postoperative complications, and results in patient dissatisfaction. Although the preemptive use of multimodal measures is currently considered the principle of pain management after TKA, no gold standard pain management protocol has been established. Peripheral nerve blocks have been used as part of a contemporary multimodal approach to pain control after TKA. Femoral nerve block (FNB) has excellent postoperative analgesia and is now a commonly used analgesic modality for TKA pain control. However, FNB leads to quadriceps muscle weakness, which impairs early mobilization and increases the risk of postoperative falls. In this context, emerging evidence suggests that adductor canal block (ACB) facilitates postoperative rehabilitation compared with FNB because it primarily provides a sensory nerve block with sparing of quadriceps strength. However, whether ACB is more appropriate for contemporary pain management after TKA remains controversial. The objective of this study was to review and summarize recent studies regarding practical issues for ACB and comparisons of analgesic efficacy and functional recovery between ACB and FNB in patients who have undergone TKA.

Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα.

Tuberculosis is a global health problem and at least one-third of the world's population is infected with Mycobacterium tuberculosis (MTB). MTB is a successful pathogen that enhances its own intracellular survival by inhibiting inflammation and arresting phago-lysosomal fusion. We previously demonstrated that Toxoplasma gondii (T. gondii) dense granule antigen (GRA) 7 interacts with TNF receptor-associated factor 6 via Myeloid differentiation primary response gene 88, enabling innate immune responses in macrophages. To extend these studies, we found that GRA7 interacts with host proteins involved in antimicrobial host defense mechanisms as a therapeutic strategy for tuberculosis. Here, we show that protein kinase C (PKC)α-mediated phosphorylation of T. gondii GRA7-I (Ser52) regulates the interaction of GRA7 with PYD domain of apoptosis-associated speck-like protein containing a carboxy-terminal CARD, which is capable of oligomerization and inflammasome activation can lead to antimicrobial defense against MTB. Furthermore, GRA7-III interacted with the PX domain of phospholipase D1, facilitating its enzyme activity, phago-lysosomal maturation, and subsequent antimicrobial activity in a GRA7-III (Ser135) phosphorylation-dependent manner via PKCα. Taken together, these results underscore a previously unrecognized role of GRA7 in modulating antimicrobial host defense mechanism during mycobacterial infection.

Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.

Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS.

The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice.

Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG)-c-Src SH3 peptide, which is a ß-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate-induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox.

Genome-wide identification and functional analysis of genes expressed ubiquitously in rice.

Genes that are expressed ubiquitously throughout all developmental stages are thought to be necessary for basic biological or cellular functions. Therefore, determining their biological roles is a great challenge. We identified 4034 of these genes in rice after studying the results of Agilent 44K and Affymetrix meta-anatomical expression profiles. Among 105 genes that were characterized by loss-of-function analysis, 79 were classified as members of gene families, the majority of which were predominantly expressed. Using T-DNA insertional mutants, we examined 43 genes and found that loss of expression of six genes caused developing seed- or seedling-defective phenotypes. Of these, three are singletons without similar family members and defective phenotypes are expected from mutations. Phylogenomic analyses integrating genome-wide transcriptome data revealed the functional dominance of three ubiquitously expressed family genes. Among them, we investigated the function of Os03g19890, which is involved in ATP generation within the mitochondria during endosperm development. We also created and evaluated functional networks associated with this gene to understand the molecular mechanism. Our study provides a useful strategy for pheonome analysis of ubiquitously expressed genes in rice.

Anesthesia for cesarean section in a patient with respiratory failure -A case report-.

We present successful epidural anesthesia and assisted mechanical ventilation in a parturient woman with respiratory failure. A 41-year-old woman at 35 weeks' of gestation was entering labor. She was pneumonectomized on the left, had bronchiectasis on the remnant lung, and was under assisted mechanical ventilation by continuous positive airway pressure (CPAP) because of severely restricted lung function and superimposed pneumonia. We administered continuous epidural analgesia for vaginal delivery, and extended it for cesarean section after failure of vaginal delivery. During the procedure, her ventilation was continuously assisted by CPAP. The maternal and fetal outcomes were successful.

Proinflammatory and anti-inflammatory cytokine balance in patients with cirrhotic hepatitis during live-donor liver transplant.

OBJECTIVES: The immune system releases cytokines during the stress response, and the balance between proinflammatory and anti-inflammatory cytokines is important. This prospective study was done to determine which cytokines are responsible for maintaining cytokine balance during live-donor liver transplant surgery. MATERIALS AND METHODS: Recipients undergoing live-donor liver transplant surgery due to cirrhotic hepatitis were allocated to a recipient group (n=44), and healthy donors were placed in the donor group (n=45). In donors, blood sampling for cytokine level analysis was performed after anesthetic induction (before the start of surgery, time point 1). In recipients, blood samples were collected before the start of surgery (time point 1), 60 minutes after the start of the anhepatic period (time point 2), and 60 minutes after reperfusion (time point 3). The proinflammatory cytokines measured were interleukin-1 ß, interleukin-6, and tumor necrosis factor-α; the anti-inflammatory cytokines were interleukin-10 and interleukin-4. Cytokines were quantified using sandwich enzyme-linked immunoassays. The time course of proinflammatory and anti-inflammatory cytokine concentrations during surgery in the recipient group was evaluated. RESULTS: Interleukin-6, interleukin-10 and tumor necrosis factor-α showed significant changes in concentration during surgery, with interleukin-6 reaching levels 40 times higher than the preoperative value at the anhepatic stage. Interleukin-10 reached a peak at the neohepatic phase, with values 60 times higher than the preoperative value. The preoperative concentrations of interleukin-6 and interleukin-10 in the recipient group were higher than those in the donor group with a median of 4.48 vs 1.98 pg/mL (P < .001) and 2.98 vs 1.22 (P = .026). CONCLUSIONS: Interleukin-6 and interleukin-10 play a major role in cytokine balance before and during live-donor liver transplant surgery.