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Wonsuk Shin,1 Kyoung Soo Lim,1 Min-Kyoung Kim,1 Hyun Sook Kim,2 Jihwa Hong,3 Stanford Jhee,3 Joseph Kim,3 Sungeun Yoo,4 Yeon-Tae Chung,4 Jae Moon Lee,4 Doo-Yeoun Cho1 1Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea; 2Department of Neurology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea; 3Department of Scientific Affairs, PAREXEL International, Waltham, MA, USA; 4Kainos Medicine Inc., Seongnam, Republic of Korea Background: KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson’s disease as a disease-modifying drug.Methods: This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts.Results: After a single dose, the KM-819 plasma exposure showed a less than dose-proportional increase across a dose range of 10–400 mg. After repeated dosing, KM-819 plasma exposure increased in an approximately dose-proportional manner across the evaluated dose range (30–400 mg once daily for 7 days). The mean elimination half-life was 1.8 to 4.8 h with the lower KM-819 doses (≤30 mg), which increased to around 9 h with the higher doses (100–400 mg). When administered to the elderly population, KM-819 plasma exposure increased to 102% after a 200 mg once-daily dosing for 7 days. No clear treatment-related effects on the estimated pharmacodynamic variables were observed. Single or multiple doses of KM-819 were generally well tolerated. Conclusion: The data from this study can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Keywords: first-in-human, KM-819, pharmacokinetics, pharmacodynamics, safety

Sun-Hee Cho,1,* Ahreum Kim,1,* Woojung Shin,2 Min Beom Heo,1 Hyun Jong Noh,1 Kwan Soo Hong,3,4 Jee-Hyun Cho,3,4 Yong Taik Lim1,2 1SKKU Advanced Institute of Nanotechnology (SAINT), 2School of Chemical Engineering, Sungkyunkwan University, Suwon, 3Bioimaging Research Team, Korea Basic Science Institute, Cheongju, 4Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea *These authors contributed equally to this work Abstract: Injectable and stimuli-responsive hydrogels have attracted attention in molecular imaging and drug delivery because encapsulated diagnostic or therapeutic components in the hydrogel can be used to image or change the microenvironment of the injection site by controlling various stimuli such as enzymes, temperature, pH, and photonic energy. In this study, we developed a novel injectable and photoresponsive composite hydrogel composed of anticancer drugs, imaging contrast agents, bio-derived collagen, and multifaceted anionic polypeptide, poly (γ-glutamic acid) (γ-PGA). By the introduction of γ-PGA, the intrinsic temperature-dependent phase transition behavior of collagen was modified to a low viscous sol state at room temperature and nonflowing gel state around body temperature. The modified temperature-dependent phase transition behavior of collagen/γ-PGA hydrogels was also evaluated after loading of near-infrared (NIR) fluorophore, indocyanine green (ICG), which could transform absorbed NIR photonic energy into thermal energy. By taking advantage of the abundant carboxylate groups in γ-PGA, cationic-charged doxorubicin (Dox) and hydrophobic MnFe2O4 magnetic nanoparticles were also incorporated successfully into the collagen/γ-PGA hydrogels. By illumination of NIR light on the collagen/γ-PGA/Dox/ICG/MnFe2O4 hydrogels, the release kinetics of Dox and magnetic relaxation of MnFe2O4 nanoparticles could be modulated. The experimental results suggest that the novel injectable and NIR-responsive collagen/γ-PGA hydrogels developed in this study can be used as a theranostic platform after loading of various molecular imaging probes and therapeutic components. Keywords: hydrogel, photothermal, near-infrared, drug delivery, magnetic nanoparticles

Here, we first demonstrated the neuroprotective effect of acupuncture after SCI. Acupuncture applied at two specific acupoints, Shuigou (GV26) and Yanglingquan (GB34) significantly alleviated apoptotic cell death of neurons and oligodendrocytes, thereby leading to improved functional recovery after SCI. Acupuncture also inhibited caspase-3 activation and reduced the size of lesion cavity and extent of loss of axons. We also found that the activation of both p38 mitogen-activated protein kinase and resident microglia after injury are significantly attenuated by acupuncture. In addition, acupuncture significantly reduced the expression or activation of pro-nerve growth factor, proinflammatory factors such as tumor necrosis factor-α, interleukin-1β, interleukin-6, nitric oxide synthase, cycloxygenase-2, and matrix metalloprotease-9 after SCI. Thus, our results suggest that the neuroprotection by acupuncture may be partly mediated via inhibition of inflammation and microglial activation after SCI and acupuncture can be used as a potential therapeutic tool for treating acute spinal injury in human.

Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.

Purpose : This study describes changes in the utilization pattern of emergency departments (EDs) by neonates during the coronavirus disease 2019 pandemic to ensure efficient resource allocation during future infectious disease outbreaks. Methods : We performed a retrospective observational study by reviewing the medical records of neonates (≤ 30 days) who visited the ED. They were divided into pre-pandemic (February 2018-January 2020) and pandemic (February 2020-January 2022) groups. We compared data regarding ED utilization, including length of stay, disposition, and chief complaints. Results : A total of 156 neonates visited the ED during the study period. A 42.4% decrease in the visits was observed during the pandemic group (n = 57), compared with the pre-pandemic group (n = 99). In particular, the proportion of visits by neonates aged 7 days or younger has decreased from 14.1% (14/99) to 3.5% (2/57; P = 0.035). The proportion of plain radiography performed and median ED length of stay increased from 36.4% (36/99) to 63.2% (36/57; P = 0.001), and from 66.0 minutes (interquartile range, 42.0-116.0) to 86.0 minutes (59.0-153.0; P = 0.007), respectively. Among the chief complaints, fever, respiratory symptoms, and minor clinical problems increased during the pandemic (29.3% to 36.8%, 11.1% to 14.0%, and 9.1% to 14.0%, respectively). Conclusion : The pandemic led to a marked reduction in neonatal ED visits, particularly among those aged 7 days or younger. Increases were noted in the rates of plain radiography performed, fever, respiratory, and minor clinical symptoms, as well as median ED length of stay. EDs should prepare for efficient emergency treatments tailored to neonates.

Abstract Background Tire wear particles (TWPs) produced by the abrasion between tires and road surfaces have been recognized as an emerging threat to soil health globally in recent years. They can be transported from the road surface to adjacent soil at different delivery rates, with precipitation a main driver underpinning this movement. However, studies typically assume an abrupt exposure of TWPs in their experimental design. In this study, we investigated the impacts of abrupt and gradual delivery of TWPs on soil physicochemical properties and microbial activities. We used two different delivery rates of TWPs (abrupt and gradual) and devised two experimental phases, namely the TWPs-delivery period (phase 1) and the end-of-delivery period (phase 2). Results We found that the gradual TWPs delivery treatments negatively influenced the activity of carbon cycle-related enzymes (β-glucosidase and β-D-1,4-cellobiosidase). Furthermore, the abrupt treatment highly increased the effects on nitrogen cycle-related enzyme activity (β-1,4-N-acetyl-glucosaminidase). In phase 2 (end-of-delivery period), each enzyme activity was returned to a similar level as the control group, and these changes between phases 1 and 2 depended on the prior delivery rates. Conclusion Abruptly and gradually delivered TWPs induce different responses to soil microbial activities. Our findings imply that the delivery rate of TWPs could be a key factor changing the effects of TWPs, further enhancing our understanding of the ecological impacts of TWPs. Graphical Abstract

Abstract Background The Diabetic Retinopathy Extended Screening Study (DRESS) aims to develop and validate a new DR/diabetic macular edema (DME) risk stratification model in patients with Type 2 diabetes (DM) to identify low-risk groups who can be safely assigned to biennial or triennial screening intervals. We describe the study methodology, participants’ baseline characteristics, and preliminary DR progression rates at the first annual follow-up. Methods DRESS is a 3-year ongoing longitudinal study of patients with T2DM and no or mild non-proliferative DR (NPDR, non-referable) who underwent teleophthalmic screening under the Singapore integrated Diabetic Retinopathy Programme (SiDRP) at four SingHealth Polyclinics. Patients with referable DR/DME (> mild NPDR) or ungradable fundus images were excluded. Sociodemographic, lifestyle, medical and clinical information was obtained from medical records and interviewer-administered questionnaires at baseline. These data are extracted from medical records at 12, 24 and 36 months post-enrollment. Baseline descriptive characteristics stratified by DR severity at baseline and rates of progression to referable DR at 12-month follow-up were calculated. Results Of 5,840 eligible patients, 78.3% (n = 4,570, median [interquartile range [IQR] age 61.0 [55–67] years; 54.7% male; 68.0% Chinese) completed the baseline assessment. At baseline, 97.4% and 2.6% had none and mild NPDR (worse eye), respectively. Most participants had hypertension (79.2%) and dyslipidemia (92.8%); and almost half were obese (43.4%, BMI ≥ 27.5 kg/m2). Participants without DR (vs mild DR) reported shorter DM duration, and had lower haemoglobin A1c, triglycerides and urine albumin/creatinine ratio (all p

