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BACKGROUND:Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While MIBC subtyping has primarily been based on messenger RNA (mRNA), long non-coding RNAs (lncRNAs) may provide additional resolution. METHODS:LncRNA expression was quantified from microarray data of a MIBC cohort treated with neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) (n = 223). Unsupervised consensus clustering of highly variant lncRNAs identified a four-cluster solution, which was characterized using a panel of MIBC biomarkers, regulon activity profiles, gene signatures, and survival analysis. The four-cluster solution was confirmed in The Cancer Genome Atlas (TCGA) cohort (n = 405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and validated in two independent cohorts (n = 255 and n = 94). RESULTS:NAC and TCGA cohorts both contained an lncRNA cluster (LC3) with favorable prognosis that was enriched with tumors of the luminal-papillary (LP) subtype. In both cohorts, patients with LP tumors in LC3 (LPL-C3) were younger and had organ-confined, node-negative disease. The LPL-C3 tumors had enhanced FGFR3, SHH, and wild-type p53 pathway activity. In the TCGA cohort, LPL-C3 tumors were enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts. CONCLUSIONS:Using lncRNA expression profiles, we identified a biologically distinct subgroup of luminal-papillary MIBC with a favorable prognosis. These data suggest that lncRNAs provide additional information for higher-resolution subtyping, potentially improving precision patient management.

Abstract Understanding how marine organisms adapt to local environments is crucial for predicting how populations will respond to global climate change. The genomic basis, environmental factors and evolutionary processes involved in local adaptation are however not well understood. Here we use Atlantic herring, an abundant, migratory and widely distributed marine fish with substantial genomic resources, as a model organism to evaluate local adaptation. We examined genomic variation and its correlation with environmental variables across a broad environmental gradient, for 15 spawning aggregations in Atlantic Canada and the United States. We then compared our results with available genomic data of northeast Atlantic populations. We confirmed that population structure lies in a fraction of the genome including likely adaptive genetic variants of functional importance. We discovered 10 highly differentiated genomic regions distributed across four chromosomes. Nine regions show strong association with seasonal reproduction. One region, corresponding to a known inversion on chromosome 12, underlies a latitudinal pattern discriminating populations north and south of a biogeographic transition zone on the Scotian Shelf. Genome–environment associations indicate that winter seawater temperature best correlates with the latitudinal pattern of this inversion. The variation at two so‐called ‘islands of divergence’ related to seasonal reproduction appear to be private to the northwest Atlantic. Populations in the northwest and northeast Atlantic share variation at four of these divergent regions, simultaneously displaying significant diversity in haplotype composition at another four regions, which includes an undescribed structural variant approximately 7.7 Mb long on chromosome 8. Our results suggest that the timing and geographic location of spawning and early development may be under diverse selective pressures related to allelic fitness across environments. Our study highlights the role of genomic architecture, ancestral haplotypes and selection in maintaining adaptive divergence in species with large population sizes and presumably high gene flow.

Background: GP trainees may not have experienced a systematic and comprehensive education in safe prescribing. Therefore, a self-assessment prescribing review was developed. Aim: To determine whether the assessment was feasible, had face validity, and did not disadvantage particular groups of participants. Design & setting: An online survey that evaluates the opinions of GPs in training of a prescribing assessment in the UK. All full-time UK trainees who started their final year of GP training in August 2019 undertook the prescribing assessment along with their trainers, after which they completed an online anonymous feedback questionnaire. Method: The questionnaire completed by trainees sought their opinions of the assessment, and collected ethnicity and disability data. The trainer questionnaire was similar but did not include any demographic information. Results: The questionnaire was completed by 1741 trainees and 1576 trainers. There was no evidence that ethnic group and disability were related to aspects of the review. Most of the trainees (76.4%, n = 1330) and trainers (82.0%, n = 1293) agreed or strongly agreed that the prescribing review was helpful for assessing and learning about the trainee’s prescribing. However, most participants (63.2%, n = 1092) took >4 hours to review their prescriptions. A majority of trainees (90.2%, n = 1571) reported that completing the assessment had resulted in a change in their prescribing practice. Conclusion: The majority of trainers and trainees reported that the prescribing assessment was helpful. The study was not able to assess whether there had been an actual change in practice that resulted in an error reduction.

