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BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:326 pages:249-261 ispartof: location:Netherlands status: published

Malignancy may lead to sarcoidosis, which is referred to as sarcoid reaction. This reaction is believed to be a host immune response to the release of soluble antigens from cancer cells. Studies have shown strong 2'-deoxy-2'-[F-18]fluoro-D-glucose (F-18 FDG) uptake in sarcoid reaction and in true sarcoidosis. Therefore, in patients with malignancy, sarcoid reactions can mimic metastasis or recurrence on F-18 FDG positron emission tomography/computed tomography (PET/CT). Herein, we report the case of a 58-year-old woman with a history of left breast cancer whose FDG PET/CT evaluated at 3 months after adjuvant chemotherapy presented hypermetabolic lymphadenopathy in the right supraclavicular and right mediastinal areas. We interpreted these as metastases because the involved lymph nodes were intensely hypermetabolic and appeared newly. Pathologic evaluation of the excised lymph node revealed noncaseating chronic granulomas without malignant cells, indicating a sarcoid reaction. After appropriate steroid therapy, both the size and metabolic activity of the lymphadenopathy substantially decreased. Most sarcoid reactions present as bilateral hilar and peribronchial lymphadenopathies. Our patient presents an atypical example that a sarcoid reaction can also present in a unilateral pattern, making its diagnosis challenging. When interpreting FDG PET/CT images, considering that the sarcoid reaction pattern can vary is crucial.

Epidermal inclusion cyst is a relatively common benign lesion of the skin, and it can occur anywhere in the hair-bearing area of the body. It usually appears as an asymptomatic mass, which is less than 4 cm in size. However, rarely it can occur as a large mass in the axilla, and in such cases, the location and size tend to cause more complications. The author encountered a patient with a large epidermal inclusion cyst of the axilla. Ultrasound examination showed an oval-shaped hypoechoic subcutaneous mass with dermal attachment, intralesional echogenic reflectors, filiform anechoic areas, and no vascularity. These characteristic imaging features could lead to an accurate preoperative imaging diagnosis without biopsy and avoid subsequent complications. Excision of the mass was performed due to discomfort because of the large size and growing nature of the lesion, and histological examination confirmed the diagnosis of an epidermal inclusion cyst. Therefore, recognition of diagnostic ultrasound features of this entity may enable an accurate preoperative diagnosis, even when it has an unusual size and location.

Bloody nipple discharge in pediatric patients is rare and mostly associated with benign conditions.Despite the generally benign nature, a thorough investigation of the cause and treatment is required if a palpable lesion is present. Here, the author reports a case of bloody nipple discharge in an adolescent girl with no significant medical history. Breast ultrasound demonstrated a solid, oval-shaped, circumscribed mass in the left subareolar region that was categorized as category 4a according to the breast imaging reporting and data system (BI-RADS). An excisional biopsy and histological examination confirmed a diagnosis of intraductal papilloma. While intraductal papilloma is rare in the pediatric population, ultrasound evaluation and knowledge of characteristic findings are useful for noninvasive diagnostics and image-guided treatment planning.

As cement manufacturing is associated with CO2 emissions that contribute to environmental problems, cement usage must be reduced and alternative aggregates must be developed. Thus, we developed and evaluated a mortar that uses feldspar as a fine aggregate, which does not require additional mineral admixtures. Feldspar and conventional plastering sand-based specimens were prepared with a fine aggregate proportion of 75%, 80%, or 85%. The compressive strength test results confirmed that the strength of the feldspar-based mortar was 1.1–4.5 times higher than conventional plastering sand-based mortar. Microstructure analysis after 3 and 7 d of curing revealed the existence of capillary micropores and gel pores, which improved water tightness. C-S-H and C-S-H gel hydration was also observed at the early stage, and the amount of C-S-H also increased. Further, an additional reaction may have occurred between feldspar compounds, SiO2 and Al2O3, and Ca(OH)2 that accelerated C-S-H production and contributed to the higher compressive strength. The relatively high-strength feldspar-based mortar is expected to reduce cement dependency, which can be achieved using a fine-aggregate feldspar mixing ratio according to project requirements. Thus, the proposed fine aggregate alternative can help alleviate the environmental problems associated with cement usage. It also has potential as an eco-friendly building material.

In the central nervous system, microglia are regarded as the main cells responsible for phagocytosis, contributing to neural circuit refinement and homeostasis through synapse elimination. However, recent findings have shown that astrocytes also actively participate in synapse homeostasis through phagocytosing synapses, neuronal debris, axonal mitochondria, and pathological protein aggregates. In addition, it has been also suggested that astrocytes may regulate microglial phagocytosis by secreting molecules such as IL-33 and C3. Here, we have introduced key findings regarding direct and indirect astrocyte-mediated phagocytosis in CNS development, the sleep/wake cycle, and aging. We have also discussed current information about reactive astrocytes and their phagocytic function in the diseased brain, focusing on ischemia and Alzheimer's disease. Through this review, we aim to provide an overview of the current status as well as future perspectives regarding the important role of astrocytic control of phagocytosis.