Abstract The emergence and dissemination of carbapenem-resistant species of Acinetobacter and Pseudomonas have become a serious health concern. Routine antimicrobial disk susceptibility tests in clinical laboratories cannot distinguish between isolates that are highly carbapenem-resistant and those that are moderately carbapenem-resistant. The present study describes antimicrobial susceptibility tests using disks containing high doses (1000 μg) of meropenem. The diameters of inhibition zones were significantly negatively correlated with the MICs of Pseudomonas and Acinetobacter species for meropenem (R2: 0.93 and 0.91, respectively) and imipenem (R2: 0.75 and 0.84, respectively). Double disk synergy tests using clavulanic acid or sodium mercaptoacetate can detect ESBL or MBL producers. Susceptibility tests using disks containing high doses of meropenem can easily detect highly carbapenem-resistant isolates in a quantitative manner. These disks may be useful in bacteriological laboratories because of their technical ease, stability, and relatively low cost.

Abstract Converging evidence suggests that handgrip strength is linked to cognition in older adults, and this may be subserved by shared age-related changes in brain function and structure. However, the interplay among handgrip strength, brain functional connectivity, and cognitive function remains poorly elucidated. Hence, our study sought to examine these relationships in 148 community-dwelling older adults. Specifically, we examined functional segregation, a measure of functional brain organization sensitive to ageing and cognitive decline, and its associations with handgrip strength and cognitive function. We showed that higher handgrip strength was related to better processing speed, attention, and global cognition. Further, higher handgrip strength was associated with higher segregation of the salience/ventral attention network, driven particularly by higher salience/ventral attention intra-network functional connectivity of the right anterior insula to the left posterior insula/frontal operculum and right midcingulate/medial parietal cortex. Importantly, these handgrip strength-related inter-individual differences in salience/ventral attention network functional connectivity were linked to cognitive function, as revealed by functional decoding and brain-cognition association analyses. Our findings thus highlight the importance of the salience/ventral attention network in handgrip strength and cognition, and suggest that inter-individual differences in salience/ventral attention network segregation and intra-network connectivity could underpin the handgrip strength-cognition relationship in older adults.

Background: The expansion of artificial intelligence (AI) within large language models (LLMs) has the potential to streamline healthcare delivery. Despite the increased use of LLMs, disparities in their performance particularly in different languages, remain underexplored. This study examines the quality of ChatGPT responses in English and Japanese, specifically to questions related to anaesthesiology. Methods: Anaesthesiologists proficient in both languages were recruited as experts in this study. Ten frequently asked questions in anaesthesia were selected and translated for evaluation. Three non-sequential responses from ChatGPT were assessed for content quality (accuracy, comprehensiveness, and safety) and communication quality (understanding, empathy/tone, and ethics) by expert evaluators. Results: Eight anaesthesiologists evaluated English and Japanese LLM responses. The overall quality for all questions combined was higher in English compared with Japanese responses. Content and communication quality were significantly higher in English compared with Japanese LLMs responses (both P

Background Limited clinical reports have investigated the effects of maternal coronavirus disease 2019 (COVID-19) on fetuses and neonates. Purpose This retrospective study aimed to assess the impact of maternal COVID-19 on neonates during the perinatal period, including neonatal clinical outcomes, versus the outcomes of neonates of mothers without COVID-19. Methods Neonates born to COVID-19-infected mothers at the National Health Insurance Service Ilsan Hospital between February 2021 and March 2022 were included. Those with gestational age (GA) ≥35+0 weeks who were born within 2 weeks of the maternal infection were matched 1:2 with a control group based on GA. The main outcomes were respiratory diseases, including transient tachypnea of the newborn (TTN), respiratory distress syndrome, meconium aspiration syndrome, the need for respiratory support, and length of hospital stay. Uni- and multivariate logistic regression analyses were performed and adjusted for relevant covariates, including maternal age, obstetric complications (hypertension and gestational diabetes), delivery mode, birth weight, sex, and small-for-gestational-age status. Results The case group comprised 103 neonates (mean GA, 38.5±1.3 weeks; mean birth weight, 3,121±397 g), while the control group included 206 neonates (mean GA, 38.4±1.2 weeks; mean birth weight, 3088±428 g). In the case and control groups, the proportion of cesarean sections was 91% and 40%, respectively, while the proportion of male infants was 56% and 47%, respectively. After adjusting for covariates, the case group had a higher risk of TTN (adjusted odd ratio [AOR], 3.69; 95% confidence interval [CI], 1.69–8.07), noninvasive respiratory ventilator use (AOR, 2.28; 95% CI, 1.05–4.97), and oxygen support (AOR, 4.83; 95% CI, 1.46–15.95). Conclusion Newborns born to COVID-19-infected mothers are at increased risk of TTN and may require respiratory support. Close monitoring of respiratory symptoms is crucial in neonates.

Aims: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. Methods and results: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. Conclusions: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF.

Jung-Ick Byun,1 Tae-Won Yang,2– 4 Jun-Sang Sunwoo,5 Won Chul Shin,1,6 Oh-Young Kwon,2,4,7,* Ki-Young Jung8,* 1Department of Neurology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 2Department of Neurology, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 3Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; 4Institute of Science, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 5Department of Neurology, Kangbuk Samsung Hospital, Seoul, Republic of Korea; 6Department of Medicine, AgeTech-service Convergence Major, Kyung Hee University, Seoul, Republic of Korea; 7Department of Neurology, Gyeongsang National University Hospital, Jinju, Republic of Korea; 8Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Oh-Young Kwon, Department of Neurology, Gyeongsang National University College of Medicine, 15, Jinjudae-ro 816beon-gil, Jinju, 52727, Republic of Korea, Tel +82-55-750-8288, Email oykwon@gnu.ac.kr Ki-Young Jung, Department of Neurology, Seoul National University Hospital, Neuroscience Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 110-744, Republic of Korea, Tel +82-2-920-6649, Email jungky@snu.ac.krPurpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by REM sleep without atonia (RWA) and is regarded as the prodromal stage of α-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). RWA is also associated with neurodegeneration driven by α-synucleinopathy. However, the level of RWA across the α-synucleinopathy spectrum remains elusive. We aimed to rate the percentage of RWA across the α-synucleinopathy spectrum, encompassing prodromal and overt phenotypes.Methods: A systematic search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases. We included cohort, cross-sectional, and case–control studies comparing the RWA percentage during REM sleep evaluated by tonic chin activity (RWA%-T) or by phasic chin activity (RWA%-P) across the α-synucleinopathy spectrum. Bayesian network meta-analysis was used to combine both direct and indirect evidence regarding the group differences in the RWA%-T and RWA%-P. The surface under the cumulative ranking curve was used to estimate the ranked probability.Results: Fifteen articles met the inclusion criteria. The investigations included 204 iRBD, 295 PD with RBD (PDwtRBD), 187 PD without RBD (PDwoRBD), 42 MSAwtRBD, 9 DLBwtRBD patients, and 246 controls. MSAwtRBD ranked first in RWA%-T, whereas iRBD ranked first in RWA%-P. RWA% in PDwoRBD patients was comparable to that in the controls and was lower than that in PDwtRBD patients.Conclusion: Overt phenotypes such as MSAwtRBD and PDwtRBD ranked high in RWA%-T, whereas iRBD, a prodromal type, ranked highest in RWA%-P. Taken together, our data suggest that the percentage of neurodegeneration in RBD patients may be associated with RWA%-T rather than RWA%-P.Prospero Registration Number: CRD42021276445.Keywords: REM sleep behavior disorder, α-synucleinopathy, REM sleep without atonia, network meta-analysis

