BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

BACKGROUND AND PURPOSE: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA). EXPERIMENTAL APPROACH: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq. KEY RESULTS: TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 µM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE2) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways. CONCLUSION AND IMPLICATIONS: This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.

Novel molecule BBC0901 inhibits BRD4 and acts as a catabolic regulator in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is induced by matrix degradation and inflammation mediated by bromo-domain-containing protein 4 (BRD4)-dependent catabolic factors. BRD4 acts as both a transcriptional regulator and an epigenetic reader. BBC0901 was identified as an inhibitor of BRD4 using a DNA-encoded library screening system. We aimed to demonstrate the effects of BBC0901 on OA pathogenesis by in vitro, ex vivo, and in vivo analyses. BBC0901 inhibited the expression of catabolic factors that degrade cartilage without significantly affecting the viability of mouse articular chondrocytes. Additionally, ex vivo experiments under conditions mimicking OA showed that BBC0901 suppressed extracellular matrix degradation. RNA sequencing analysis of gene expression patterns showed that BBC0901 inhibited the expression of catabolic factors, such as matrix metalloproteinases (MMPs) and cyclooxygenase (COX)2, along with reactive oxygen species (ROS) production. Furthermore, intra-articular (IA) injection of BBC0901 into the knee joint blocked osteoarthritic cartilage destruction by inhibition of MMP3, MMP13, COX2, interleukin (IL)6, and ROS production, thereby obstructing the nuclear factor kappa-light-chain-enhancer of activated B cell and mitogen activated protein kinase signaling. In conclusion, BBC0901-mediated BRD4 inhibition prevented OA development by attenuating catabolic signaling and hence, can be considered a promising IA therapeutic for OA.

Mesencephalic astrocyte-derived neurotrophic factor promotes axonal regeneration and the motor function recovery after sciatic nerve injury.

Peripheral nerve injuries have common clinical problems that are often accompanied by sensory and motor dysfunction and failure of axonal regeneration. Although various therapeutic approaches have been attempted, full functional recovery and axonal regeneration are rarely achieved in patients. In this study, we investigated the effects of recombinant adeno-associated virus (AAV) of mesencephalic astrocyte-derived neurotrophic factor (AAV-MANF) or placental growth factor (AAV-PlGF) transduced into mesenchymal stem cells (hMSC-MANF and hMSC-PlGF), which were then transplanted using human decellularized nerves (HDN) into sciatic nerve injury model. Our results showed that both AAV-MANF and AAV-PlGF were expressed in MSCs transplanted into the injury site. Behavioral measurements performed 2, 4, 6, 8, and 12 weeks after injury indicated that MANF facilitated the rapid and improved recovery of sensory and motor functions than PlGF. In addition, immunohistochemical analysis was used to quantitatively analyze the myelination of neurofilaments, Schwann cells, and regrowth axons. Both hMSC-MANF and hMSC-PlGF increased axon numbers and immunoreactive areas of axons and Schwann cells compared with the hMSC-GFP group. However, hMSC-MANF significantly improved the thickness of axons and Schwann cells compared with hMSC-PlGF. G-ratio analysis also showed a marked increase in axon myelination in axons thicker than 2.0 µm treated with MANF than that treated with PlGF. Our study suggests that transplantation of hMSC transduced with AAV-MANF has a potential to provide a novel and efficient strategy for promoting functional recovery and axonal regeneration in peripheral nerve injury.

Association of Blood Pressure With Cardio-Renal Events and Mortality in Type 2 DM: A National Health Insurance Database.