Purpose Emerging data suggest that higher radiation doses in post-mastectomy radiotherapy may be associated with an increased risk of reconstruction complications. This study aimed to validate previous findings regarding the impact of radiation dose on complications among women with breast cancer using a multi-center dataset. Methods Fifteen institutions participated, and women with breast cancer who received radiotherapy after either autologous or prosthetic breast reconstruction were included. The primary endpoint was major post-radiation therapy complications requiring re-operation for explantation, flap failure, or bleeding control. Results In total, 314 patients were included. Radiotherapy was performed using both conventional fractionation and hypofractionation in various schedules. The range of the radiation therapy dose in Equivalent Dose in 2 Gy fractions (EQD2; α/β = 3.5) varied from 43.4 to 71.0 Gy (median dose: 48.6 Gy). Boost radiation therapy was administered to 49 patients. Major post-radiation therapy complications were observed in 24 (7.6%) patients. In multivariate analysis, an increasing EQD2 per Gy (odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.26–1.98; p, Highlights • Radiation dose is associated with the risk of breast reconstruction complications. • We conducted a retrospective multi-center observational study of 314 women in Korea. • Complication-related risk factors were identified using multivariate analysis. • Use of hypofractionated radiation therapy may improve breast reconstruction outcomes. • A prospective multi-center study is under way to further validate our findings.

Objectives This study aimed to compare the discontinuation rates attributed to adverse events and treatment outcomes between clarithromycin (CLR) and azithromycin (AZM) in patients with Mycobacterium avium complex lung disease (MAC-LD). Methods Among patients diagnosed with MAC-LD during 2001–2013, 560 for whom treatment was initiated as a guideline-based therapy until May 2018 were selected for adverse event analysis. Of them, 316 who underwent treatment for ≥12 months were selected for outcome analysis. Their medical records were retrospectively reviewed. The discontinuation and treatment success rates were analysed after adjustments using the inverse probability of treatment weighted (IPTW) method. Results Among the 560 patients, 466 (83.2%) and 94 (16.8%) started CLR-containing and AZM-containing regimens, respectively. The IPTW method using propensity scoring revealed that the discontinuation rate attributed to adverse events was significantly higher with CLR than AZM use (24.6% vs. 9.6%; P = 0.001). The overall treatment success rate of the 316 patients who received guideline-based therapy for ≥12 months was 83.2%. Analysis adjusted by the IPTW method showed no significant difference in the treatment success rate between the use of CLR and AZM. Furthermore, 1-year and 3-year recurrence rates were similar with the two drugs (6.8% vs. 6.0%; P > 0.999 and 31.0% vs. 37.5%; P = 0.482, respectively). Conclusions These findings suggest that an AZM-containing regimen may be the better initial treatment choice for MAC-LD as it resulted in lesser discontinuation rates attributed to adverse events while offering similar patient outcomes when compared with CLR.

Salmonella is one of the main foodborne pathogens that affect humans and farm animals. The Salmonella genus comprises a group of food-transmitted pathogens which cause highly prevalent foodborne diseases throughout the world. The aim of this study was to appraise the viability of Salmonella Typhimurium biofilm under water treatment at room temperature on different surfaces, specifically stainless steel (SS), plastic (PLA), rubber (RB), and eggshell (ES). After 35 days, the reduction of biofilm on SS, PLA, RB, and ES was 3.35, 3.57, 3.22, and 2.55 log CFU/coupon without water treatment and 4.31, 4.49, 3.50, and 1.49 log CFU/coupon with water treatment, respectively. The dR value (time required to reduce bacterial biofilm by 99% via Weibull modeling) of S. Typhimurium without and with water treatment was the lowest on PLA (176.86 and 112.17 h, respectively) and the highest on ES (485.37 and 2436.52 h, respectively). The viability of the S. Typhimurium on ES and the three food-contact surfaces was monitored for 5 weeks (35days). The results of this study provides valuable information for the control of S. Typhimurium on different surfaces in the food industry, which could reduce the risk to consumers.

Background: We aimed to evaluate the influence of cold airflow from the air conditioner on skin barrier function and filaggrin degradation products (FDPs) in children with atopic deramtitis (AD). Methods: In a case-control study, 28 children with AD and 12 normal children without AD were exposed to one of two air conditioner modes (conventional or wind-free) for 2 h. Skin temperature, transepidermal water loss (TEWL), and skin pH were measured on right cheek and forearm at pre- and post-exposure time points. We also measured filaggrin and FDPs from the volar surface of the forearm. Results: In AD patients, skin temperature on the forearm decreased after exposure to the conventional and wind-free modes (P