Background: This study compared clinical outcomes between arthroscopic and open repair of triangular fibrocartilage complex (TFCC) foveal tears in chronic distal radioulnar joint (DRUJ) instability patients. Methods: A total of 79 patients who had gone through foveal repair of TFCC using arthroscopic technique (n = 35) or open technique (n = 44) between 2016 and 2020 were retrospectively analyzed. The visual analog scale (VAS) score for pain, active range of motion (ROM), grip strength, Mayo Modified Wrist Score (MMWS), Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score, and Patient-Rated Wrist Evaluation (PRWE) score at 2-4-6-12-24 months postoperatively were compared between two groups. Results: Two years after the operation, clinical parameters (VAS, MMWS, DASH, and PRWE), grip strength, and ROM showed significant advancement in the two groups in comparison to their values measured preoperatively (p < 0.001). Nonetheless, we could not identify any statistically significant differences in the above clinical factors between the two groups. The arthroscopic group showed a better flexion–extension arc at 2 months and supination–pronation arc at 2 and 4 months than the open group (p < 0.001). There were no significant differences between the two groups at 2 years postoperatively. Ten patients (12.6%) had recurrent instability (three in the arthroscopic group and seven in the open group, p = 0.499). Similarly, both groups showed no significant difference in the return to work period. Conclusions: Arthroscopic foveal repair of TFCC provided similarly favorable outcomes and early recovery of pain and ROM compared to open repair.

Kwang Je Lee,1 Jae-Kean Ryu,2 Yun-Hyeong Cho,3 Won Yong Shin,4 Jeong Su Kim,5 Young Won Yoon,6 Ji Yong Jang,7 Won Ho Kim,8 Jong Wook Beom,9 Seok-Min Kang10 On behalf of LG-VROS001 STUDY INVESTIGATOR GROUP1Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 2Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, Korea; 3Cardiovascular Center, Myongji Hospital, Goyang, Korea; 4Department of Cardiology, Soon Chun Hyang University Hospital Cheonan, Cheonan, Korea; 5Cardiovascular Center, Pusan National University Yangsan Hospital, Yangsan, Korea; 6Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 7Department of Cardiology, National Health Insurance Service Ilsan Hospital, Ilsan, Korea; 8Eulji University School of Medicine, Daejeon, Korea; 9Department of Cardiology, Jeju National University Hospital, Jeju, Korea; 10Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Seok-Min Kang, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea, Tel +82 2-2647-3225, Email SMKANG@yuhs.acPurpose: This study aimed to assess the effectiveness and safety of a fixed-dose combination of rosuvastatin and valsartan (Rovatitan®) in Korean patients with concomitant hypertension and hyperlipidemia.Patients and Methods: A total of 1008 eligible patients with concomitant hypertension and hyperlipidemia were enrolled and treated for 12 weeks. Both upward and downward drug dose titrations were allowed based on the investigator’s discretion. This study evaluated the effectiveness of the study drug, defined by the percentage of patients achieving the blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) treatment targets. Additionally, regression analyses were conducted to evaluate the factors associated with the effectiveness and safety of the study drug. Of the 1008 patients enrolled in the study, 911 were analyzed for clinical effectiveness.Results: At 12 weeks, 84.6% and 75.9% of patients treated with the study drug achieved their BP and LDL-C targets, respectively, and 64.8% of patients achieved both targets simultaneously. Furthermore, the percentage of patients who achieved their BP and LDL-C treatment targets demonstrated a trend across the respective risk groups; the higher the risk group, the lower the success of attaining the respective target. This trend was also observed regardless of the prior antihypertensive and/or lipid-lowering treatments. According to regression analysis, poor metabolic profiles, including a higher body mass index (BMI) and higher BP and LDL-C levels at baseline, were significantly associated with treatment failure for BP. Among the 1005 patients included in the safety analysis, 17 patients (1.7%) experienced serious adverse events; however, none were considered related to the study drug.Conclusion: The study drug used for the treatment of concomitant hypertension and hyperlipidemia in a real-world setting was effective and was well tolerated. Therefore, the study drug is suggested as a good alternative to increase patient convenience and compliance, particularly in those taking multiple medications.Keywords: hypertension, hyperlipidemia, rosuvastatin, valsartan, effectiveness, safety

An on-chip quantum light source based on spontaneous four-wave mixing is an essential element for developing quantum photonic integrated circuit technology, which has the advantage of no connection loss owing to the integration of the source into photonic circuits. The waveguide-based quantum light source inevitably causes propagation loss owing to imperfections in the fabrication process, but the propagation loss effects on photon-pair generation have not been extensively studied. In this study, propagation loss effects were examined using theoretical and experimental methods. In theory, the performance of quantum light sources, such as brightness, heralding efficiency, and coincidence-to-accidental ratio, strongly depend on propagation loss. We fabricate several waveguides with a moderate propagation loss of 2.2 dB/cm to investigate the loss dependence and ascertain that the brightness, heralding efficiency, and coincidence-to-accident ratio strongly correlate with the length of the optical waveguide. The maximum coincidence-count brightness occurred at an optimization length of 1/α, where α is the absorption coefficient. In contrast, the single-count brightness shows slightly different waveguide length dependence owing to loss-induced one-photon states. We expect that the results obtained in this study will greatly assist in determining the proper waveguide length for photon-pair generation according to the source’s application fields. The results will be helpful in the development of a quantum light source suitable for practical and quantum optical integrated circuits and will lead to the development of high-fidelity quantum technologies.

Abstract Lumbar spinal stenosis (LSS) and sagittal imbalance are relatively common in elderly patients. Although the goals of surgery include both functional and radiological improvements, the criteria of correction may be too strict for elderly patients. If the main symptom of patients is not forward-stooping but neurogenic claudication or pain, lumbar decompression without adding fusion procedure may be a surgical option. We performed cost-utility analysis between lumbar decompression and lumbar fusion surgery for those patients. Elderly patients (age > 60 years) who underwent 1–2 levels lumbar fusion surgery (F-group, n = 31) or decompression surgery (D-group, n = 40) for LSS with sagittal imbalance (C7 sagittal vertical axis, C7-SVA > 40 mm) with follow-up ≥ 2 years were included. Clinical outcomes (Euro-Quality of Life-5 Dimensions, EQ-5D; Oswestry Disability Index, ODI; numerical rating score of pain on the back and leg, NRS-B and NRS-L) and radiological parameters (C7-SVA; lumbar lordosis, LL; the difference between pelvic incidence and lumbar lordosis, PI-LL; pelvic tilt, PT) were assessed. The quality-adjusted life year (QALY) and incremental cost-effective ratio (ICER) were calculated from a utility score of EQ-5D. Postoperatively, both groups attained clinical and radiological improvement in all parameters, but NRS-L was more improved in the F-group (p = 0.048). ICER of F-group over D-group was 49,833 US dollars/QALY. Cost-effective lumbar decompression may be a recommendable surgical option for certain elderly patients, despite less improvement of leg pain than with fusion surgery.

Difference of onset of increase of PRL content in the anterior pituitary gland and plasma PRL concentration during the late stage of chicken embryogenesis is well known. To investigate the disagreement, changes in PRL content and PRL mRNA levels, and the effects of vasoactive intestinal polypeptides (VIP) on PRL release and PRL mRNA expression were examined using western blot analysis and real-time PCR quantification. Changes in SPRL content were strongly correlated with PRL mRNA levels. The increase in PRL content on day 17 of incubation may be caused by the increase in PRL mRNA levels on day 16 of incubation. Additionally, the effects of VIP on PRL release from the embryonic anterior pituitary gland were not observed until day 18 of embryogenesis. These results suggest that increased levels of PRL mRNA and PRL content in the anterior pituitary gland are closely correlated. However, the increased expression of PRL mRNA observed on day 17 and the initiation of PRL release from the anterior pituitary gland on day 19 were differentially regulated. According to the results of western blot analysis, the proportion of glycosylated PRL (G-PRL) and non-glycosylated PRL (NG-PRL) in the anterior pituitary gland at the end stage of development differed from the proportion of PRL released from the anterior pituitary gland. According to the results of two-dimensional western blot analysis, no isoforms with different isoelectric points were detected in the culture medium on days 19 and 20. These data suggest that the peptide chains of G-PRL and NG-PRL were not modified. In conclusion, the differentiation of PRL-producing cells and the maturation of the hypothalamus and anterior pituitary gland were completed at the end stage of incubation, and that different factors regulated the initiation of PRL mRNA expression before day 18 of incubation.

