Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

Determination of optimal positive end-expiratory pressure using electrical impedance tomography in infants under general anesthesia: Comparison between supine and prone positions.

AIMS: This study determined the optimal positive end-expiratory pressure levels in infants in supine and prone positions under general anesthesia using electrical impedance tomography (EIT). METHODS: This prospective observational single-centre study included infants scheduled for surgery in the prone position. An electrical impedance tomography sensor was applied after inducing general anesthesia. The optimal positive end-expiratory pressure in the supine position was determined in a decremental trial based on EIT and compliance. Subsequently, the patient's position was changed to prone. Electrical impedance tomography parameters, including global inhomogeneity index, regional ventilation delay, opening pressure, the centre of ventilation, and pendelluft volume, were continuously obtained up to 1 h after prone positioning. The optimal positive end-expiratory pressure in the prone position was similarly determined. RESULTS: Data from 30 infants were analyzed. The mean value of electrical impedance tomography-based optimal positive end-expiratory pressure in the prone position was significantly higher than that in the supine position [10.9 (1.6) cmH2O and 6.1 (0.9) cmH2O, respectively (p < .001)]. Significant differences were observed between electrical impedance tomography- and compliance-based optimal positive end-expiratory pressure. Peak and mean airway, plateau, and driving pressures increased 1 h after prone positioning compared with those in the supine position. In addition, the centre of ventilation for balance in ventilation between the ventral and dorsal regions improved. CONCLUSION: The prone position required higher positive end-expiratory pressure than the supine position in mechanically ventilated infants under general anesthesia. EIT is a promising tool to find the optimal positive end-expiratory pressure, which needs to be individualized.

Genomic and Metabolomic Analyses of Nocardiopsis maritima YSL2 as the Mycorrhizosphere Bacterium of Suaeda maritima (L.) Dumort.

Nine bacteria were isolated from the episphere of Suaeda maritima (L.) Dumort. Among them, the bacterial strain YSL2 displayed the highest antimicrobial activity on agar plates and exhibited significant novelty compared with other bacteria based on 16S rRNA analysis. Consequently, Nocardiopsis maritima YSL2T was subjected to phenotypic characterization and whole-genome sequencing. Phylogenetic analysis revealed its close association with Nocardiopsis aegyptia SNG49T. Furthermore, genomic analysis of strain YSL2T revealed the presence of various gene clusters, indicating its potential for producing antimicrobial secondary metabolites. Upon cultivation on a large scale, maritiamides A and B (1 and 2) were isolated and characterized as cyclic hexapeptides based on nuclear magnetic resonance, ultraviolet, infrared, and mass spectrometric data. The absolute configurations of the amino acid residues in the maritiamides were determined through chiral derivatization, utilizing FDAA and GITC. Maritiamides 1 and 2 exhibited promising antibacterial activities against Staphylococcus epidermidis and weakly inhibited the growth of Escherichia coli and Pseudomonas fluorescens.

Effectiveness of head-mounted ultrasound display for radial arterial catheterisation in paediatric patients by anaesthesiology trainees: A randomised clinical trial.