Background: Humidified high-flow nasal cannula (HHFNC) has gained popularity because it is easier to use, more comfortable for babies, and advantageous for mother-infant bonding. HHFNC is not inferior to other non-invasive ventilators for preventing adverse outcomes, but more studies are needed to ensure the safe use of HHFNC as an initial respiratory support for newborns. The aim of this study was to investigate risk factors for treatment failure of HHFNC as an initial respiratory support in newborns with respiratory distress after birth. Methods: We included 97 newborns who required non-invasive respiratory support within 24 h after birth. The success group included 68 infants who were successfully managed only on HHFNC, and 29 infants were the failure group who required other respiratory support because of respiratory acidosis, hypoxia, or apnea. Results: Compared with the success group, the failure group had lower GA, a higher rate of antenatal steroid use, prolonged rupture of membrane, lower pH, higher pCO2 on blood-gas analysis after HHFNC application and higher incidence of respiratory distress syndrome of newborn (RDS). After adjusting for GA, higher FiO2 settings during acidosis, hypercarbia after the application of HHFNC shown on blood-gas analysis and the presence of RDS remained significant. The rate of treatment failure was 16.2% for ≥36 weeks, 19.3% for ≥34 weeks, and 22.1% for ≥33 weeks. Conclusion: Treatment failure of HHFNC should be considered a risk for newborns of less than 34 weeks and infants with respiratory distress from RDS. Higher FiO2 settings during HHFNC, and acidosis and hypercarbia after the application of HHFNC shown on blood-gas analysis may help identify high-risk newborns for other non-invasive ventilators or intubation. Key Words: high-flow nasal cannula, newborn infant, noninvasive ventilation, respiratory distress

Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity, which is closely associated with inflammation. Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of pro-inflammatory cytokines or prostaglandins. However, its role in osteoclast differentiation and function remains unknown. Here, we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism. BA inhibited osteoclast differentiation and strongly suppressed interleukin-1β (IL-1β) production. BA inhibited osteoclast formation and bone resorption when added to bone marrow-derived macrophages and differentiated osteoclasts, and the inhibitory effect was reversed by IL-1β treatment. The reporter assay and the inhibitor study of IL-1β transcription suggested that BA inhibited nuclear factor-κB and activator protein-1 by regulating IκB kinase, extracellular signal regulated kinase and P38, resulting in the down-regulation of IL-1β expression. BA also promoted osteoblast differentiation. Furthermore, BA protected lipopolysaccharide- and ovariectomy-induced bone loss in mice, suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis., Graphical abstract The role of BA was explored in regulating osteoclast differentiation and the underlying mechanism was elucidated. BA inhibits osteoclast differentiation and resorption by suppressing IL-1β synthesis via down-regulation of IKK, ERK and P38, and promotes osteoblast differentiation.Image 1

Summary: Heterochromatin functions as a scaffold for factors responsible for gene silencing and chromosome segregation. Heterochromatin can be assembled by multiple pathways, including RNAi and RNA surveillance. We identified factors that form heterochromatin using dense profiles of transposable element integration in Schizosaccharomyces pombe. The candidates include a large number of essential proteins such as four canonical mRNA cleavage and polyadenylation factors. We find that Iss1, a subunit of the poly(A) polymerase module, plays a role in forming heterochromatin in centromere repeats that is independent of RNAi. Genome-wide maps reveal that Iss1 accumulates at genes regulated by RNA surveillance. Iss1 interacts with RNA surveillance factors Mmi1 and Rrp6, and importantly, Iss1 contributes to RNA elimination that forms heterochromatin at meiosis genes. Our profile of transposable element integration supports the model that a network of mRNA cleavage and polyadenylation factors coordinates RNA surveillance, including the mechanism that forms heterochromatin at meiotic genes. : Lee et al. use dense profiles of transposon integration to identify genes important for the formation of heterochromatin. Among many candidates, Iss1 is a canonical mRNA cleavage and polyadenylation factor found to be important for heterochromatin at meiotic genes by recruiting the nuclear exosome. Keywords: Tn-seq, heterochromatin, polyadenylation, Schizosaccharomyces pombe, Iss1, RNA elimination, Rrp6, ssm4, Mmi1, mei4

Highlights • The rudimentary noncommunicating horn with a functional endometrial cavity is should be treated promptly to prevent obstetric and gynecologic complications. • The MRI is essential in assessing Müllerian anomaly. • The presence of concomitant congenital malformation, renal and skeletal anomalies, should raise the high suspicion of Müllerian anomaly., Introduction The rudimentary noncommunicating horn with a functional endometrial cavity is rare and often challenging to diagnose because of the variety in clinical features. We present a case of a patient for whom the diagnosis of a uterine horn was missed during the prior cesarean section, which later successfully treated with robotic-assisted laparoscopic removal of a rudimentary noncommunicating horn of uterus and ipsilateral tube. Presentation of case A 20-year old woman, gravida 3 para 2, presented with a complaint of acute and severe pelvic pain with fever. Multiple imaging modalities of pelvis and abdomen showed an 8 cm right-sided pelvic mass with a tubular structure adjacent to the uterus. The pelvic inflammatory disease was diagnosed and treated with intravenous antibiotics. After reviewing multiple radiology images, Müllerian anomaly was suspected, and the rudimentary horn with the fallopian tube was confirmed via diagnostic hysteroscopy and laparoscopy. Subsequently, robotic-assisted laparoscopic removal of the right horn with the fallopian tube was performed. Discussion Assessment of a rudimentary noncommunicating horn with unicornuate uterus can be achieved by several radiology methods, including computed tomography, magnetic resonance imaging, two and 3-dimensional ultrasonography, hysterosalpingogram, and sonohysterography. In addition, evaluation of concomitant skeletal and renal anomalies is essential in enhancing diagnostic accuracy. In our case, the Müllerian anomaly with delayed onset complications was diagnosed by multiple imaging studies and treated successfully. Conclusion The early and correct diagnosis of the Müllerian anomaly remains difficult but essential as misdiagnosis can be associated with serious complications in patients.