CONTEXT: The relationship of blood pressure (BP) with cardio-renal events and all-cause mortality in type 2 diabetes mellitus (T2DM) is still controversial. OBJECTIVE: To investigate the optimal BP target in Korean individuals with T2DM. METHODS: Using the Korean National Health Insurance System database, data of individuals with T2DM who underwent regular health checks from January 1, 2007, to December 31, 2007, were extracted (N = 1 800 073). Among them, a total of 326 593 individuals were included in the final study. The study population was divided into 7 groups according to their observed systolic blood pressure (SBP) (<110, 110-119, 120-129, 130-139, 140-149, 150-159, 160-169, and ≥170 mmHg) and diastolic blood pressure (DBP) (<65, 65-69, 70-74, 75-79, 80-84, 85-89, and ≥90 mmHg). Hazard ratios (HRs) of cardio-renal events and all-cause mortality according to BP categories were analyzed. RESULTS: Compared with SBP of 120-129 mmHg and DBP of 75-79 mmHg, SBP of ≥130 mmHg and DBP of ≥ 80 mmHg were associated with an increase in HR of major cardiovascular adverse events (MACEs). SBP of 120-129 mmHg and DBP 75-79 mmHg were associated with the lowest HR of all-cause mortality. Both lower BP (SBP/DBP <120/70 mm) and higher BP (SBP/DBP ≥130/80 mmHg) were associated with an increased HR of all-cause mortality. Contrary to MACE, the lower the SBP, the lower the HR of renal events. CONCLUSION: In patients with T2DM, the optimal cutoff value of BP associated with a lower incidence of MACE and mortality may be 120-129 mmHg for SBP and 75-79 mmHg for DBP. However, lower SBP may be helpful for T2DM patients with a high risk of renal disease.

Schisandra extract ameliorates arthritis pathogenesis by suppressing the NF-κB and MAPK signalling pathways.

Schisandra chinensis is a medicinal plant used to treat various diseases. Extracts from the leaves or fruits of S. chinensis and their components are used in osteoarthritis (OA). The OA inhibitory effect of schisandrol A, one of its components, has been previously confirmed. We aimed to confirm the OA inhibitory effect of Schisandra (including components like schisandrol A) to identify why the inhibitory effect of the Schisandra extract is better. First, we investigated the effects of the Schisandra extract on OA as a potential therapeutic. Experimental OA was induced in a mouse model via destabilized medial meniscus surgery. The animals were orally administered the Schisandra extract; the inhibition of cartilage destruction was confirmed using histological analysis. In vitro analysis showed that the Schisandra extract attenuated osteoarthritic cartilage destruction by regulating IL-1ß-induced MMP3 and COX-2 levels. The Schisandra extract inhibited IL-1ß-induced degradation of IκB (NF-κB pathway) and IL-1ß-induced phosphorylation of p38 and JNK (mitogen-activated protein kinase (MAPK) pathway). RNA-sequencing analysis showed that the Schisandra extract decreased the expression of IL-1ß-induced MAPK and NF-κB signalling pathway-related genes more than schisandrol A alone. Therefore, Schisandra extract may be more effective than schisandrol A in preventing OA progression by regulating MAPK and NF-κB signalling.

Blockade of Activin Receptor IIB Protects Arthritis Pathogenesis by Non-Amplification of Activin A-ACVR2B-NOX4 Axis Pathway.

Although activin receptor IIB (ACVR2B) is emerging as a novel pathogenic receptor, its ligand and assembled components (or assembly) are totally unknown in the context of osteoarthritis (OA) pathogenesis. The present results suggest that upregulation of ACVR2B and its assembly could affect osteoarthritic cartilage destruction. It is shown that the ACVR2B ligand, activin A, regulates catabolic factor expression through ACVR2B in OA development. Activin A Tg mice (Col2a1-Inhba) exhibit enhanced cartilage destruction, whereas heterozygous activin A KO mice (Inhba+/- ) show protection from cartilage destruction. In silico analysis suggests that the Activin A-ACVR2B axis is involved in Nox4-dependent ROS production. Activin A Tg:Nox4 KO (Col2a1-Inhba:Nox4-/- ) mice show inhibition of experimental OA pathogenesis. NOX4 directly binds to the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction through SMAD2/3 signaling. Together, the findings reveal that the ACVR2B assembly, which comprises Activin A, ACVR2B, ACVR1B, Nox4, and AP-1-induced HIF-2α, accelerates OA development. Furthermore, it is shown that shRNA-mediated ACVR2B knockdown or trapping ligands of ACVR2B abrogate OA development by competitively disrupting the ACVR2B-Activin A interaction. These results suggest that the ACVR2B assembly is required to amplify osteoarthritic cartilage destruction and could be a potential therapeutic target in efforts to treat OA.

Molecular and microscopic identification of Eomarteilia granula infection in Manila clam Ruditapes philippinarum off the south coast of Korea.