BACKGROUND: The effectiveness of head mounted real-time ultrasound displays (hereafter referred to as 'smart glasses') in improving hand-eye coordination in less experienced individuals, such as trainees in anaesthesia, is unclear. OBJECTIVES: To compare the first-attempt success rate of smart glasses-assisted ultrasound-guided paediatric radial artery catheterisation with conventional ultrasound guided catheterisation performed by anaesthesiology trainees. DESIGN: Prospective randomised controlled trial. SETTINGS: Tertiary university hospital from September 2021 to February 2023. PATIENTS: One hundred and twenty-two paediatric patients (age <7 years, weight ≥3 kg) who required radial artery cannulation during general anaesthesia. INTERVENTIONS: The participants were randomly assigned to either the ultrasound screen group (control) or the smart glasses group prior to radial artery catheterisation. MAIN OUTCOME MEASURES: The primary outcome was the first attempt success rate. Secondary outcomes included the number of attempts, use of transfixion technique, overall complication rate, and clinical anaesthesiology (CA) year of the operators. RESULTS: A total of 119 paediatric patients were included in the analysis. The smart glasses group exhibited higher first-attempt success rate than did the control group (89.8% [53/59] vs. 71.7% [43/60]; P = 0.023; odds ratio (OR) 3.49; (95% confidence interval (CI) 1.27-9.6). The overall number of attempts [median, 1; interquartile range (IQR), 1-1; range, 1-3 vs. median, 1; IQR, 1-2; range, 1-4; P  = 0.006], use of transfixion technique (12/59 [20.3%] vs. 28/60 [46.7%]; P = 0.002), and overall complication rate (6.8% [4/59] vs. 30.0% [18/60]; P = 0.002) were lower in the smart glasses group than in the control group. However, among paediatric anaesthesiology fellows (CA 5 years), the first- (89.3% [25/28] vs. 80.8% [21/26]; P = 0.619) and second-attempt success rates (96.4% [27/28] vs. 80.8% [21/26]; P = 0.163) did not differ between the two groups. CONCLUSIONS: Smart glasses-assisted ultrasound guided radial artery catheterisation improved the first attempt success rate among anaesthesiology trainees, reducing the number of attempts and overall complication rates in small paediatric patients. Smart glasses were more effective for anaesthesia residents (CA 2-4 years) but were not effective for paediatric anaesthesiology fellows (CA 5 years). TRIAL REGISTRATION: ClinicalTrials.gov (NCT05030649; registered 1 September 2021; principal investigator, Prof. Jin-Tae Kim) (https://classic.clinicaltrials.gov/ct2/show/NCT05030649).

Lyoprotectant Constituents Suited for Lyophilization and Reconstitution of Stem-Cell-Derived Extracellular Vesicles.

Stem-cell-derived extracellular vesicles (EVs) are emerging as an alternative approach to stem cell therapy. Successful lyophilization of EVs could enable convenient storage and distribution of EV medicinal products at room temperature for long periods, thus considerably increasing the accessibility of EV therapeutics to patients. In this study, we aimed to identify an appropriate lyoprotectant composition for the lyophilization and reconstitution of stem-cell-derived EVs. MSC-derived EVs were lyophilized using different lyoprotectants, such as dimethyl sulfoxide, mannitol, trehalose, and sucrose, at varying concentrations. Our results revealed that a mixture of trehalose and sucrose at high concentrations could support the formation of amorphous ice by enriching the amorphous phase of the solution, which successfully inhibited the acceleration of buffer component crystallization during lyophilization. Lyophilized and reconstituted EVs were thoroughly evaluated for concentration and size, morphology, and protein and RNA content. The therapeutic effects of the reconstituted EVs were examined using a tube formation assay with human umbilical vein endothelial cells. After rehydration of the lyophilized EVs, most of their generic characteristics were well-maintained, and their therapeutic capacity recovered to levels similar to those of freshly collected EVs. The concentrations and morphologies of the lyophilized EVs were similar to the initial features of the fresh EV group until day 30 at room temperature, although their therapeutic capacity appeared to decrease after 7 days. Our study suggests an appropriate composition of lyoprotectants, particularly for EV lyophilization, which could encourage the applications of stem-cell-derived EV therapeutics in the health industry.

Isolation of New Diterpenoids from the Halophyte, Vitex rotundifolia, and their Antioxidant and Anti-inflammatory Activities.

In this study, three diterpenoids (1-3), including one known compound (1), were isolated from the fruits of Vitex rotundifolia and their structures were determined via spectroscopic analysis. In lipopolysaccharide-stimulated RAW264.7 cells, these compounds dose-dependently decreased the intracellular reactive oxygen species levels and nitric oxide production compared to those in the control cells. At 25 µM/mL, these compounds also diminished the protein expression of the pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-6, with compound 3 exhibiting the most potent inhibitory effect.