Highlights • FR generation and persist time should be studied to avoid its risk in clinic. • FR generation and persist time were measured by SCL with a PMT in nanoseconds. • The measured FR persist time reaches a maximum of 1000 ms. • It is recommended to set the shock wave irradiation frequency below 1 Hz., The shock wave used in extracorporeal shock wave lithotripsy (ESWL) induces strong cavitation and generates a large amount of free radicals (FR). In order to evaluate the harmfulness of FR in the ESWL, information on the incidence and persist time of FR caused by shock waves is required. FR markers can estimate the amount of FR generated, but not how long the FRs will survive. The OH* FR generated by the ESWL shock wave reacts with luminol and emits blue light, which is called sonochemical luminescence (SCL) phenomenon. In this study, FR generation and persist time were measured by recording SCL phenomenon with a sensitive photomultiplier tube (PMT) that responds in nanoseconds. As a result of measurement with the PMT, when the electromagnetic shock wave used in clinical practice was irradiated to the luminol solution, the amount of light emitted per unit time reached its maximum value within a very short time (< ∼600us) and then exponentially decreased for a long time (∼several hundred ms). The measured FR persist time reaches a maximum of 1000 ms. As the output setting of the shock wave generator increases, the minimum or average FR persist time increases, but the maximum value does not show a high correlation with the output setting. The amount of generated FR shows a very high correlation with the shock wave setting, and when the setting is changed from low to high, it increases very sensitively, rapidly and non-linearly. In order to reduce the risk of FR in patient treatment using lithotripsy, the output setting of the shock wave should be minimized, and the interval between the shock wave pulses should be sufficiently larger than the FR persist time. Therefore, it is recommended to avoid increasing the output setting and setting the shock wave irradiation frequency below 1 Hz to shorten the treatment time in clinical practice. For the purpose of formulating these recommendations, additional studies on the generation and persist time of FR depending on the shock wave generation method and set conditions in living tissue or similar environment are required in the future.

To replace one-size-fits-all cancer immunotherapy with personalized treatment, biomarkers of response and resistance as well as assays to evaluate them in each patient are essential. Among likely determinants of response, the spatial locations and activation states of the immune infiltrate appear critical. Current clinical methods for tissue analysis such as immunohistochemistry are poorly matched to the heterogeneity of the tumor immune microenvironment (TIME). However, multiple tools for analysis of the TIME can now image panels of biomarkers in a single experiment, permit deep profiling to measure dozens of immune features in each sample, and/or facilitate unbiased multiomic analysis at high spatial resolution. Several assays are commercialized with some nearing clinical adoption. In this chapter, we present a broad overview of established and emerging technologies that enable multiplexed detection and spatial mapping of cellular and molecular features of the TIME, highlighting advantages and disadvantages as well as opportunities for future development.

The proteomics data included in this article supplement the research article titled “Predictive protein markers for the severity of depression in mood disorders: A preliminary trans-diagnostic approach study (manuscript ID: JPSYCHIATRES-D-20-00437).” Plasma protein was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This data article included 370 plasma protein profiles expressed in patients with bipolar II disorder (BD-II) and major depressive disorder (MDD). The tables present the comparison of protein expressions between BD-II and MDD, and the relationship between the severity of the depressive symptoms and protein expression. In addition, details of results adjusting the use of each psychotropic medication (antipsychotics, mood stabilizers, and antidepressants) for 20 proteins that showed a significant relationship with the severity of the depressive symptom were presented in the table. Results of the bioinformatics analysis of proteins, which were significantly related to the severity of depressive symptom, are presented. The blood protein profiles and the results of the analyses presented in this data article provide detailed information on the proteins associated with mood disorders, and could be used as the basis for further mass spectrometry studies in psychiatric disorders.

Ginger is a tropical plant widely grown in tropical and subtropical countries and used as a spice and traditional medicine in Asia, but its effectiveness against obesity and associated mechanisms have not been thoroughly studied. We investigated steamed ginger extract’s (SGE) potential anti-obesity effects in high-fat diet (HFD) mouse model. It was observed that HFD-fed mice showed low body weight gain and a significant decrease in epididymal fat and inguinal fat mass. Also, SGE inhibited serum hepatic enzymes and controlled lipid profile and adipokines in HFD-fed mice. In the white adipose tissues (WAT), morphological alteration and fatty acid synthesis genes such as SREBP1 and FAS were decreased by SGE supplementation. In the SGE-supplemented groups, whitening of brown adipose tissue (BAT) characterized by increased lipid deposition and mitochondrial dysfunction was inhibited, and there was a recovery of the reduced mitochondrial DNA and complex I and III enzyme activities and thermogenesis genes, including UCP1. In the liver and adipocyte tissues, hyper-nutrient condition-based mTOR-SREBP1-ER stress-induced ROS amplification leading to mitochondrial dysfunction. Here, cellular-based pathological signaling for hepatic and adipocytic dysmetabolism is controlled by the SGE in which AMPK-SIRT1 is involved. To summarize, SGE significantly reduced liver steatosis and adipocyte metabolic deterioration with AMPK-SIRT-1 activation and ROS-linked interstitial disorders related to the endoplasmic reticulum (ER) and mitochondrial redox.