Abstract Background The incidence and prevalence of musculoskeletal disorders (MSDs) is about twice as high in women compared to men, and those of the neck/shoulder region are particularly high among women. Fatigue and responses towards pain are known risk factor for MSDs. However, women have been shown to be less fatigable than men, but more sensitive to experimental pain. From a general standpoint, sex differences in the relationships between the fatigue and pain pathways are poorly understood. This may be due to differences in how men and women conceptually define the sensations of fatigue and pain. The objective of this study was to compare physical and verbal descriptors of fatigue and pain between men and women undergoing an experimental protocol where fatigue and pain were manipulated. Methods Healthy adult volunteers (14 men and 14 women) underwent experimental pain tests to identify pressure pain threshold (PPT) at biceps brachii (BIC), anterior deltoid (AD), and upper trapezius (UT) followed by the Short-form McGill Pain Questionnaire (SF-MPQ) and Pain Catastrophizing Scale (PCS) before and after a repetitive arm task performed at shoulder height until reaching a rating of neck/shoulder perceived exertion, using the Borg Category Ratio 10 (CR10), greater than 8/10. PPT and MPQ data were analyzed using repeated measures analyses of variance (ANOVA) (time × sex). Correlational analyses were used to investigate relationships between pain measures with time and fatigue. Results UT PPT was reduced following the fatiguing task (p ≤ 0.01). Men overall reported higher AD PPT levels compared to women (p ≤ 0.05). MPQ and PCS magnification scores were significantly higher after the fatiguing task (p ≤ 0.05), with no sex differences. Time to fatigue correlated with changes in AD PPT in men and with PCS scores in women. Conclusions Findings suggest that mechanisms underlying the sensation of acute pain following a repetitive shoulder height task are closely linked with PPT changes in shoulder stabilizers (UT) irrespective of sex, and more so with physical pain responses in men and in attitudes towards pain in women. Sex differences in pain perception may contribute to a better understanding of sex-specific mechanisms underlying neck/shoulder MSDs.

BackgroundWomen involved in repetitive, fatiguing, jobs develop more neck and/or shoulder musculoskeletal disorders than men. Sex differences in the pain response to exercise could contribute to the higher prevalence of neck/shoulder musculoskeletal disorders in women. The objective of this study was to assess sex differences in pain sensitivity following a fatiguing upper limb task. Relationships between measures of fatigue and of the sensitivity to nociceptive and to non-nociceptive stimulations were also explored.MethodsThirty healthy adults (15 women) performed a fatiguing repetitive pointing task with their dominant arm. Upper limb electromyography was recorded from the dominant upper trapezius, anterior deltoid and bicep brachii and from the contralateral tibialis anterior. Before and immediately after the repetitive pointing task, pressure pain and light touch sensitivity thresholds were measured over the same muscles.ResultsElectromyographic signs of fatigue were observed only in the anterior deltoid and biceps brachii muscles. Pressure pain thresholds over both muscles increased slightly (effect size ≤ 0.34), but no changes occurred over the upper trapezius and the tibialis anterior. Light touch thresholds increased moderately to importantly after the repetitive pointing task over all four muscles (effect sizes = 0.58 to 0.87). No sex differences were observed in any sensory variable. Moreover, no or weak correlations (r = -0.27 to 0.39) were observed between electromyographical signs of fatigue, light touch threshold and pressure pain threshold variables.ConclusionsWe observed sex-independent effects of a repetitive upper limb task on the sensitivity to painful and to nonpainful stimuli. Moreover, the hypoalgesia induced by the repetitive pointing task was weak and localized, and did not directly correlate with the induced muscle fatigue. Results suggest that fatigue-related changes in the sensitivity to noxious and innocuous stimuli could not explain women's greater prevalence of neck/shoulder musculoskeletal disorders.

Background and Purpose: Amyloid-β (Aβ) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aβ aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aβ(1-42) and cell-derived Aβ oligomers.Experimental Approach: Surface plasmon resonance studies measured binding of SEN1269 to Aβ(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ(1-42) -induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aβ(1-42) and cell-derived Aβ oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.Key Results: SEN1269 demonstrated direct binding to monomeric Aβ(1-42) , produced a concentration-related blockade of Aβ(1-42) aggregation and protected neuronal cell lines exposed to Aβ(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ(1-42) and cell-derived Aβ oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aβ oligomers.Conclusions and Implications: SEN1269 protected cells exposed to Aβ(1-42) , displayed central activity with respect to reducing Aβ-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aβ-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aβ-mediated synaptic toxicity as potential neuroprotective agents for treating AD. [ABSTRACT FROM AUTHOR]