A report on the new species Eomarteilia (=Marteilia) granula infecting Manila clam Ruditapes philippinarum from Japan in 2014 suggests the possibility of E. granula infecting other Manila clam populations in the Northwest Pacific region, including Korea. In this study, we report the first infections by E. granula in Manila clams off the south coast of Korea. Histology revealed Marteilia-like plasmodia in the digestive tubule epithelia. Tissue imprints demonstrated that each parasite sporangium enclosed 4 spores and transmission electron microscopy (TEM) revealed ultrastructure of primary cells enclosing secondary cells, which contained spores. Mature spores consisted of 3 sporoplasms: outermost, intermediate, and innermost. The outermost sporoplasm showed a peripheral electron-dense monolayer characteristic of E. granula. The 18S rDNA amplified from the Marteilia-like parasite yielded 1784-bp PCR amplicon sequences which were 99.8% similar to that of E. granula previously reported (as M. granula) from Japan. In the molecular phylogenetic analysis, the novel Marteilia-like organism formed a well-supported clade with E. granula. Accordingly, we concluded that the novel Marteilia-like parasite that we found infecting some Korean Manila clams is Eomarteilia granula. Field surveys revealed that the infection was limited to clams of the south coast of Korea, with the prevalence ranging from 3.3 to 5.0%.

Dominance of the scleractinian coral Alveopora japonica in the barren subtidal hard bottom of high-latitude Jeju Island off the south coast of Korea assessed by high-resolution underwater images.

Coastal benthic communities in temperate regions have been influenced by climate change, including increasing sea-surface temperature. Nevertheless, scleractinian coral Alveopora japonica Eguchi, 1968, is thriving in shallow subtidal hard bottoms around Jeju Island, off the southern coast of Korea. The presence of this corals has negatively impacted subtidal kelp populations in Jeju Island. However, there is no study to document how the presence or absence of this coral relates to other benthic communities. This study investigated the benthos in three shallow subtidal sites (Shinheung (SH), Bukchon (BC), and Seongsan (SS)) in northern Jeju using underwater photography. Macro-benthic organisms appearing on a 1 × 20 m line transect installed at depths of 5, 10, and 15 m at each site were analyzed. Results showed that of the three sites investigated, A. japonica colonies were most abundant at BC, accounting for 45.9% and 72.8% of the total transect area at 10 m and 15 m, respectively. At SS, A. japonica occupied 15.3% of the total area at 15 m and less than 1% at 5 m and 10 m. The same at SH accounted for 10% of the total area at 5 m, and less than 1% at 10 m and 15 m. Dead and bleached colonies accounted for 1.2-11.5% and 1.8-5.7%, respectively, at 5, 10, and 15 m at three sites. At SS, canopy-forming brown algae Ecklonia cava and Sargassum spp. accounted for 20.2 and 24.3% of the total transect area, respectively, at 5 m depth. In contrast, the percent cover of E. cava and Sargassum spp. at SH and BC ranged from 0.1 to 1.8%, respectively. Moreover, non-geniculate coralline algae dominated the subtidal substrate at SH, ranging between 60.2 and 69% at 15 and 10 m. The low cover of A. japonica in SS (at 5 m) coincided with a high percent cover of canopy-forming brown algae. However, canopy-forming brown algae were rare at all depths at SH and BC and were dominated instead by coralline algae and the scleractinian corals. This study, by utilizing a non-destructive method, provides a baseline qualitative and quantitative information for understanding the site and depth-dependent distribution of A. japonica and algal populations, which is important to understand climate change related changes in benthic communities in Jeju and elsewhere.

Induction of Nanog in neural progenitor cells for adaptive regeneration of ischemic brain.