Summary Fragile X syndrome (FXS) is an inherited intellectual disability with a high risk for comorbid autism spectrum disorders. Since FXS is a genetic disease, patients are more susceptible to environmental factors aggravating symptomatology. However, this confounding interaction between FXS environmental and genetic risk factors is under-investigated. Here, Fmr1 knock-out (KO) mice and the immune stimulus lipopolysaccharide (LPS) were used to explore this interaction between FXS development and inflammation in microglia, the brain’s primary immune cell. Our results demonstrate that Fmr1 KO and wild-type (WT) microglia are not different in inflammatory outcomes without LPS. However, Fmr1 KO microglia produces an elevated pro-inflammatory and phagocytic response following LPS treatment when compared to WT microglia. Our experiments also revealed baseline differences in mitochondrial function and morphology between WT and Fmr1 KO microglia, which LPS treatment exaggerated. Our data suggest an altered inflammatory mechanism in Fmr1 KO microglia implicating a gene and environment interaction., Graphical abstract, Highlights • Fmr1 KO microglia display elevated LPS-induced pro-inflammatory gene expressions • Fmr1 KO microglia display elevated LPS-induced pro-inflammatory cytokine releases • Fmr1 KO microglia demonstrate increased LPS-induced phagocytic responses • Fmr1 KO microglial mitochondria have altered properties and LPS-stimulated responses, Molecular biology; Neuroscience; Immunology

Finding motivations for customer brand loyalty is one of the most popular academic and practical research fields; in this regard, some scholars have explored motivations in the retail industry. As the concept of private brands has been one of the most widely employed strategies for business success in the industry, comparing private and national brands in terms of customer loyalty is an important topic in the retail industry. Thus, the current research focuses on exploring antecedents of customer loyalty in private and national brands, as well as investigating whether there are notable structural differences between the brands. The results, based on 1,631 responses, indicate that customer perceived service/product quality, satisfaction, trust, and cost are notable determinants of brand loyalty, while the relationship between customer satisfaction and service quality of private brands is not supported. Moreover, both indirect and direct effects of the employed factors on customer brand loyalty are reported.

Hepatocyte growth factor (HGF) is a neurotrophic factor and its role in peripheral nerves has been relatively unknown. In this study, biological functions of HGF and its receptor c-met have been investigated in the context of regeneration of damaged peripheral nerves. Axotomy of the peripheral branch of sensory neurons from embryonic dorsal root ganglia (DRG) resulted in the increased protein levels of HGF and phosphorylated c-met. When the neuronal cultures were treated with a pharmacological inhibitor of c-met, PHA665752, the length of axotomy-induced outgrowth of neurite was significantly reduced. On the other hand, the addition of recombinant HGF proteins to the neuronal culture facilitated axon outgrowth. In the nerve crush mouse model, the protein level of HGF was increased around the injury site by almost 5.5-fold at 24 h post injury compared to control mice and was maintained at elevated levels for another 6 days. The amount of phosphorylated c-met receptor in sciatic nerve was also observed to be higher than control mice. When PHA665752 was locally applied to the injury site of sciatic nerve, axon outgrowth and injury mediated induction of cJun protein were effectively inhibited, indicating the functional involvement of HGF/c-met pathway in the nerve regeneration process. When extra HGF was exogenously provided by intramuscular injection of plasmid DNA expressing HGF, axon outgrowth from damaged sciatic nerve and cJun expression level were enhanced. Taken together, these results suggested that HGF/c-met pathway plays important roles in axon outgrowth by directly interacting with sensory neurons and thus HGF might be a useful tool for developing therapeutics for peripheral neuropathy.

Radiation induced carotid vasculopathy may present as steno-occlusive disease or less commonly as a pseudoaneurysm. Rupture of internal carotid artery (ICA) pseudoaneurysm can be a fatal complication in patients with nasopharyngeal carcinoma (NPC). Location of the pseudoaneurysm at the skull base makes surgical treatment very difficult. Endovascular therapy may be the treatment of choice. Preserving patency of the carotid artery is a desirable option, but incomplete occlusion of bleeding point of pseudoaneurysm may cause re-bleeding. Both angiographic and nasal endoscopy confirmation of occlusion may help to avoid re-bleeding. We describe a case of endovascular treatment for massive epistaxis due to rupture of radiation-induced ICA pseudoaneurysm in a patient with NPC, and would like to discuss significance of angiographic and nasal endoscopic confirmation.