Ultrasound-guided selective supraclavicular nerve block for postoperative pain control in children receiving Hickman catheter or chemoport insertion: A randomized controlled trial.

BACKGROUND: Optimal pain management after insertion of a central venous catheter in children remains unclear. AIM: This study aimed to evaluate the effects of a selective supraclavicular nerve block on postoperative analgesia in pediatric patients undergoing hickman catheter or chemoport insertion. METHODS: Fifty patients aged 3-18 years scheduled for elective Hickman or chemoport insertion were randomized into two groups of 25 each: one group received an ultrasound-guided selective supraclavicular nerve block with 0.1 mL/kg of 0.5% ropivacaine (SSCNB group), and the other group did not receive a nerve block (control group). The primary outcome was the postoperative Wong-Baker Faces Pain Rating Scale score measured between 10 and 30 min after surgery. Secondary outcomes included pain scores at 1, 3, and 24 h after the surgery, block-related complications, length of stay in the postanesthesia care unit, postoperative analgesic consumption, and time to first analgesic use 24 h after surgery. RESULTS: The worst pain score within 30 min in the recovery room was significantly lower in the SSCNB group compared to the control group (6 [5-7] vs. 3 [2-4]; median difference, -3; 95% CI, -4 to -1; p < .001). Pain scores at 1, 3, and 24 h after surgery were also significantly lower in the SSCNB group. The need for both opioid and non-opioid analgesics in the postoperative period was significantly lower in the SSCNB group (36.0% vs. 0%; p = .002 and 44.0% vs. 16.0%; mean difference, -28%; 95% CI, -56 to 0.19; p = .033, respectively), while other secondary outcomes were not significantly different between the two groups. CONCLUSIONS: Ultrasound-guided SSCNB is an effective method for managing postoperative pain in children undergoing Hickman catheter or chemoport insertion, reducing the need for analgesics within 24 h after surgery.

Perioperative Respiratory-Adverse Events Following General Anesthesia Among Pediatric Patients After COVID-19.

BACKGROUND: The perianesthetic morbidity, mortality risk and anesthesia-associated risk after preoperative coronavirus disease 2019 (COVID-19) omicron variant in pediatric patients have not been fully demonstrated. We examined the association between preoperative COVID-19 omicron diagnosis and the incidence of overall perioperative adverse events in pediatric patients who received general anesthesia. METHODS: This retrospective study included patients aged < 18 years who received general anesthesia between February 1 and June 10, 2022, in a single tertiary pediatric hospital. They were divided into two groups; patients in a COVID-19 group were matched to patients in a non-COVID-19 group during the omicron-predominant period in Korea. Data on patient characteristics, anesthesia records, post-anesthesia records, COVID-19-related history, symptoms, and mortality were collected. The primary outcomes were the overall perioperative adverse events, including perioperative respiratory adverse events (PRAEs), escalation of care, and mortality. RESULTS: In total, 992 patients were included in the data analysis (n = 496, COVID-19; n = 496, non-COVID-19) after matching. The overall incidence of perioperative adverse events was significantly higher in the COVID-19 group than in the non-COVID-19 group (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.89-1.94). The difference was significant for PRAEs (OR, 2.00; 95% CI, 1.96-2.02) but not in escalation of care or mortality. The most pronounced difference between the two groups was observed in instances of high peak inspiratory pressure ≥ 25 cmH2O during the intraoperative period (OR, 11.0; 95% CI, 10.5-11.4). Compared with the non-COVID-19 group, the risk of overall perioperative adverse events was higher in the COVID-19 group diagnosed 0-2 weeks before anesthesia (OR, 6.5; 95% CI, 2.1-20.4) or symptomatic on the anesthesia day (OR, 6.4; 95% CI, 3.30-12.4). CONCLUSION: Pediatric patients with the preoperative COVID-19 omicron variant had increased risk of PRAEs. Patients within 2 weeks after COVID-19 or those with symptoms had a higher risk of PRAEs.