Objective To analyze the correlation between standardized language assessment batteries of toddlers and developmental language delays. Methods A total of 319 children with suspected language developmental delays were enrolled in this study retrospectively. They underwent the Receptive and Expressive Vocabulary Test (REVT) for vocabulary development assessment and at least one of two language assessment batteries: The Sequenced Language Scale for Infants (SELSI) or the Preschool Receptive-Expressive Language Scale (PRES) for language development assessment. The correlation of the results for receptive and expressive language between the scales were analyzed. Results The participants were divided into two groups: SELSI and REVT (n=45) and PRES and REVT (n=273). When the children’s results were classified into groups (average, mild delay, and delay), receptive and expressive scores were significantly correlated with each other in both SELSI-REVT and PRES-REVT groups. In addition, the correlation of mean developmental age between tests are analyzed. In the SELSI-REVT group, there was weak correlation of mean developmental age between tests for receptive and expressive language. In the PRES-REVT group, there was a strong positive correlation of mean developmental age for receptive and expressive language in children aged >36 months. Attention deficits during the test was found to be the statistically significant factor affecting the differences between the tests. The odds ratios for receptive and expressive language were 2.60 (95% confidence interval,1.15–5.84) and 1.94 (95% confidence interval, 1.15–3.27), respectively. Conclusion This study examined the correlations and influencing factors between language development evaluation tools for toddlers. An integrated interpretation of comprehensive language and vocabulary evaluation tools may be possible in children older than 3 years of language developmental age.

Abstract The zebrafish is widely used as a model in biological studies. In particular, the heart rate and cortisol levels of zebrafish are commonly measured to elucidate the pharmacological effects of chemical substances. Meanwhile, although ventilation is also an important physiological index reflecting emotion-like states, few studies have evaluated the effects of chemicals on ventilation in adult zebrafish. In this study, we assessed whether it is possible to evaluate the pharmacological effects elicited by caffeine in adult zebrafish under free-swimming conditions. We measured the ventilation in adult zebrafish exposed to multiple concentrations of caffeine under restraint and free-swimming conditions and evaluated the pharmacological effects of caffeine using linear mixed model analysis. In addition, results of electrocardiogram analysis and swimming speeds were compared with those in previous reports to ensure that an appropriate dose of caffeine was administered. Under restraint conditions, caffeine significantly decreased heart rate and increased ventilation in a concentration-dependent manner. Under free-swimming conditions, the ventilation rate significantly increased with increasing caffeine concentration. These results indicate that the pharmacological effects elicited by chemicals on ventilation can be evaluated in free-swimming zebrafish.

Yujin Choi,1,&ast; Byunwoo Son,2,&ast; Woo-Chul Shin,3,4 Seong-uk Nam,5 Jaehong Lee,6 Jinwoong Lim,3,7 Sungha Kim,1 Changsop Yang,1 Hyeonhoon Lee8– 10 1KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 2Combined Dispensary, 7th Corps, Republic of Korea Army, Icheon, Republic of Korea; 3Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; 4Medical Company, 1st Airborne Special Forces Brigade, Republic of Korea Army, Seoul, Republic of Korea; 5 28th Division, Republic of Korea Army, Yangju-si, Republic of Korea; 6Medical Corps, The Capital Defense Command, Seoul, Republic of Korea; 7Department of Acupuncture and Moxibustion, Wonkwang University Gwangju Korean Medicine Hospital, Gwangju, Republic of Korea; 8Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 9Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; 10 9th Division, Republic of Korea Army, Goyang, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Changsop Yang, KM Science Research Division, Korea Institute of Oriental Medicine, 1672, Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea, Tel +82-42-869-2705, Fax +82-42-868-9395, Email yangunja@kiom.re.kr Hyeonhoon Lee, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Tel +82-2-2072-0505, Fax +82-2-747-5639, Email hhoon@snu.ac.krPurpose: Sleep quality among military service members is important for enhancing their capabilities and preventing psychiatric problems. We aimed to explore the association of dietary behaviors with poor sleep quality and increased risk of obstructive sleep apnea (OSA) in military men on active duty.Patients and Methods: A large-scale multi-site cross-sectional survey was conducted in five units of the Republic of Korea’s army. Poor sleep quality and increased risk of OSA were defined using the Pittsburgh sleep quality index (PSQI) and Berlin Questionnaire, respectively. Information on dietary behaviors, including the frequency of skipping breakfast, eating snacks, consuming a night meal, and overeating, were collected.Results: From August 2021 to September 2021, 4389 male respondents, mean age (20.8 ± 1.3 years), completed the survey; 2579 (58.8%) were assessed as having poor sleep quality, and 614 (14.0%) increased risk of OSA. After adjusting for lifestyle and occupational covariates, skipping breakfast 1– 2 times weekly was associated with an increased likelihood of experiencing poor sleep quality, compared with not skipping breakfast (odds ratio: 1.23 [95% CI 1.02– 1.47]). Eating night meals 5– 6 times weekly was also associated with poor sleep quality (odds ratio: 5.54 [95% CI 2.49– 14.18]). In addition, skipping breakfast daily (odds ratio: 2.28 [95% CI 1.27– 4.03]) and eating night meals daily (odds ratio: 2.30 [95% CI 1.21– 4.22]) were related to an increased risk of OSA.Conclusion: Dietary behaviors appear to be related to poor sleep quality and a high risk of OSA. To improve sleep quality, dietary factors could be considered when promoting health programs for military personnel in further research.Keywords: sleep, dietary behavior, insomnia, obstructive sleep apnea, military

Carbon export from mangrove forests to the oceans partly acts as a sink for atmospheric CO2, exceeding the rate of carbon burial in mangrove soils. Primary production in ecosystems adjacent to mangroves may prevent degassing and enhance further carbon export from mangroves to the oceans. In this study, we continuously monitored carbonate chemistry parameters (pCO2, dissolved inorganic carbon (DIC), total alkalinity (TA)) and dissolved organic carbon (DOC) in a tidal flat adjacent to a fringe mangrove forest over a spring-neap tidal cycle. Mean pCO2 during the entire period was 923 ± 318 μatm, and the export of TA, DIC, and DOC from the mangroves to the ocean was 36 ± 26 mmol m−2 d−1, 42 ± 39 mmol m−2 d−1, and 10 ± 9 mmol m−2 d−1, respectively. Semi-monthly pCO2 variations in the mangrove front were controlled by the tidal level during spring tide and by photosynthesis and respiration on the tidal flat during neap tide. This means that during neap tide, photosynthesis on the tidal flat offset the increase in pCO2 caused by the porewater export from the mangrove soil. The DIC/TA export ratio in this study was 1.17 ± 0.08, which was lower than the global average of 1.41 ± 1.39, indicating that the tidal flat adjacent to the mangrove forest may act as a buffer zone to mitigate the increase in pCO2, resulting in much of the exported DIC being stored in the ocean.

Despite numerous studies, the pathogenesis of ossification of the posterior longitudinal ligament (OPLL) is still unclear. Previous genetic studies proposed variations in genes related to bone and collagen as a cause of OPLL. It is unclear whether the upregulations of those genes are the cause of OPLL or an intermediate result of endochondral ossification process. Causal variations may be in the inflammation-related genes supported by clinical and updated genomic studies. OPLL demonstrates features of genetic diseases but can also be induced by mechanical stress by itself. OPLL may be a combination of various diseases that share ossification as a common pathway and can be divided into genetic and idiopathic. The phenotype of OPLL can be divided into continuous (including mixed) and segmental (including localized) based on the histopathology, prognosis, and appearance. Continuous OPLL shows substantial overexpression of osteoblast-specific genes, frequent upper cervical involvement, common progression, and need for surgery, whereas segmental OPLL shows moderate-to-high expression of these genes and is often clinically silent. Genetic OPLL seems to share clinical features with the continuous type, while idiopathic OPLL shares features with the segmental type. Further genomic studies are needed to elucidate the relationship between genetic OPLL and phenotype of OPLL.