NANOG plays a key role in cellular plasticity and the acquisition of the stem cell state during reprogramming, but its role in the regenerative process remains unclear. Here, we show that the induction of NANOG in neuronal cells is necessary for the physiological initiation of neuronal regeneration in response to ischemic stress. Specifically, we found that NANOG was preferentially expressed in undifferentiated neuronal cells, and forced expression of Nanog in neural progenitor cells (NPCs) promoted their self-renewing expansion both in ex-vivo slice cultures and in vitro limiting dilution analysis. Notably, the upstream region of the Nanog gene contains sequence motifs for hypoxia-inducible factor-1 alpha (HIF-1α). Therefore, cerebral neurons exposed to hypoxia significantly upregulated NANOG expression selectively in primitive (CD133+) cells, but not in mature cells, leading to the expansion of NPCs. Notably, up to 80% of the neuronal expansion induced by hypoxia was attributed to NANOG-expressing neuronal cells, whereas knockdown during hypoxia abolished this expansion and was accompanied by the downregulation of other pluripotency-related genes. Moreover, the number of NANOG-expressing neuronal cells were transiently increased in response to ischemic insult, predominantly in the infarct area of brain regions undergoing neurogenesis, but not in non-neurogenic loci. Together, these findings reveal a functional effect of NANOG-induction for the initiation of adaptive neuronal regeneration among heterogeneous NPC subsets, pointing to cellular plasticity as a potential link between regeneration and reprogramming processes.

A Novel Propofol Dosing Regimen for Pediatric Sedation during Radiologic Tests.

The dose of propofol for pediatric sedation during radiologic tests has been proposed as an equation of 0.75 + 0.14 × age (months) + 45.82 × body surface area (m2) based on results in a previous study. We compared this equation and the conventional dosing strategy for sedation in children undergoing radiologic tests. An amount of 180 children scheduled for magnetic resonance imaging (MRI) were randomized to experimental and control groups. The initial induction dose of propofol calculated using the equation was administered in the experimental group. In the control group, children received 1 mg/kg of the initial induction dose of propofol. Then, 0.5 mg/kg of the additional dose was followed to induce sedation in both groups. When awake or moving, a rescue injection of 0.5 mg/kg propofol was given. The total induction dose was more significant in the experimental group. The number of injections for induction in the experimental group was lesser. The dose and number of rescue injections in the experimental group were significantly less. The equation for the induction dose of propofol in a previous study could achieve quick induction of sedation and prevent a rescue injection during sedation. However, caution is needed when using the equation.

Risk of malignancy in kidney transplant recipients: a nationwide population-based cohort study.

BACKGROUND: Post-transplant malignancy is major morbidity complicated in kidney transplantation (KT). In Korea, a few studies have investigated the sex- and age-dependent risk for post-transplant malignancy among KT recipients on a large scale. METHODS: We utilized a national health insurance database in Korea to investigate the relative risk of post-transplant malignancy in 12,634 KT recipients between 2007 and 2017. The same number of patients with acute appendicitis was included as a control group. The relative risk of malignancy was estimated using a multivariable-adjusted Cox model, and interaction analysis was performed to investigate age- and sex-predominant patterns. RESULTS: KT recipients had an overall 1.8-fold higher risk for post-transplant malignancy with an increased risk for 14 of 29 cancer types, among which Kaposi's sarcoma, non-Hodgkin's lymphoma, kidney, uterus, and bladder/urinary tract cancers were most prominent. Although the overall risk for post-transplant malignancy was similar between male and female KT recipients, head and neck cancer had a higher risk among male KT recipients, whereas non-Hodgkin's lymphoma and bladder/urinary tract cancer had a higher risk among female KT recipients. Overall, the young (< 50 years) KT recipients had a higher risk for post-transplant malignancy than older ones (≥ 50 years), whose pattern was most prominent in non-Hodgkin's lymphoma. In contrast, breast and nonmelanoma skin cancer showed a higher risk among older KT recipients. CONCLUSION: KT recipients had an increased risk for a wide range of cancer types, some of which showed differential risk patterns with age and sex. Our result suggests that focused screening for predominant post-transplant malignancies may be an effective strategy for selected KT recipients.

Effects of positive end-expiratory pressure on pulmonary atelectasis after paediatric laparoscopic surgery as assessed by ultrasound: A randomised controlled study.