Higher portal venous pulsatility is associated with worse clinical outcomes following congenital heart surgery: a single-centre prospective cohort study.

PURPOSE: Increased portal venous flow pulsatility is associated with major complications after adult cardiac surgery. Nevertheless, no data are available for pediatric patients with congenital heart disease. We hypothesized that Doppler parameters including portal flow pulsatility could be associated with postoperative outcomes in children undergoing various cardiac surgeries. METHODS: We conducted a prospective observational cohort study in children undergoing congenital cardiac surgery. We obtained postoperative portal, splenic, and hepatic venous Doppler data and perioperative clinical data including major postoperative complications. Portal and splenic venous flow pulsatility were calculated. We evaluated the association between venous Doppler parameters and adverse outcomes. The primary objective was to determine whether postoperative portal flow pulsatility could indicate major complications following congenital heart surgery. RESULTS: In this study, we enrolled 389 children, 74 of whom experienced major postoperative complications. The mean (standard deviation) portal pulsatility (44 [30]% vs 25 [14]%; 95% confidence interval [CI] for mean difference, 12 to 26; P < 0.001] and splenic pulsatility indices (41 [30]% vs 26 [16]%; 95% CI, 7 to 23; P < 0.001) were significantly higher in children with postoperative complications than in those without complications. The portal pulsatility index was able to help identify postoperative complications in biventricular patients and univentricular patients receiving bidirectional cavopulmonary shunt whereas it did not in other univentricular patients. An increased postoperative portal pulsatility index was significantly associated with major complications after pediatric cardiac surgery (odds ratio, 1.40; 95% CI, 1.29 to 1.91; P < 0.001). CONCLUSIONS: Higher portal venous pulsatility is associated with major postoperative complications in children undergoing cardiac surgery. Nevertheless, more data are needed to conclude the efficacy of portal venous pulsatility in patients with univentricular physiology. STUDY REGISTRATION: ClinicalTrials.gov (NCT03990779); registered 19 June 2019.

RéSUMé: OBJECTIF: L'augmentation de la pulsatilité du flux de la veine porte est associée à des complications majeures après une chirurgie cardiaque chez l'adulte. Néanmoins, aucune donnée n'est disponible pour la patientèle pédiatrique atteinte de cardiopathie congénitale. Nous avons émis l'hypothèse que les paramètres Doppler, y compris la pulsatilité du flux de la veine porte, pourraient être associés aux devenirs postopératoires des enfants bénéficiant de diverses chirurgies cardiaques. MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective portant sur des enfants bénéficiant d'une chirurgie cardiaque congénitale. Nous avons obtenu des données Doppler des veines porte, spléniques et hépatiques postopératoires ainsi que des données cliniques périopératoires, y compris les complications postopératoires majeures. La pulsatilité du flux des veines porte et spléniques a été calculée. Nous avons évalué l'association entre les paramètres Doppler veineux et les issues indésirables. L'objectif principal était de déterminer si la pulsatilité du flux postopératoire de la veine porte pouvait constituer un indicateur des complications majeures après une chirurgie cardiaque congénitale. RéSULTATS: Dans cette étude, nous avons recruté 389 enfants, dont 74 ont présenté des complications postopératoires majeures. La pulsatilité moyenne de la veine porte (écart type) (44 [30] % vs 25 [14] %; intervalle de confiance [IC] à 95 % pour la différence moyenne, 12 à 26; P < 0,001] et les indices de pulsatilité splénique (41 [30] % vs 26 [16] %; IC 95 %, 7 à 23; P < 0,001) étaient significativement plus élevés chez les enfants présentant des complications postopératoires que chez les enfants sans complications. L'indice de pulsatilité de la veine porte a permis d'identifier les complications postopératoires chez les patient·es biventriculaires et les patient·es univentriculaires recevant une anastomose cavo-pulmonaire bidirectionnelle (procédure de Glenn), alors que ce n'était pas le cas chez les autres patient·es univentriculaires. Une augmentation postopératoire de l'indice de pulsatilité de la veine porte était significativement associée à des complications majeures après une chirurgie cardiaque pédiatrique (rapport de cotes, 1,40; IC 95 %, 1,29 à 1,91; P < 0,001). CONCLUSION: Une pulsatilité plus élevée de la veine porte est associée à des complications postopératoires majeures chez les enfants bénéficiant d'une chirurgie cardiaque. Néanmoins, davantage de données sont nécessaires pour conclure à l'efficacité de la pulsatilité de la veine porte chez les patient·es présentant une physiologie univentriculaire. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03990779); enregistrée le 19 juin 2019.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Comparison of Normative Percentiles of Brain Volume Obtained from NeuroQuant® vs. DeepBrain® in the Korean Population: Correlation with Cranial Shape.