Abstract MRI is the primary diagnostic modality for spinal cord tumors. However, its validity has never been vigorously scrutinized in daily routine clinical practice, where MRI tissue diagnosis is usually not a single one but multiple ones with several differential diagnoses. Here, we aimed to assess the validity of MRI in terms of predicting the pathology and location of the tumor in routine clinical settings. We analyzed 820 patients with primary spinal cord tumors, who have a pathological diagnosis and location in the operation record which were confirmed. We modified traditional measures for validity based upon a set of diagnoses instead of a single diagnosis. Sensitivity and specificity and positive and negative predictabilities were evaluated for the tumor location and pathology. For tumor location, 456 were intradural extramedullary; 165 were intramedullary, and 156 were extradural. The overall sensitivity and specificity were over 90.0%. However, the sensitivity became lower when the tumor resided simultaneously in two spaces such as in the intradural-and-extradural or intramedullary-and-extramedullary space (54.6% and 30.0%, respectively). Most common pathology was schwannoma (n = 416), followed by meningioma (114) and ependymoma (87). Sensitivities were 93.3%, 90.4%, and 89.7%, respectively. Specificities were 70.8%, 82.9%, and 76.0%. In rare tumors such as neurofibromas, and diffuse midline gliomas, the sensitivity was much lower (less than 30%). For common locations and pathologies, the validity of MRI is generally acceptable. However, for rare locations and pathologies, MRI diagnosis still needs some improvement.

Objective Total en bloc spondylectomy (TES) is a curative surgical method for spinal tumors. After resecting the 3 spinal columns, reconstruction is of paramount importance. We present cases of mechanical failure and suggest strategies for salvage surgery. Methods The medical records of 19 patients who underwent TES (9 for primary tumors and 10 for metastatic tumors) were retrospectively reviewed. Previously reported surgical techniques were used, and the surgical extent was 1 level in 16 patients and 2 levels in 3 patients. A titanium-based mesh-type interbody spacer filled with autologous and cadaveric bone was used for anterior support, and a pedicle screw/rod system was used for posterior support. Radiotherapy was performed in 11 patients (pre-TES, 5; post-TES, 6). They were followed up for 59 ± 38 months (range, 11–133 months). Results During follow-up, 8 of 9 primary tumor patients (89%) and 5 of 10 metastatic tumor patients (50%) survived (mean survival time, 124 ± 8 months vs. 51 ± 13 months; p=0.11). Mechanical failure occurred in 3 patients (33%) with primary tumors and 2 patients (20%) with metastatic tumors (p=0.63). The mechanical failure-free time was 94.4 ± 14 months (primary tumors, 95 ± 18 months; metastatic tumors, 68 ± 16 months; p=0.90). Revision surgery was performed in 4 of 5 patients, and bilateral broken rods were replaced with dual cobalt-chromium alloy rods. Repeated rod fractures occurred in 1 of 4 patients 2 years later, and the third operation (with multiple cobalt-chromium alloy rods) was successful for over 6 years. Conclusion Considering the difficulty of reoperation and patients’ suffering, preemptive use of a multiple-rod system may be advisable.

Abstract Elemental analysis based on muonic X-rays resulting from muon irradiation provides information about bulk material composition without causing damage, which is essential in the case of precious or otherwise unreachable samples, such as in archeology and planetary science. We developed a three-dimensional (3D) elemental analysis technique by combining the elemental analysis method based on negative muons with an imaging cadmium telluride double-sided strip detector (CdTe-DSD) designed for the hard X-ray and soft $$\gamma$$ γ -ray observation. A muon irradiation experiment using spherical plastic samples was conducted at the Japan Proton Accelerator Research Complex (J-PARC); a set of projection images was taken by the CdTe-DSD, equipped with a pinhole collimator, for different sample rotation angles. The projection images measured by the CdTe-DSD were utilized to obtain a 3D volumetric phantom by using the maximum likelihood expectation maximization algorithm. The reconstructed phantom successfully revealed the 3D distribution of carbon in the bulk samples and the stopping depth of the muons. This result demonstrated the feasibility of the proposed non-destructive 3D elemental analysis method for bulk material analysis based on muonic X-rays.

Peripheral nerve disorder of the lower extremities causes drop foot and disturbs the daily living activities of patients. The ankle joint hybrid assistive limb (HAL) provides voluntary ankle joint training using surface bioelectrical signals from the muscles of the lower extremities. We investigated the neurological effects of ankle joint HAL training in three patients. Sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs) were analyzed for the peroneal and tibial nerves prior to the first ankle joint HAL training session. Integrated surface electromyography EMG signals were recorded before and after the HAL training sessions to evaluate the effects of training for neuromuscular disorders. The patients were hospitalized to receive rehabilitation with HAL training for 2 weeks. The HAL training was performed daily with two 60 min sessions. All cases demonstrated severe neuromuscular impairment according to the result of the CMAP. All integrated EMG measurements of antagonistic muscle activities decreased after the ankle joint HAL training. The manual muscle testing (MMT) scores of each muscle were slightly increased after the HAL intervention for Case 2(tibialis anterior, from 2 to 2+; gastrocnemius muscles, from 2− to 2; extensor digitorum longus, and extensor hallucis longus, from 1 to 3). The MMT scores were also slightly increased except for gastrocnemius muscle for Case 3 (tibialis anterior, extensor digitorum longus, and extensor hallucis longus, from 2− to 2). These two patients demonstrated voluntary muscle contractions and nerve signals in the CMAP before the HAL training. Even though the amplitude of CMAPs was low, the HAL training may provide voluntary ankle joint movements by reducing the antagonistic muscle contraction via computer processing. The HAL training may enhance muscle movement and coordination through motor learning feedback.

Abstract Background This study examined how meeting the medical needs of injured workers after initial treatment may affect their return to work, using data from the Panel Study of Workers’ Compensation Insurance. Methods This study was designed as a longitudinal study, which used data from the second-year, follow-up survey conducted in the secondary cohort of the Panel Study of Workers’ Compensation Insurance. The odds ratio (OR) and 95% confidence interval were estimated through binomial and multinomial logistic regression analyses to examine the effects of unmet medical needs on workers’ return to original work and return to work overall (including reemployment). Results The returned to original work OR of workers whose rehabilitation needs were met was 1.35 (1.12–1.63) while the return to work OR was 1.20 (1.03–1.41). The returned to original work OR of workers whose medical needs were met was 1.64 (1.18–2.27) while the return to work OR was 1.39 (1.07–1.80). In terms of disability rating, the return to work ORs of workers with mild disabilities whose medical/rehabilitation needs were not met and those of workers without disabilities were 1.71 (1.17–2.49) and 1.97 (1.27–3.08), respectively. In the case of regular/temporary workers, the returned-to-work ORs of workers whose medical/rehabilitation needs were not met were 1.54 (1.12–2.13) and 1.27 (1.03–1.56), respectively. Conclusions For workers who sustained work-related injuries, providing medical accessibility and meeting rehabilitation needs were found to be important predictors of return to work after initial treatment.

A strain of Clostridium perfringens was isolated from the bile sample of a patient with emphysematous cholecystitis who underwent a laparoscopic cholecystectomy, followed by treatment with meropenem and recovery. Metagenomic analysis of the bile sample showed that 99.73% of the bile microbiota consisted of C. perfringens, indicating that C. perfringens JUM001 was the causative pathogen of acute emphysematous cholecystitis in this patient. Complete genome sequencing showed that C. perfringens JUM001 contained a circular chromosome of 3,231,023 bp and two circular plasmids, pJUM001-1 of 49,289 bp and pJUM001-2 of 47,855 bp. JUM001 was found to possess a typing toxin gene, plc, but no other typing toxin genes, indicating that its toxinotype is type A. The plasmids pJUM001-1 and pJUM001-2 belonged to the pCP13-like and pCW3-like families of plasmids, respectively, which are characteristic conjugative and archetypical plasmids of C. perfringens. Phylogenetic analysis showed that JUM001 was closely related to C. perfringens strain JXNC-DD isolated from a dog in China. To our knowledge, this is the first report of whole-genome sequences of a clinical isolate of C. perfringens causing acute emphysematous cholecystitis.