The development of cerebral organoid technology has allowed the human neural tissue to be collected for studying human brain development and neurological diseases. Human pluripotent stem cell-derived cerebral organoids (hCOs) are a theoretically infinite source of fresh human brain tissue for various research purposes. However, hCOs have limitations, including core necrotic cell death. To solve this problem, we tested a simple method, which has been previously overlooked. In this study, we mechanically cut 70-day-old hCOs with a scalpel blade into 2 to 4 pieces, each depending on their original size. After culturing cut hCOs for additional 7 days, their size was less variable and smaller than uncut hCOs and there were no histological differences between uncut and cut hCOs. Note that hypoxia-inducible factor (HIF)−1α was expressed in the central area of uncut hCOs but not in cut hCOs. Uncut hCOs, therefore, showed broad core areas stained with terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), whereas cut hCOs did not. In conclusion, this simple mechanical cutting method allowed us to acquire a larger number of hCOs without a necrotic core., Human pluripotent stem cell; Cerebral organoids; Necrosis; Mechanical cutting.

Traffic congestion is one of the most notorious troubles, one that undermines social costs in urbanized areas in the world. Because of the congestion problem, drivers are trying to find the shortest and most reliable paths. Regarding the reliability of travel time, there already exist a few measures, such as Standard Deviation, Buffer Time, and Buffer Index. However, they have fundamental limitations in calculation or in application.Therefore, we tried to apply the Gini Coefficient, which is a well-known measure of statistical dispersion, which describes the inequality of income or wealth distribution among a nation’s residents, as a new measure for evaluating travel time reliability.In order to verify the new measure, we calculated Gini coefficients of five different expressway sections on AADTday and Chuseok and reviewed the potential advantage of the alternative by comparing the result with those from existing measures.In the analysis, the new measure showed us reasonable and reliable results and proved its applicability of appraising travel time reliability. Keywords: Travel time, Reliability, Gini coefficient, Buffer time, Buffer index

Chylomicron metabolism is critical for determining plasma levels of triacylglycerols (TAGs) and cholesterol, both of which are risk factors for CVD. The rates of chylomicron secretion and remnant clearance are controlled by intracellular and extracellular factors, including apoC-III. We have previously shown that human apoC-III overexpression in mice (apoC-III(Tg) mice) decreases the rate of chylomicron secretion into lymph, as well as the TAG composition in chylomicrons. We now find that this decrease in chylomicron secretion is not due to the intracellular effects of apoC-III, but instead that primary murine enteroids are capable of taking up TAG from TAG-rich lipoproteins (TRLs) on their basolateral surface; and via Seahorse analyses, we find that mitochondrial respiration is induced by basolateral TRLs. Furthermore, TAG uptake into the enterocyte is inhibited when excess apoC-III is present on TRLs. In vivo, we find that dietary TAG is diverted from the cytosolic lipid droplets and driven toward mitochondrial FA oxidation when plasma apoC-III is high (or when basolateral substrates are absent). We propose that this pathway of basolateral lipid substrate transport (BLST) plays a physiologically relevant role in the maintenance of dietary lipid absorption and chylomicron secretion. Further, when apoC-III is in excess, it inhibits BLST and chylomicron secretion.

Summary: Background: Among rectal cancer patients, some of good responders after neoadjuvant chemoradiotherapy (nCRT) are considered for non-operative treatments to avoid postoperative morbidities and permanent stoma. However, oncologic feasibility of non-operative treatment has not been fully understood. Methods: From 2008 to 2017, we retrospectively reviewed patient's records who had lower or mid rectal cancer and diagnosed to clinical complete response by magnetic resonance imaging after nCRT. Clinical differences and oncologic outcomes were compared among Radical surgery (RS), Local excision (LE) and Wait-and-see (WS) group. Results: Number of 129, 25, 15 patients included to RS, LE, WS groups. Local recurrence was frequent type of recurrence in both of LE and WS group (RS; 31.3%, LE; 80%, WS; 66.7%), and many patients in WS group omitted salvage treatment (RS; 75%, LE; 100%, WS; 33.3%). 5-years local-recurrence/disease-free survival rate (LRFS, DFS) between RS and LE were similar between each group, but WS showed significantly inferior outcomes than that of RS (LRFS; p = 0.001, DFS; p = 0.001). In multivariate analysis, WS protocol (OR; 7.163, 95% CI; 1.995–25.715) and cT4 stage (OR; 8.206, 95% CI; 1.596–42.198) were independent factors for LRFS. Conclusions: Wait-and-see group showed high rate of rejection of salvage treatments for recurrence, and poor oncologic outcomes. However, recent low-level evidences reported favorable outcome of WS protocol when salvage treatment was followed after recurrence. It seems that the application of WS protocol should be postponed until the results of randomized-controlled trials are available. Local excision seems to be good alternative option to radical surgery when salvage treatment is followed. Keywords: Rectal cancer, Complete response, Local excision, Wait-and-see