Purpose: This study aimed to compare the volume and normative percentiles of brain volumetry in the Korean population using quantitative brain volumetric MRI analysis tools NeuroQuant® (NQ) and DeepBrain® (DB), and to evaluate whether the differences in the normative percentiles of brain volumetry between the two tools is related to cranial shape. Materials and Methods: In this retrospective study, we analyzed the brain volume reports obtained from NQ and DB in 163 participants without gross structural brain abnormalities. We measured three-dimensional diameters to evaluate the cranial shape on T1-weighted images. Statistical analyses were performed using intra-class correlation coefficients and linear correlations. Results: The mean normative percentiles of the thalamus (90.8 vs. 63.3 percentile), putamen (90.0 vs. 60.0 percentile), and parietal lobe (80.1 vs. 74.1 percentile) were larger in the NQ group than in the DB group, whereas that of the occipital lobe (18.4 vs. 68.5 percentile) was smaller in the NQ group than in the DB group. We found a significant correlation between the mean normative percentiles obtained from the NQ and cranial shape: the mean normative percentile of the occipital lobe increased with the anteroposterior diameter and decreased with the craniocaudal diameter. Conclusion: The mean normative percentiles obtained from NQ and DB differed significantly for many brain regions, and these differences may be related to cranial shape.

Low dose administration of mature silkworm powder induces gastric mucosal defense factors in ethanol-induced gastric injury rat model.

Gastric mucosa is important to protect the gastric damage against external factors. We previously reported the gastro-protective effects of steamed and freeze-dried mature silkworm larval powder (SMSP) in ethanol-treated rats. However, the factors that promote mucosal formation still remain unclarified. In this study, we evaluated the effect of SMSP on the restoration and maintenance of gastric mucosal layer as well as anti-inflammatory response in ethanol-induced stomach injury in rats. A significant decrease of ulcer indexes, histopathological scores and pro-inflammatory cytokine levels was observed in SMSP-treated group. In addition, SMSP protected the mucosal layer from ethanol-induced gastric damage by increasing the expression of nitric oxide synthases and heat shock proteins, along with promoting genes related gastric mucosal protection and biosynthesis including mucin 5AC and trefoil factors. These results demonstrate that SMSP attenuates the pro-inflammatory responses and strengthens the gastric mucosal layer, thus exhibiting gastro-protective effect against ethanol-induced gastric injury in rats.

Effect of tidal volume change on pressure-based prediction of fluid responsiveness in children.