Abstract In this study, we report highly efficient green phosphorescent organic light-emitting diodes (OLEDs) with ultra-thin emission layers (EMLs). We use tris[2-phenylpyridinato-C2,N]iridium(III) (Ir(ppy)3), a green phosphorescent dopant, for creating the OLEDs. Under systematic analysis, the peak external quantum efficiency (EQE) of an optimized device based on the ultra-thin EML structure is found to be approximately 24%. This result is highest EQE among ultra-thin EML OLEDs and comparable to the highest efficiency achieved by OLEDs using Ir(ppy)3 that are fabricated via conventional doping methods. Moreover, this result shows that OLEDs with ultra-thin EML structures can achieve ultra-high efficiency.

ABSTRACT The genus Pseudomonas, a complex Gram-negative genus, includes species isolated from various environments, plants, animals, and humans. We compared whole-genome sequencing (WGS) with clinical bacteriological methods and evaluated matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to identify Pseudomonas species. Clinical isolates (N = 42) identified as P. putida or P. fluorescens by a bacterial identification system based on biochemical properties were reexamined by another identification system based on biochemical properties, two systems based on MALDI-TOF MS, and WGS. WGS revealed that 30 of the 42 isolates belonged to one of 14 known Pseudomonas species, respectively. The remaining 12 belonged to one of 9 proposed novel Pseudomonas species, respectively. MALDI-TOF MS analysis showed that the 9 novel species had unique major peaks. These results suggest that WGS is the optimal method to identify Pseudomonas species and that MALDI-TOF MS may complement WGS in identification. Based on their morphologic, physiologic, and biochemical properties, we propose nine novel Pseudomonas species. IMPORTANCE Most of the clinical isolates, identified as P. putida or P. fluorescens, were misidentified in clinical laboratories. Whole-genome sequencing (WGS) revealed that these isolates belonged to different Pseudomonas species, including novel species. WGS is a gold-standard method to identify Pseudomonas species, and MALDI-TOF MS analysis has the potential to complement WGS to reliably identify them.

Abstract The intestinal microbiome changes dynamically in early infancy. Colonisation by Bifidobacterium and Bacteroides and development of intestinal immunity is interconnected. We performed a prospective observational cohort study to determine the influence of antibiotics taken by the mother immediately before delivery on the intestinal microbiome of 130 healthy Japanese infants. Faecal samples (383) were collected at 1, 3, and 6 months and analysed using next-generation sequencing. Cefazolin was administered before caesarean sections, whereas ampicillin was administered in cases with premature rupture of the membranes and in Group B Streptococcus-positive cases. Bifidobacterium and Bacteroides were dominant (60–70% mean combined occupancy) at all ages. A low abundance of Bifidobacterium was observed in infants exposed to antibiotics at delivery and at 1 and 3 months, with no difference between delivery methods. A lower abundance of Bacteroides was observed after caesarean section than vaginal delivery, irrespective of antibiotic exposure. Additionally, occupancy by Bifidobacterium at 1 and 3 months and by Bacteroides at 3 months differed between infants with and without siblings. All these differences disappeared at 6 months. Infants exposed to intrapartum antibiotics displayed altered Bifidobacterium abundance, whereas abundance of Bacteroides was largely associated with the delivery method. Existence of siblings also significantly influenced the microbiota composition of infants.

Adaptive thermogenesis is regulated by central neuronal circuits. Here, the authors show that microRNA-33 in the brain contributes to the maintenance of brown adipose tissue thermogenesis and whole-body energy balance via enhanced sympathetic nerve tone, and regulating the expression of GABAa receptor subunits.

Abstract The viewing angle characteristics and light extraction efficiency of organic light-emitting diodes (OLEDs) with a micro-cavity structure were enhanced. This was accomplished by inserting a diffusion layer composed of nano-sized structures of a transparent polymer poly(methyl methacrylate) (PMMA) combined with a zinc oxide (ZnO) semi-planarization layer with a high refractive index (n = 2.1) into the devices. The PMMA nanostructures were fabricated by employing a reactive ion etching (RIE) process. The height and density of the PMMA nanostructures were controlled by varying the speed at which the PMMA was spin-coated onto the substrate. The insertion of the diffusion layer into the micro-cavity OLEDs (MC-OLEDs) improved the external quantum efficiency (EQE) by as much as 17% when compared to that of a MC-OLED without a diffusion layer. Furthermore, adjustment of the viewing angle from 0° to 60° halved the peak shift distance of the electroluminescence (EL) spectra from 42 to 20 nm. Additionally, changing the viewing angle from 0° to 60° changed the color coordinate movement distance of the MC-OLED with the diffusion layer to 0.078, less than half of the distance of the MC-OLED without the diffusion layer (0.165).

Animal studies have shown that amphoteric detergent and nuclease (DNase I and ribonuclease A) is the most reliable decellularization method of the peripheral nerve. However, the optimal combination of chemical reagents for decellularization of human nerve allograft needs further investigation. To find the optimal protocol to remove the immunogenic cellular components of the nerve tissue and preserve the basal lamina and extracellular matrix and whether the optimal protocol can be applied to larger-diameter human peripheral nerves, in this study, we decellularized the median and sural nerves from the cadavers with two different methods: nonionic and anionic detergents (Triton X-100 and sodium deoxycholate) and amphoteric detergent and nuclease (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), deoxyribonuclease I, and ribonuclease A). All cellular components were successfully removed from the median and sural nerves by amphoteric detergent and nuclease. Not all cellular components were removed from the median nerve by nonionic and anionic detergent. Both median and sural nerves treated with amphoteric detergent and nuclease maintained a completely intact extracellular matrix. Treatment with nonionic and anionic detergent decreased collagen content in both median and sural nerves, while the amphoteric detergent and nuclease treatment did not reduce collagen content. In addition, a contact cytotoxicity assay revealed that the nerves decellularized by amphoteric detergent and nuclease was biocompatible. Strength failure testing demonstrated that the biomechanical properties of nerves decellularized with amphoteric detergent and nuclease were comparable to those of fresh controls. Decellularization with amphoteric detergent and nuclease better remove cellular components and better preserve extracellular matrix than decellularization with nonionic and anionic detergents, even in large-diameter human peripheral nerves. In Korea, cadaveric studies are not yet legally subject to Institutional Review Board review.

This study proposes a novel process that integrates the molding and patterning of solid-state polymers with the force generated from the volume expansion of the microcellular-foaming process (MCP) and the softening of solid-state polymers due to gas adsorption. The batch-foaming process, which is one of the MCPs, is a useful process that can cause thermal, acoustic, and electrical characteristic changes in polymer materials. However, its development is limited due to low productivity. A pattern was imprinted on the surface using a polymer gas mixture with a 3D-printed polymer mold. The process was controlled with changing weight gain by controlling saturation time. A scanning electron microscope (SEM) and confocal laser scanning microscopy were used to obtain the results. The maximum depth could be formed in the same manner as the mold geometry (sample depth: 208.7 μm; mold depth: 200 μm). Furthermore, the same pattern could be imprinted as a layer thickness of 3D printing (sample pattern gap and mold layer gap: 0.4 mm), and surface roughness was increased according to increase in the foaming ratio. This process can be used as a novel method to expand the limited applications of the batch-foaming process considering that MCPs can impart various high-value-added characteristics to polymers.

In response to the need for validating high-fidelity deterministic neutronics solvers capable of pin-resolved neutron flux distributions, an instrumented fuel rod was designed for the experimental reactor CROCUS, operated by EPFL’s Laboratory for Reactor Physics and Systems Behaviour. This rod aims at obtaining intra-pin data using activation dosimetry techniques. Placed in the outer region of the reactor core, the rod utilizes spaces between four metal uranium cigars (25 cm each) to house various disk dosimeters, targeting different neutron energy ranges and allowing retrieval of radial and azimuthal intra-pin neutron reaction rates. A design of experiment (DOE) study, aided by Serpent2 Monte Carlo calculations, facilitated the selection of dosimeter material and rod design, ensuring detection of within-pin neutron flux v ariations w hile adhering to mechanical and regulatory constraints. Azimuthal divisions of activation dosimeters were irradiated at the core center and subsequently subjected to activity determination using an HPGe gamma spectrometer. The objectives were met, detecting expected azimuthal variations within dosimeters and confirming uncertainties on reconstructed activity to be smaller than the amplitude of the observed variations. A permit from the Swiss nuclear regulatory authority ENSI-IFSN was obtained, allowing installation and usage of the instrumented fuel rod in CROCUS, known as the NECTAR experiments.