Purpose: The purpose of this study was to explore psychological distress and examine the relationship between this distress and individual, family, and school factors among adolescents in four low- and middle-income countries (LAMICs) in Asia (i.e., Laos, Mongolia, Nepal, and Sri Lanka). Methods: A total of 4,098 adolescents attending public schools in the four LAMICs were surveyed as part of the Healthy School Development Project, which aimed to develop school capacity for improving (1) health among all school members and (2) the school environment through tailored school health programs. Psychological distress, family factors (i.e., parental understanding and monitoring, and parental tobacco and alcohol use), and school factors (i.e., having close friends, not bullied, school attendance, and health education) were assessed using self-report questionnaires. Data were collected from September to November in 2012 and 2013. Data analysis comprised descriptive statistics, Chi-squared testing, and logistic regression. Results: Over half of the participants were women (53.2%–64.1%), and 33.7% (in Sri Lanka) to 53.8% (in Laos) were aged older than 15 years. Approximately 32.9% reported the presence of psychological distress; moreover, 7.9%–13.2% reported suicidal ideation. Parental monitoring and being bullied were associated with psychological distress in all four countries. Conclusion: One-third of adolescents experience psychological distress across these four LAMICs, which poses a substantial public health issue. Adolescents can benefit from family and school-based approaches for screening, ameliorating, and preventing psychological distress. Keywords: adolescent, developing countries, school health services, stress, psychological

Summary: There are abundant peroxiredoxin (Prx) enzymes, but an increase of cellular H2O2 level always happens in apoptotic cells. Here, we show that cellular H2O2 switches different apoptosis pathways depending on which type of Prx enzyme is absent. TNF-α-induced H2O2 burst preferentially activates the DNA damage-dependent apoptosis pathway in the absence of PrxI. By contrast, the same H2O2 burst stimulates the RIPK1-dependent apoptosis pathway in the absence of PrxII by inducing the destruction of cIAP1 in caveolar membrane. Specifically, H2O2 induces the oxidation of Cys308 residue in the cIAP1-BIR3 domain, which induces the dimerization-dependent E3 ligase activation. Thus, the reduction in cIAP level by the absence of PrxII triggers cell-autonomous apoptosis in cancer cells and tumors. Such differential functions of PrxI and PrxII are mediated by interaction with H2AX and cIAP1, respectively. Collectively, this study reveals the distinct switch roles of 2-Cys Prx isoforms in apoptosis signaling. : Lee et al. show that the 2-Cys peroxiredoxin (Prx) isoforms, Prx I and Prx II, discretely regulate different apoptosis pathways. Specifically, the absence of Prx I augments apoptosis through the DNA damage response, while the absence of Prx II switches RIPK1-dependent apoptosis by causing cIAP1 depletion. Keywords: peroxiredoxin, apoptosis, H2O2, TNF-α, cIAP, DNA damage, RIPK1

Background: We recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages. Given the prominent role of macrophages in the pathogenesis of rheumatoid arthritis (RA), we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA. Methods: Arthritis was induced in wild type and myeloid Sirt6 knockout (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Sirt6 expression (or activity) and inflammatory activities were compared in peripheral blood mononuclear cells (PBMCs) and monocytes/macrophages obtained from patients with RA or osteoarthritis. Findings: Based on clinical score, ankle thickness, pathology, and radiology, arthritis was more severe in mS6KO mice relative to wild type, with a greater accumulation of macrophages in the synovium. Consistent with these findings, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocyte-derived chemoattractants. Mechanistically, Sirt6 deficiency in macrophages caused an inflammation with increases in acetylation and protein stability of forkhead box protein O1. Conversely, ectopic overexpression of Sirt6 in knockout cells reduced the inflammatory responses. Lastly, PBMCs and monocytes/macrophages from RA patients exhibited lower expression of Sirt6 than those from patients with osteoarthritis, and their Sirt6 activity was inversely correlated with disease severity. Interpretation: Our data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. Fund: Medical Research Center Program and Basic Science Research Program through the National Research Foundation of Korea. Keywords: Sirt6, RA, Macrophage, Inflammation, FoxO1

Background The establishment of patient-derived models for pancreatic ductal adenocarcinoma (PDAC) using conventional methods has been fraught with low success rate, mainly because of the small number of tumour cells and dense fibrotic stroma. Here, we sought to establish patient-derived model of PDAC and perform genetic analysis with responses to anticancer drug by using the conditionally reprogrammed cell (CRC) methodology. Methods We performed in vitro and in vivo tumourigenicity assays and analysed histological characteristics by immunostaining. We investigated genetic profiles including mutation patterns and copy number variations using targeted deep sequencing and copy-number analyses. We assessed the responses of cultured CRCs to the available clinical anticancer drugs based on patient responsiveness. Findings We established a total of 28 CRCs from patients. Of the 28 samples, 27 showed KRAS mutations in codon 12/13 or codon 61. We found that somatic mutations were shared in the primary-CRC pairs and shared mutations included key oncogenic mutations such as KRAS (9 pairs), TP53 (8 pairs), and SMAD4 (3 pairs). Overall, CRCs preserved the genetic characteristics of primary tumours with high concordance, with additional confirmation of low-AF NPM1 mutation in CRC (35 shared mutations out of 36 total, concordance rate=97.2%). CRCs of the responder group were more sensitive to anticancer agents than those of the non-responder group (P Interpretation These results show that a pancreatic cancer cell line model can be efficiently established using the CRC methodology, to better support a personalized therapeutic approach for pancreatic cancer patients. Funding 2014R1A1A1006272, HI19C0642-060019, 2019R1A2C2008050, 2020R1A2C209958611, and 2020M3E5E204028211