INTRODUCTION: It is known that pulse pressure variation and systolic pressure variation cannot predict fluid responsiveness in children. In adults, the ability of these dynamic parameters to predict fluid responsiveness is improved by increasing tidal volume. We planned to investigate whether pulse pressure variation or systolic pressure variation can predict fluid responsiveness in children when augmented by increasing tidal volume by conducting a prospective study. METHODS: We enrolled children younger than 7 years who underwent cardiac surgery for atrial septal defect or ventricular septal defect. After sternum closure, pulse pressure variation and systolic pressure variation were continuously recorded while changing the tidal volume to 6, 10, and 14 mL/kg. Fluid loading was done with 10 mL/kg of crystalloids for 10 min, and stroke volume index was measured via transesophageal echocardiography. Children whose stroke volume index increased by more than 15% after the fluid loading were defined as responders to fluid therapy. We set primary outcome as the predictability of pulse pressure variation and systolic pressure variation for fluid responsiveness and measured the area under the curve of receiver operating characteristics curve. RESULTS: Twenty-six children were included, of which 15 were responders. At the tidal volume of 14 mL/kg, the area under the curves of receiver operating characteristics curves of pulse pressure variation and systolic pressure variation were 0.576 (p = .517) and 0.548 (p = .678), respectively. The differences in dynamic parameters between responders and nonresponders were not significant. DISCUSSION: Failure of pulse pressure variation or systolic pressure variation at augmented tidal volume in children may be due to difference in their arterial compliance from those of adults. Large compliance of thoracic wall may be another reason. CONCLUSIONS: Augmented pulse pressure variation or systolic pressure variation due to increased tidal volume cannot predict fluid responsiveness in children after simple cardiac surgery.

Association of Visceral Fat Obesity, Sarcopenia, and Myosteatosis with Non-Alcoholic Fatty Liver Disease without Obesity.

BACKGROUND/AIMS: To investigate whether non-alcoholic fatty liver disease (NAFLD) in individuals without generalized obesity is associated with visceral fat obesity (VFO), sarcopenia, and/or myosteatosis. METHODS: This cross-sectional analysis included 14,400 individuals (7,470 men) who underwent abdominal computed tomography scans during routine health examinations. The total abdominal muscle area (TAMA) and skeletal muscle area (SMA) at the 3rd lumbar vertebral level were measured. The SMA was divided into the normal attenuation muscle area (NAMA) and low attenuation muscle area, and the NAMA/TAMA index was calculated. VFO was defined by visceral to subcutaneous fat ratio, sarcopenia by body mass index-adjusted SMA, and myosteatosis by the NAMA/TAMA index. NAFLD was diagnosed with ultrasonography. RESULTS: Of the 14,400 individuals, 4,748 (33.0%) had NAFLD, and the prevalence of NAFLD among non-obese individuals was 21.4%. In regression analysis, both sarcopenia (men: odds ratio [OR] 1.41, 95% confidence interval [CI] 1.19-1.67, P<0.001; women: OR=1.59, 95% CI 1.40-1.90, P<0.001) and myosteatosis (men: OR=1.24, 95% CI 1.02-1.50, P=0,028; women: OR=1.23, 95% CI 1.04-1.46, P=0.017) were significantly associated with non-obese NAFLD after considering for VFO and other various risk factors, whereas VFO (men: OR=3.97, 95% CI 3.43-4.59 [adjusted for sarcopenia], OR 3.98, 95% CI 3.44-4.60 [adjusted for myosteatosis]; women: OR=5.42, 95% CI 4.53-6.42 [adjusted for sarcopenia], OR=5.33, 95% CI 4.51-6.31 [adjusted for myosteatosis]; all P<0.001) was strongly associated with non-obese NAFLD after adjustment with various known risk factors. CONCLUSION: In addition to VFO, sarcopenia and/or myosteatosis were significantly associated with non-obese NAFLD.

Association Between Insulin Resistance and Myosteatosis Measured by Abdominal Computed Tomography.