Background/Aims To investigate epidemiologic characteristics, clinical and economic burdens, and factors associated with mortality in complicated skin and skin structure infection (cSSSI) patients in Korea. Methods A retrospective, observational, nationwide study was conducted between April to July 2012 at 14 tertiary-hospitals in Korea. Eligible patients were hospitalized adults with community acquired cSSSI, who underwent surgical intervention and completed treatment between November 2009 and October 2011. Data on demography, clinical characteristics, outcomes and medical resource utilization were collected through medical record review. Direct medical costs were calculated by multiplying quantities of resources utilized by each unit price in Korea. Results Of 473 patients enrolled, 449 patients (except 24 patients with no record on surgical intervention) were eligible for analysis. Microbiological testing was performed on 66.1% of patients and 8.2% had multiple pathogens. Among culture confirmed pathogens (n = 297 patients, 340 episodes), 76.2% were gram-positive (Staphylococcus aureus; 41.2%) and 23.8% were gram-negative. The median duration of hospital stay was 16 days. Among treated patients, 3.3% experienced recurrence and 4.2% died in-hospital. The mean direct medical costs amounted to $4,195/ person, with the greatest expenses for hospitalization and antibiotics. The in-hospital mortality and total medical costs were higher in combined antibiotics therapy than monotherapy (p < 0.05). Charlson’s comorbidity index ≥ 3, standardized early warning scoring ≥ 4, sub-fascia infections and combined initial therapy, were all found to be associated with higher mortality. Conclusions Korean patients with community-onset cSSSI suffer from considerable clinical and economic burden. Efforts should be made to reduce this burden through appropriate initial treatment.

Woong-Hee Shin,1 Keiko Kumazawa,2 Kenichiro Imai,3 Takatsugu Hirokawa,3 Daisuke Kihara4– 7 1Department of Chemical Science Education, Sunchon National University, Suncheon 57922, Republic of Korea; 2Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Tokyo 191-8512, Japan; 3Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan; 4Department of Biological Sciences, Purdue University, West Lafayette, IN 47906, USA; 5Department of Computer Science, Purdue University, West Lafayette, IN 47906, USA; 6Center for Cancer Research, Purdue University, West Lafayette, IN 47906, USA; 7Department of Pediatrics, Cincinnati Children’s Hospital Medical Care, University of Cincinnati, Cincinnati, OH 45229, USACorrespondence: Daisuke Kihara Email dkihara@purdue.eduAbstract: It has been noticed that the efficiency of drug development has been decreasing in the past few decades. To overcome the situation, protein–protein interactions (PPIs) have been identified as new drug targets as early as 2000. PPIs are more abundant in human cells than single proteins and play numerous important roles in cellular processes including diseases. However, PPIs have very different physicochemical features from the conventional drug targets, which make targeting PPIs challenging. Therefore, as of now, only a small number of PPI inhibitors have been approved or progressed to a stage of clinical trial. In this article, we first overview previous works that analyzed differences between PPIs with PPI targeting ligands and conventional drugs with their binding pockets. Then, we constructed an up-to-date list of PPI targeting drugs that have been approved or are currently under clinical trial and have bound drug–target structures available. Using the dataset, we analyzed the PPIs and their ligands using several scores of druggability. Druggability scores showed that PPI sites and their drugs targeting PPIs are less druggable than conventional binding pockets and drugs, which also indicates that PPI drugs do not follow the conventional rules for drug design, such as Lipinski’s rule of five. Our analyses suggest that developing a new rule would be beneficial for guiding PPI-drug discovery.Keywords: protein–protein interaction, PPI, PPI drugs, drug discovery

IntroductionAssessing patient expectations in orthopaedic surgery has gained significant importance over time. However, there have been only a few studies on how to measure such expectations in hand surgery. Against the backdrop, the study was designed to develop a valid and reliable expectations survey for patients undergoing hand surgery and to identify the correlations between preoperative expectations and postoperative satisfaction.Materials and methodsThis is a three-phase prospective cohort study. In the first phase of the study (146 patients), patient expectations were assessed while developing a draft questionnaire based on frequency and clinical relevance. In the second phase (154 patients newly included), test-retest reliability was measured to ensure test consistency. The Intraclass Correlation Coefficient (ICC) served as a basis for developing the final survey questionnaire. In the third phase, we followed up with patients, who completed the preoperative expectations survey, 3 months after surgery to assess the fulfillment of their expectations. The Pearson correlation method was used to measure the association between preoperative expectations and postoperative satisfaction.ResultsIn the first phase, 146 patients shared 406 different expectations, which were grouped into nine categories. Then, in the second phase, the final survey was populated by questionnaire items under respective category that have revealed strong test-retest reliability (ICC of 0.91). A significant positive correlation between patient expectations and satisfaction was observed (R = 0.181, p = 0.034).ConclusionThe survey was designed to offer a valid and reliable approach for the comprehensive assessment of patient expectations in hand surgery. The survey results show that patients with high expectations tend to be more satisfied with surgical outcomes. It is strongly believed that this approach would serve as a useful tool at a time when patient perspective is taken into account increasingly more in the clinical practice.

Introduction Assessing patient expectations in orthopaedic surgery has gained significant importance over time. However, there have been only a few studies on how to measure such expectations in hand surgery. Against the backdrop, the study was designed to develop a valid and reliable expectations survey for patients undergoing hand surgery and to identify the correlations between preoperative expectations and postoperative satisfaction. Materials and methods This is a three-phase prospective cohort study. In the first phase of the study (146 patients), patient expectations were assessed while developing a draft questionnaire based on frequency and clinical relevance. In the second phase (154 patients newly included), test-retest reliability was measured to ensure test consistency. The Intraclass Correlation Coefficient (ICC) served as a basis for developing the final survey questionnaire. In the third phase, we followed up with patients, who completed the preoperative expectations survey, 3 months after surgery to assess the fulfillment of their expectations. The Pearson correlation method was used to measure the association between preoperative expectations and postoperative satisfaction. Results In the first phase, 146 patients shared 406 different expectations, which were grouped into nine categories. Then, in the second phase, the final survey was populated by questionnaire items under respective category that have revealed strong test-retest reliability (ICC of 0.91). A significant positive correlation between patient expectations and satisfaction was observed (R = 0.181, p = 0.034). Conclusion The survey was designed to offer a valid and reliable approach for the comprehensive assessment of patient expectations in hand surgery. The survey results show that patients with high expectations tend to be more satisfied with surgical outcomes. It is strongly believed that this approach would serve as a useful tool at a time when patient perspective is taken into account increasingly more in the clinical practice.

Background: Impact of mechanical left ventricular (LV) unloading on myocardial tissue perfusion and its regulating factors remain unclear. This study was conducted to elucidate the predictors of regional blood flow (RBF) improvement by mechanical LV unloading.Materials and Methods: One to four weeks after percutaneous induction of myocardial infarction (MI), Yorkshire pigs (n = 15) underwent mechanical LV unloading using Impella CP. Hemodynamic parameters were collected prior to LV unloading. RBF in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading.Results: RBF showed variable responses to mechanical LV unloading. While infarct RBF improved in general (0.33 ± 0.13 to 0.42 ± 0.19 mL/min/g, p = 0.06), there were a few pigs that showed little improvement. Meanwhile, there were no clear trends in the border (1.07 ± 0.47 to 1.02 ± 0.65 mL/min/g, p = 0.73) and remote myocardial RBF (1.25 ± 0.52 to 1.23 ± 0.68 mL/min/g, p = 0.85). In the simple linear regression analysis, cardiac output, mean pulmonary arterial wedge pressure, mean left atrial pressure, minimum LV pressure, end-diastolic LV pressure, maximum dP/dt, slope of end-diastolic pressure-volume relationship (EDPVR) and end-diastolic wall stress were significantly associated with % change of infarct RBF. In the multiple regression model, slope of EDPVR and maximum dP/dt remained as independent predictors of infarct RBF change.Conclusion: Steeper EDPVR and lower maximum dP/dt were associated with increased blood perfusion in the infarct area after LV unloading. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility.