The human-induced pluripotent stem cell lines (hiPSCs) (CMCi009), derived from peripheral blood mononuclear cells (PBMCs) of a 42-year-old woman who were diagnosed as Birt-Hogg-Dubé syndrome (BHD) caused by the frameshift deletion mutation c.1285delC in FCLN gene, was generated using synthetic mRNA. Generated hiPSCs showed a typical human embryonic stem cell like morphology and expressed all pluripotency-associated markers, and directly differentiated into all three germ layers. Karyotyping of generated iPSCs showed normal 46, XY (CMCi009-A) respectively. In summary, we generated a novel patient-specific hiPSCs line containing the same mutation of FLCN gene and it can be used to provide additional insights for BHD pathophysiology.

We established a human induced pluripotent stem cells (hiPSC) line (CMCi002-A) from peripheral blood mononuclear cells (PBMCs) of 29-year-old male with Gitelman's syndrome (GIT) caused by the mutation of solute carrier family 12 member 3 (SLC12A3) gene using Sendai virus. The GIT-hiPSCs showed a typical human embryonic stem cell like morphology and expressed all pluripotency-associated markers, exhibited normal karyotype and were capable of differentiating into cells representative of three germ layers.

Background Although previous studies have suggested that insulin plays a role in brain function, it still remains unclear whether or not insulin has a region-specific association with neuronal and synaptic activity in the living human brain. We investigated the regional pattern of association between basal blood insulin and resting-state cerebral glucose metabolism (CMglu), a proxy for neuronal and synaptic activity, in older adults. Method A total of 234 nondiabetic, cognitively normal (CN) older adults underwent comprehensive clinical assessment, resting-state 18F-fluodeoxyglucose (FDG)-positron emission tomography (PET) and blood sampling to determine overnight fasting blood insulin and glucose levels, as well as apolipoprotein E (APOE) genotyping. Results An exploratory voxel-wise analysis of FDG-PET without a priori hypothesis demonstrated a positive association between basal blood insulin levels and resting-state CMglu in specific cerebral cortices and hippocampus, rather than in non-specific overall cerebral regions, even after controlling for the effects of APOE e4 carrier status, vascular risk factor score, body mass index, fasting blood glucose, and demographic variables. Particularly, a positive association of basal blood insulin with CMglu in the right posterior hippocampus and adjacent parahippocampal region as well as in the right inferior parietal region remained significant after multiple comparison correction. Conversely, no region showed negative association between basal blood insulin and CMglu. Conclusions Our finding suggests that basal fasting blood insulin may have association with neuronal and synaptic activity in specific cerebral regions, particularly in the hippocampal/parahippocampal and inferior parietal regions., Highlights • We investigated regional pattern of association between basal blood insulin and resting-state cerebral glucose metabolism. • Significant clusters with positive associations were found mainly in the hippocampal and inferior parietal regions. • Our finding suggests a region-specific association of basal blood insulin with resting-state cerebral glucose metabolism. • Further studies to elucidate underlying mechanism and implication of this region-specific association will be necessary.

Oxidative stress attributable to the activation of a Nox4-containing NADPH oxidase is involved in aging-associated vascular dysfunction. However, the Nox4-induced signaling mechanism for the vascular alteration in aging remains unclear. In an aged aorta, the expression of Nox4 mRNA and protein by Nox family of genes was markedly increased compared with a young aorta. Nox4 localization mainly to ER was also established. In the aorta of Nox4 WT mice aged 23–24 months (aged), reactive oxygen species (ROS) and endoplasmic reticulum (ER)/oxidative stress were markedly increased compared with the counter KO mice. Furthermore, endothelial functions including eNOS coupling process and acetylcholine-induced vasodilation were significantly disturbed in the aged WT, slightly affected in the counter KO aorta. Consistently, in d-galactose-induced in vitro aging condition, ER-ROS and its associated ER Nox4 expression and activity were highly increased. Also, in chronic d-galactose-treated condition, IRE1α phosphorylation and XBP-1 splicing and were transiently increased, but IRE1α sulfonation was robustly increased in the aging Nox4 WT condition when compared to the counter KO condition. In vitro D-gal-induced aging study, the phenomenon were abrogated with Nox4 knock-down condition and was significantly decreased in GKT, Nox4 inhibitor and 4-PBA, ER chemical chaperone-treated human umbilical vein endothelial cells. The state of Nox4-based ER redox imbalance/ROS accumulation is suggested to determine the pathway “the UPR; IRE1α phosphorylation and XBP-1 splicing and the UPR failure; IRE1α cysteine-based oxidation, especially sulfonation, finally controlling aging-associated vascular dysfunction., Graphical abstract Image 1