CONTEXT: Ectopic fat deposition in skeletal muscle, termed myosteatosis, is a key factor in developing insulin resistance. OBJECTIVE: This work aimed to evaluate the association between insulin resistance and myosteatosis in a large Asian population. METHODS: A total of 18 251 participants who had abdominal computed tomography were included in this cross-sectional study. Patients were categorized into 4 groups according to quartiles of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), and intermuscular adipose tissue (IMAT). The absolute values of TAMA, NAMA, LAMA, and IMAT and the ratios of NAMA/BMI, LAMA/BMI, and NAMA/TAMA were used as myosteatosis indices. RESULTS: The absolute values of TAMA, NAMA, LAMA, and IMAT appeared to increase with higher HOMA-IR levels, and LAMA/BMI showed a similar upward trend. Meanwhile, the NAMA/BMI and NAMA/TAMA index showed downward trends. As HOMA-IR levels increased, the odds ratios (ORs) of the highest quartile of NAMA/BMI and NAMA/TAMA index decreased and that of LAMA/BMI increased. Compared with the lowest HOMA-IR group, the adjusted ORs (95% CI) in the highest HOMA-IR group for the lowest NAMA/TAMA quartile were 0.414 (0.364-0.471) in men and 0.464 (0.384-0.562) in women. HOMA-IR showed a negative correlation with NAMA/BMI (r = -0.233 for men and r = -0.265 for women), and NAMA/TAMA index (r = -0.211 for men and r = -0.214 for women), and a positive correlation with LAMA/BMI (r = 0.160 for men and r = 0.119 for women); P was less than .001 for all. CONCLUSION: In this study, a higher HOMA-IR level was significantly associated with a high risk of myosteatosis.

Fed and fasted bioequivalence assessment of two formulations of extended-release fixed-dose combination dapagliflozin/metformin (10/1,000 mg) tablets in healthy subjects.

Two open-label, randomized, two-period crossover studies were conducted to investigate the pharmacokinetic (PK) properties, safety, and bioequivalence of the test formulation (KD4004), a new fixed-dose combination (FDC) formulation of dapagliflozin and metformin extended release (XR) tablets, relative to the reference formulation (10 mg dapagliflozin/1,000 mg metformin XR FDC tablet) in healthy subjects under fasting (Part A) and fed (Part B) conditions. After giving the dose, serial blood samples were collected for a period of 48 hours. Primary PK parameters (AUC0-t and Cmax) were used to assess bioequivalence between two dapagliflozin/metformin XR (10/1,000 mg) FDC formulations under fed and fasting conditions. Safety and tolerability were also evaluated. Part A and Part B were completed by 32 and 37 subjects, respectively. Bioequivalence of the two FDC formulations of dapagliflozin and metformin XR tablets was established in both the fasted and the fed conditions as the 90% confidence interval of the ratios of adjusted geometric means for AUC0-t and Cmax were contained within the predefined range of 0.800-1.250 bioequivalence criteria. Single-dose administration of dapagliflozin and metformin XR was safe and well tolerated as the two FDC formulations. In conclusion, both FDC formulations of dapagliflozin and metformin XR tablets were bioequivalent in fed and fasted subjects. All treatments were well tolerated. Trial Registration: Clinical Research Information Service Identifier: KCT0004026.

Mesenchymal Stem Cell-Extracellular Vesicle Therapy for Stroke: Scalable Production and Imaging Biomarker Studies.

A major clinical hurdle to translate MSC-derived extracellular vesicles (EVs) is the lack of a method to scale-up the production of EVs with customized therapeutic properties. In this study, we tested whether EV production by a scalable 3D-bioprocessing method is feasible and improves neuroplasticity in animal models of stroke using MRI study. MSCs were cultured in a 3D-spheroid using a micro-patterned well. The EVs were isolated with filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, and small RNA sequencing. Compared to conventional 2D culture, the production-reproduction of EVs (the number/size of particles and EV purity) obtained from 3D platform were more consistent among different lots from the same donor and among different donors. Several microRNAs with molecular functions associated with neurogenesis were upregulated in EVs obtained from 3D platform. EVs induced both neurogenesis and neuritogenesis via microRNAs (especially, miR-27a-3p and miR-132-3p)-mediated actions. EV therapy improved functional recovery on behavioral tests and reduced infarct volume on MRI in stroke models. The dose of MSC-EVs of 1/30 cell dose had similar therapeutic effects. In addition, the EV group had better anatomical and functional connectivity on diffusion tensor imaging and resting-state functional MRI in a mouse stroke model. This study shows that clinical-scale MSC-EV therapeutics are feasible, cost-effective, and improve functional recovery following experimental stroke, with a likely contribution from enhanced neurogenesis and neuroplasticity.