INTRODUCTION: Positive end-expiratory pressure (PEEP) following alveolar recruitment manoeuvre (RM) can effectively prevent anaesthesia-induced atelectasis in children. We aimed to evaluate the individual effect of PEEP following RM on atelectasis at the end of laparoscopic surgery in infants and small children. METHODS: Children undergoing laparoscopic inguinal hernia repair aged 5 weeks to 2 years were randomly allocated to either the PEEP or control group. A progressive RM was performed after intubation in all cases. The PEEP group received PEEP of 5 cmH2O until the end of mechanical ventilation, while the control group did not receive any PEEP. Lung ultrasonography was performed to compare the number of atelectatic regions between the two groups after anaesthesia induction, after RM, and at the end of surgery in 12 thoracic regions. RESULTS: Overall, 432 ultrasonographic images were acquired from 36 children. At the end of surgery, the number of atelectatic regions (median [interquartile range]) was significantly lower in the PEEP group compared to the control group (2.0 [1.0-3.0] versus 4.0 [3.0-4.0] out of 12 regions, respectively; p = 0.02). While no difference was observed between the number of atelectatic regions after induction and at the end of surgery in the control group (p = 0.30), a decrease was observed in the PEEP group (3.0 [2.0-4.0] to 2.0 [1.0-3.0], respectively; p = 0.02). CONCLUSION: RM followed by a PEEP of 5 cmH2O can effectively reduce the regions of pulmonary atelectasis at the end of laparoscopic surgery in infants and small children.

Treatment outcome following the transition to adult epilepsy care in childhood-onset epilepsy.

INTRODUCTION: Transition from pediatric to adult epilepsy care in patients with childhood-onset epilepsy can be challenging, and several aspects should be considered, including comorbidities, achieving social milestones, and adjustment of anti-seizure medications (ASMs). However, there is limited information regarding the treatment outcome following the transition to adult epilepsy care in childhood-onset epilepsy. MATERIALS AND METHODS: We performed a 13-year retrospective study of patients with childhood-onset epilepsy who had been transferred to our adult epilepsy clinic. Treatment outcomes were divided into two groups: seizure improvement (at least 50% reduction of seizure) and stationary or worsening seizures. RESULTS: Among the 2,365 patients in our epilepsy cohort, 140 with childhood-onset epilepsy were transferred to adult epilepsy care. Forty-nine patients (35.0%) experienced improvement of seizures, whereas 91 patients (65.0%) reported stationary or worsening seizures following transition. Patients in the improvement group were younger at the time of transition than patients in the stationary or worsening group (p = 0.004) and had a lower number of ASMs before the adjustment (p = 0.001). Interestingly, patients in the improvement group had a greater chance of epileptiform discharges on EEG than patients in the stationary or worsening group (38/49 vs 54/91, p = 0.03). CONCLUSION: Our study shows that one-third of patients having childhood-onset epilepsy can experience seizure improvement following transition to adult epilepsy care, and the presence of epileptiform discharges on EEG may not necessarily mean a poor prognosis or drug-resistant epilepsy following the transition.

Synthesis of Novel (S)-3-(1-Aminoethyl)-8-pyrimidinyl-2-phenylisoquinolin-1(2H)-ones by Suzuki-Miyaura Coupling and Their Cell Toxicity Activities.

A series of (S)-3-(1-aminoethyl)-8-pyrimidinyl-2-phenylisoquinoline-1(2H)-ones 3a-3k was synthesized in 40-98% yield through Suzuki-Miyaura coupling using Pd(PPh3)2Cl2, Sphos, and K2CO3 in THF/H2O mixed solvent. All newly synthesized compounds were evaluated for cell viability (IC50) against MDA-MB-231, HeLa, and HepG2 cells. The antitumor activities of 3a-3k were improved when various pyrimidine motifs were introduced at position C-8 of the isoquinolinone ring.

Effects of spawning stress on the immune capacity of blood cockle Tegillarca granosa occurring on the south coast of Korea.

Spawning in marine bivalves is a great energy-demanding process, and it often results in lethal and sublethal stresses during the post-spawning period, including depressed immune capacity. The blood cockle Tegillarca granosa (Linnaeus, 1758) distributes widely in silty-mud tidal flats on the south coast of Korea, and they spawn in late summer. To understand the impacts of spawning on immune parameters, we analyzed the total hemocyte count (THC), hemocyte mortality, phagocytosis capacity, and reactive oxygen species (ROS) production of T. granosa in pre-, and post-spawning condition using a flow cytometer. Histology indicated that the blood cockles occurring on the south coast of Korea ripe and ready to spawn in July, and they spawned in August and September. The THC in the blood cockle hemolymph declined from pre-spawning (1.2 × 108 cell mL-1) to post-spawning (0.9 × 108 cell mL-1), possibly due to the spawning stress and the massive infiltration of hemocytes in the gonad to phagocytose and resorb the residual gametes during the post-spawning period. The hemocyte mortality increased linearly from August (4.1%) to November (9.1%), as the histology revealed that the blood cockle completed spawning, and they resorbed the relict gametes. The granulocyte phagocytosis capacity declined dramatically from July (12.7%) to September (6.0%), when the cockles were engaged in active spawning. The flow cytometry revealed that the production of reactive oxygen species (ROS) from the granulocytes and the erythrocytes type II increased linearly from August (0.8-0.9 × 105 A U.) to December (2.1-2.8 × 105 A U.), which may cause stresses at a cellular level during this period. As the data indicated, spawning is a stressful activity inducing depressed immunological capacities in the blood cockles.

Cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy.

BACKGROUND: Lacosamide (LCM) is a new antiseizure medication, and intravenous (IV) loading of LCM is recently used against status epilepticus. IV loading of LCM is usually well-tolerated; however, there are concerns about LCM-induced serious adverse cardiac events. This study was aimed at investigating whether rapid IV loading of LCM is associated with adverse cardiac or hemodynamic events in cases of epilepsy emergencies in real-world settings. METHODS: We reviewed medical records of consecutive adult epilepsy patients who received a single loading dose (400 mg) of IV LCM between January 2019 and December 2020 and included patients who exhibited status epilepticus or acute repetitive seizures. Electrocardiography findings, blood pressure, and heart rate before and after the IV infusion of LCM were collected. RESULTS: Of the 85 patients included, 32.9 % (28/85 patients) had experienced at least one cardiac adverse event. The most common adverse events were new-onset first-degree atrioventricular block (19 patients) and hypotension (seven patients). Atrial fibrillation and bradycardia developed in two patients and atrial flutter in one. There were significant increases in the mean PR interval (from 169.3 msec to 184.5 msec, P < 0.01) and decreases in the mean heart rate (from 91.7 to 86.9, P = 0.01) after IV loading of LCM. Older age was significantly associated with a higher magnitude of the PR interval difference between before and after IV loading of LCM. CONCLUSIONS: In cases of epilepsy emergencies, adverse cardiac events commonly developed after IV loading of LCM, although most adverse events were mild in severity or not clinically significant. Elderly patients or patients with underlying cardiac diseases were prone to exhibiting a more prolonged PR interval after IV loading of LCM. Thus, the loading dose of IV LCM should be infused under careful ECG monitoring in these patients.

Usefulness of extended-release topiramate in patients with epilepsy: A two-year retention study.

WHAT IS KNOWN AND OBJECTIVE: Extended-release topiramate (TPM-XR) was recently approved for the treatment of epilepsy, but there is only limited real-world information on the clinical usefulness of TPM-XR in epilepsy patients. We investigated the usefulness of TPM-XR in clinical practice by analysing the retention of TPM-XR in adult epilepsy patients. METHODS: We performed a single-centre retrospective study covering two years. Epilepsy patients taking TPM-XR were included in the study and classified into one of three groups: the monotherapy group, in which patients took only TPM-XR; the adjunctive therapy group, in which patients took TPM-XR concomitant with other AEDs; and the switching AED regimen group, in which patient's AED was switched from immediate-release TPM (TPM-IR) to TPM-XR. We evaluated the retention rates of TPM-XR and analysed the differences in retention rate among the three patient groups. RESULTS AND DISCUSSION: We included 164 epilepsy patients who received TPM-XR for the treatment of epilepsy. The overall retention rate of TPM-XR was generally favourable: 79.1% after one year and 77.7% after two years. The switching AED regimen group had a better retention rate than the other two groups (p = 0.04), with a one-year retention rate of 90.6% and a two-year retention rate of 88.1%. WHAT IS NEW AND CONCLUSION: The favourable retention rate of TPM-XR shows that TPM-XR can be an effective treatment option for epilepsy patients, as either a monotherapy or as an adjunctive therapy. Additionally, switching AED regimen to TPM-XR from TPM-IR can be considered in selected epilepsy patients with poor adherence to TPM-IR.

Quality of Recovery of Patients Who Underwent Curative Pancreatectomy: Comparison of Total Intravenous Anesthesia Versus Inhalation Anesthesia Using the QOR-40 Questionnaire.