Objective: The aim of this study was to clarify the genetic and epidemiological properties of multidrug-resistant Acinetobacter baumannii in medical settings in Myanmar. Methods: A total of 45 A. baumannii clinical isolates were obtained in medical settings in Myanmar. The whole genomes were sequenced by a next generation sequencer, and the phylogenetic tree was constructed from single nucleotide polymorphism concatemers. Multilocus sequence types were deduced and drug resistance genes were identified. Results: Thirty-eight MDR Acinetobacter baumannii isolates were obtained from seven hospitals in Myanmar. The majority of MDR A. baumannii isolates belonged to ST2. Of the 38 isolates, 5 harbored blaNDM-1, and 28 did armA or armA2 Conclusions: A. baumannii ST2 producing 16S rRNA methylase ArmA has been spreading in medical settings in Myanmar.

Background There is increasing concern that moderate preterm (32–33 weeks’ gestation) and late preterm (34–36 weeks’ gestation) birth may be associated with minor neurodevelopmental problems affecting poor school performance. Purpose We explored the cognitive function, cognitive visual function, executive function, and behavioral problems at schoolage in moderate to late preterm infants. Methods Children aged 7–10 years who were born at 32+0 to 36+6 weeks of gestation and admitted to the neonatal intensive care unit from August 2006 to July 2011 at the National Health Insurance Service Ilsan Hospital were included. We excluded children with severe neurologic impairments, congenital malformations, or chromosomal abnormalities. Neuropsychological assessments consisted of 5 neuropsychological tests and 3 questionnaires. Results A total of 37 children (mean age, 9.1±1.2 years) participated. The mean gestational age at birth was 34.6±7.5 weeks, while the mean birth weight was 2,229.2±472.8 g. The mean full-scale intelligence quotient was 92.89±11.90; 24.3% scored between 70 and 85 (borderline intelligence functioning). An abnormal score was noted for at least one of the variables on the attention deficit hyperactivity disorder diagnostic system for 65% of the children. Scores below borderline function for executive quotient and memory quotient were 32.4% and 24.3%, respectively. Borderline or clinically relevant internalizing problems were noted in 13.5% on the Child Behavior Check List. There were no significant associations between perinatal factors or socioeconomic status and cognitive, visual perception, executive function, or behavior outcomes. Conclusion Moderate to late preterm infants are at risk of developing borderline intelligence functioning and attention problems at early school age. Cognitive and executive functions that are important for academic performance must be carefully monitored and continuously followed up in moderate to late preterm infants.

Abstract Background The spread of Enterobacteriaceae producing both carbapenemases and Mcr, encoded by plasmid-mediated colistin resistance genes, has become a serious public health problem worldwide. This study describes three clinical isolates of Enterobacter cloacae complex co-harboring bla IMP-1 and mcr-9 that were resistant to carbapenem but susceptible to colistin. Methods Thirty-two clinical isolates of E. cloacae complex non-susceptible to carbapenems were obtained from patients at 14 hospitals in Japan. Their minimum inhibitory concentrations (MICs) were determined by broth microdilution methods and E-tests. Their entire genomes were sequenced by MiSeq and MinION methods. Multilocus sequence types were determined and a phylogenetic tree constructed by single nucleotide polymorphism (SNP) alignment of whole genome sequencing data. Results All 32 isolates showed MICs of ≥2 μg/ml for imipenem and/or meropenem. Whole-genome analysis revealed that all these isolates harbored bla IMP-1, with three also harboring mcr-9. These three isolates showed low MICs of 0.125 μg/ml for colistin. In two of these isolates, bla IMP-1 and mcr-9 were present on two separate plasmids, of sizes 62 kb and 280/290 kb, respectively. These two isolates did not possess a qseBC gene encoding a two-component system, which is thought to regulate the expression of mcr-9. In the third isolate, however, both bla IMP-1 and mcr-9 were present on the chromosome. Conclusion The mcr-9 is silently distributed among carbapenem-resistant E. cloacae complex isolates, of which are emerging in hospitals in Japan. To our knowledge, this is the first report of isolates of E. cloacae complex harboring both bla IMP-1 and mcr-9 in Japan.

Chylothorax, the accumulation of chyle in the pleural space, is a rare condition, but can lead to serious complications in neonates. Conservative therapy for chylothorax includes enteral feeding with medium-chain triglyceride-enriched diet or parenteral nutrition and administration of octreotide. Surgical management is considered in cases where there is no response to conservative therapy; however, the standardized approach to refractory neonatal chylothorax is still controversial. Chemical pleurodesis can be used when medical therapies for chylothorax fail, to avoid more invasive surgical procedures. We report an extremely preterm infant born at 26 weeks of gestation with refractory chylothorax after patent ductus arteriosus ligation. The infant was successfully treated with pleurodesis using 4% povidone-iodine, without long-term side effects.

ObjectiveTo assess the clinical usefulness and diagnostic accuracy of ultrasonographic measurement of endometrial thickness (ET) in women with endometrial hyperplasia or cancer (EH+).MethodsThis retrospective cohort study included 29,995 consecutive women who underwent transvaginal ultrasonography (TVS) for an incidental finding of a thickened endometrium at the health screening and promotion center at Asan Medical Center between 2006 and 2010. Among 959 patients with endometrial abnormalities, 92 patients were included in this study. A total of 867 patients were excluded: 416 were lost to follow-up; 263 did not undergo endometrial biopsy; 155 had endometrial polyps; 17 had submucosal myomas; and 16 had insufficient tissue samples. Endometrial histology was the reference standard for calculating accuracy.ResultsOf the 92 patients, 78 (84.8%) had normal pathology, while 14 (15.2%) had endometrial pathology (EH+), including 5 patients (35.7%) with simple hyperplasia without atypia, 3 (21.4%) with complex hyperplasia, and 6 (42.9%) with endometrial carcinoma, all stage Ia. The area under the receiver-operating characteristic curve was 0.75 (95% confidence interval [CI], 0.593–0.906). The cut-off value for ET was 8 mm, indicating that TVS ET had a fair accuracy in diagnosing carcinoma, had a sensitivity of 100% (95% CI, 62.9–100.0%) and a specificity of 24.3% (95% CI, 15.2–36.3%).ConclusionTVS is useful for detecting EH+, with a cut-off value for ET of 8 mm having a high sensitivity for detecting endometrial pathologies and the ability to identify women highly unlikely to have EH+, thereby avoiding more invasive endometrial biopsy.

Summary: No effective treatment is yet available to reduce infarct size and improve clinical outcomes after acute myocardial infarction by enhancing early reperfusion therapy using primary percutaneous coronary intervention. The study showed that Kyoto University Substance 121 (KUS121) reduced endoplasmic reticulum stress, maintained adenosine triphosphate levels, and ameliorated the infarct size in a murine cardiac ischemia and reperfusion injury model. The study confirmed the cardioprotective effect of KUS121 in a porcine ischemia and reperfusion injury model. These findings confirmed that KUS121 is a promising novel therapeutic agent for myocardial infarction in conjunction with primary percutaneous coronary intervention. Key Words: ATP, ER stress, KUS121, myocardial infarction

Microplastics and plant litter are ubiquitous in the soil environment, and both materials can influence soil properties and biota. Plant litter releases secondary metabolites (e.g., phenolic compounds) during the decomposition process, including chemical compounds active in plant defense. Effects of microplastics and plant litter on soil biota have been studied independently but we have limited information about the combined effects of both sources of chemicals. Here, we specifically focused on the interaction between plant litter and microplastics, as well as their potential effects on soil biota (i.e., nematodes). We used soils from a previous experiment that included three different types of microplastic fibers (MFs) and four different types of plant litter, which were incubated in the soil in all combinations of materials. After soil incubation (42 days) in the previous experiment, we here tested for effects on nematodes (Caenorhabditis elegans). Plant litter treatments negatively affected the reproduction of nematodes, but these effects were reduced when the soils were incubated along with MFs. We measured the phenolic concentrations in plant litter extracts in a kinetic experiment and found that phenolic concentrations significantly decreased with some of the MF additions. Our results suggest that microplastics can affect the potential effects of natural chemicals such as plant phenolic compounds. We urge future studies to consider this possibility as a key explanatory process underpinning effects of microplastic in the soil environment.