Evaluation of Portal, Splenic, and Hepatic Vein Flows in Children Undergoing Congenital Heart Surgery.

OBJECTIVE: Little is known about changes in portal, splenic, and hepatic vein flow patterns in children undergoing congenital heart surgery. This study aimed to determine the characteristics of portal, splenic, and hepatic vein flow patterns using ultrasonography in children undergoing cardiac surgery. DESIGN: Single-center, prospective observational study. SETTING: Tertiary children's hospital, operating room. PARTICIPANTS: Children undergoing cardiac surgery. MEASUREMENT AND MAIN RESULTS: The authors obtained ultrasound data from the heart, inferior vena cava, portal, splenic, and hepatic veins before and after surgeries. In the biventricular group, which included children with atrial and ventricular septal defects and pulmonary stenosis (n = 246), the portal pulsatility index decreased from 38.7% to 25.6% (p < 0.001) after surgery. The preoperative portal pulsatility index was significantly higher in patients with pulmonary hypertension (43.3% v 27.4%; p < 0.001). In the single-ventricle group (n = 77), maximum portal vein flow velocities of Fontan patients were significantly lower (13.5 cm/s) compared with that of patients with modified Blalock-Taussig shunt (19.7 cm/s; p = 0.035) or bidirectional cavopulmonary shunt (23.1 cm/s; p < 0.001). The cardiac index was inversely correlated with the portal pulsatility index in the bidirectional cavopulmonary shunt and Fontan circulation. (ß = -5.693, r2 = 0.473; p = 0.001) The portal pulsatility index was correlated with splenic venous pulsatility and hepatic venous atrial reverse flow velocity in biventricular and single-ventricle groups. CONCLUSIONS: The characteristics of venous Doppler patterns in the portal, splenic, and hepatic veins differed according to congenital heart disease. Further studies are required to determine the association between splanchnic venous Doppler findings and clinical outcomes in this population.

Effectiveness of an Online Dementia Prevention Program on Cognitive Function and Depression in Community-Dwelling Older Adults during the COVID-19 Pandemic in Korea.

(1) Background: Continuous participation in a comprehensive dementia prevention program is important for community-dwelling older adults during the coronavirus disease (COVID-19) pandemic, as limitations on their communities and social participation have increased and participation in daily tasks has decreased. These factors can negatively affect their cognitive function and symptoms of depression. This study aimed to introduce an evidence-based online dementia prevention program in the South Korean context and to identify its effect on cognitive function and symptoms of depression in community-dwelling older adults during the COVID-19 pandemic. (2) Methods: One hundred and one community-dwelling older adults without dementia participated in twelve sessions of an online dementia prevention program designed by occupational therapists. Cognitive function and symptoms of depression were assessed before and after the program. Cognitive function was tested using the Cognitive Impairment Screening Test and symptoms of depression were assessed using the Korean version of the Short Geriatric Depression Scale. The participants' opinions were gathered using open-ended questions. (3) Results: After the program, according to the raw score, orientation was maintained and attention, visuospatial function, executive function, memory, and language function increased. The memory and total cognitive score was improved significantly. Symptoms of depression significantly decreased. The program's benefits according to the participants were participation in new activities, boredom reduction, online communication, and reminiscence. (4) Conclusions: An online dementia prevention program is effective in maintaining and increasing cognitive function and preventing depression in community-dwelling older adults. An online dementia prevention program is a useful method in providing opportunities to participate in cognitive training and continuous daily activities during the COVID-19 pandemic.