BACKGROUND: There has been increasing attention on the subjective recovery of patients undergoing cancer surgery. Total intravenous anesthesia (TIVA) and inhaled anesthesia with volatile anesthetics (INHA) are safe and common anesthetic techniques. Currently, TIVA and INHA have only been compared for less invasive and less complex surgeries. This prospective randomized trial aimed to compare the quality of recovery between TIVA and INHA in patients undergoing pancreatoduodenectomy (PD) or distal pancreatectomy (DP) using the Quality of Recovery (QOR)-40 questionnaire. METHODS: We enrolled 132 patients who were randomly assigned to either the desflurane (DES) (INHA, balanced anesthesia with DES and remifentanil infusion) or TIVA (effect-site target-controlled infusion of propofol and remifentanil) groups and completed the QOR-40 questionnaire postoperatively. RESULTS: The mean global QOR-40 score on postoperative day 3 was significantly higher in the TIVA group than in the DES group. In the PD group, the total QOR-40 score was significantly higher in the TIVA group than in the DES group. Moreover, the TIVA group had significantly higher scores in the physical comfort and psychological support QOR-40 dimensions than the DES group. CONCLUSION: TIVA provides better quality of recovery scores on POD 3 for patients undergoing curative pancreatectomy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03447691.

A comparison of the gut microbiota among adult patients with drug-responsive and drug-resistant epilepsy: An exploratory study.

BACKGROUND: Approximately one-third of epilepsy patients suffer from drug-resistant epilepsy. The gut microbiome, which is the total genetic makeup of all of the total microbes inhabiting the gut, can affect the CNS through various mechanisms. However, there are only limited studies about the relationship between the gut microbiome and epilepsy. We investigated the composition and characteristics of the gut microbiota among adult patients who have drug-responsive and drug-resistant epilepsy. METHODS: We prospectively included 44 adult epilepsy patients and classified them into drug-responsive and drug-resistant groups. We collected fecal samples for the next-generation sequencing analysis. We statistically estimated the bacterial differences and alpha and beta diversities in each category. RESULTS: Although there was no difference in demographic factors between the drug-responsive and drug-resistant groups, there was a significant difference in the composition of the gut microbiota. While the relative abundance of Bacteroides finegoldii and Ruminococcus_g2 increased in the drug-responsive group, the relative abundance of Negativicutes, which belong to Firmicutes increased in the drug-resistant group. Bifidobacterium was relatively abundant in epilepsy patients with a normal electroencephalogram. There was no significant difference between the two groups in analyses of alpha and beta diversities. CONCLUSIONS: We found a significant difference in the composition of the gut microbiota among adult patients with drug-responsive and drug-resistant epilepsy. Difference in gut microbiota can be used as a novel biomarker to predict prognosis and evaluate treatment response in epilepsy patients. In addition, modification of gut microbiome can be an effective treatment strategy for patient with drug-resistant epilepsy.

Effect of upper respiratory infection on anaesthesia induced atelectasis in paediatric patients.

Upper respiratory tract infection (URI) symptoms are known to increase perioperative respiratory adverse events (PRAEs) in children undergoing general anaesthesia. General anaesthesia per se also induces atelectasis, which may worsen with URIs and yield detrimental outcomes. However, the influence of URI symptoms on anaesthesia-induced atelectasis in children has not been investigated. This study aimed to demonstrate whether current URI symptoms induce aggravation of perioperative atelectasis in children. Overall, 270 children aged 6 months to 6 years undergoing surgery were prospectively recruited. URI severity was scored using a questionnaire and the degree of atelectasis was defined by sonographic findings showing juxtapleural consolidation and B-lines. The correlation between severity of URI and degree of atelectasis was analysed by multiple linear regression. Overall, 256 children were finally analysed. Most children had only one or two mild symptoms of URI, which were not associated with the atelectasis score across the entire cohort. However, PRAE occurrences showed significant correspondence with the URI severity (odds ratio 1.36, 95% confidence interval 1.10-1.67, p = 0.004). In conclusion, mild URI symptoms did not exacerbate anaesthesia-induced atelectasis, though the presence and severity of URI were correlated with PRAEs in children.Trial registration: Clinicaltrials.gov (NCT03355547).