Intact immunoglobulin G antibody has a relatively large molecule size of approximately 150 kDa that remains in the bloodstream for many weeks, which is a considerable disadvantage when it is used to carry radioactive materials for imaging. To lower background activity and increase the contrast of images, we investigated antivascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) conjugated dextran for VEGF receptor 2 imaging in tumor xenografted mice. DTPA-conjugated aminodextran was synthesized, reacted with sulfo-LC-SPDP, and then reacted with DC101. The binding affinity of DTPA-dextran-DC101 to Flk-1 was measured. The gamma imaging and biodistributions of (99m)Tc-DTPA-dextran-DC101, (99m)Tc-DTPA-DC101, and (125)I-DC101 were studied in B16F10 melanoma xenografted mice. The dissociation values for DC101, DTPA-DC101, and DTPA-dextran-DC101 were 22.48, 3.05, and 14.74 pM, respectively. In gamma images, (99m)Tc-DTPA-dextran-DC101 showed weak liver uptake and rapid kidney elimination. In biodistribution results, the liver uptake of (99m)Tc-DTPA-dextran-DC101 was similar with that of (99m)Tc-DTPA-DC101 at each time point. However, the blood activity of (99m)Tc-DTPA-dextran-DC101 has shown significant differences, compared with (99m)Tc-DTPA-DC101 at all time points. The tumor accumulation of dextran-conjugated antibody was increased with time, whereas that of dextran nonconjugated antibody decreased. In particular, the pattern of tumor uptake of (99m)Tc-DTPA-dextran-DC101 was similar to that of (125)I-DC101, so this was thought to reflect the kinetics of DC101, unlike the nonconjugated form. The results of this study suggested that introduction of dextran moiety to make (99m)Tc-radiolabeled DC101 imaging agent could provide better images with the impaired background and the steady increasing binding to the receptor. However, further studies are necessary to improve clinical pharmacokinetics, such as enhancement of tumor uptake and impaired renal uptake. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the cytotoxicity of natural killer (NK) cells and the level of differentiation of hematopoietic stem cells (HSCs) into NK cells in systemic lupus erythematosus (SLE). METHODS: Patients with SLE (n = 108), rheumatoid arthritis (RA; n = 90), Behçet's disease (n = 39), or ankylosing spondylitis (n = 41) and healthy control subjects (n = 173) were enrolled in the study. NK cell levels, NK cell cytotoxicities, and lymphokine-activated killer (LAK) activities against K562 cells were measured by flow cytometry. Gene expression was assessed by reverse transcription-polymerase chain reaction. NK cells were differentiated from peripheral blood and bone marrow HSCs in vitro. RESULTS: Percentages and absolute numbers of NK cells, cytotoxicities, and LAK activities were significantly lower in the peripheral blood of SLE and RA patients than in that of healthy controls. In particular, this NK cell deficiency was more prominent in patients with lupus nephritis and those with thrombocytopenia. Notably, purified NK cells derived from SLE patients, but not RA patients, were found to have lower cytotoxicities and LAK activities than those from healthy controls. This defect of NK cells in SLE patients was found to be related to lower numbers of NK precursors and to the down-regulation of perforin and granzyme in NK cells. The proliferative capacity of HSCs, the percentages of NK cells differentiated from HSCs, and NK cell cytotoxicities were significantly lower in SLE patients. CONCLUSION: In SLE patients, circulating levels of NK cells were diminished and their cytotoxicities were impaired. Furthermore, the differentiation of HSCs into NK cells was found to be defective. These abnormalities possibly contribute to immune system dysregulation in SLE. [ABSTRACT FROM AUTHOR]

Introduction The Institute of Translational Health Sciences (ITHS), a Clinical and Translational Science Award (CTSA)-funded program at the University of Washington (UW), established the Drug and Device Advisory Committee (DDAC) to provide product-specific scientific and regulatory mentoring to investigators seeking to translate their discoveries into medical products. An 8-year retrospective analysis was undertaken to evaluate the impact of the DDAC programs on commercialization metrics. Methods Tracked metrics included the number of teams who consulted with the DDAC, initiated a clinical trial, formed a startup, or were successful obtaining federal small business innovation awards or venture capital. The review includes historical comparisons of the startup rates for the UW School of Medicine and the Fred Hutchinson Cancer Research Center, two ITHS-affiliated institutions that have had different DDAC utilization rates. Results Between 2008 and 2016, the DDAC supported 161 unique project teams, 28% of which went on to form a startup. The commercialization rates for the UW School of Medicine increased significantly following integration of the DDAC into the commercialization programs offered by the UW technology transfer office. Conclusions A formalized partnership between preclinical consulting and the technology transfer programs provides an efficient use of limited development funds and a more in-depth vetting of the business opportunity and regulatory path to development.

The use of robots in health care has increased dramatically over the last decade. One area of research has been to use robots to conduct ultrasound examinations, either controlled by a physician or autonomously. This paper examines the possibility of using the commercial robot UR5 from Universal Robots to make a tele-operated robotic ultrasound system. Physicians diagnosing patients using ultrasound probes are prone to repetitive strain injuries, as they are required to hold the probe in uncomfortable positions and exert significant static force. The main application for the system is to relieve the physician of this strain by letting the them control a robot that holds the probe. A set of requirements for the system is derived from the state-of-the-art systems found in the research literature. The system is developed through a low-level interface for the robot, effectively building a new software framework for controlling it. Compliance force control and forward flow haptic control of the robot was implemented. Experiments are conducted to quantify the performance of the two control schemes. The force control is estimated to have a bandwidth of 16.6 Hz, while the haptic control is estimated to have a bandwidth of 65.4 Hz for the position control of the slave and 13.4 Hz for the force control of the master. Overall, the system meets the derived requirements and the main conclusion is that it is feasible to use the UR5 robot for robotic ultrasound applications.

In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [11C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [11C]acetate. No significant differences of the rate constant of oxidation of [11C]acetate (k3) were found among the three groups of subjects. The net metabolic clearance of [11C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P

Actigraphy as an objective measure of sleep and wakefulness in infants and children has gained popularity over the last 20 years. However, the field lacks published guidelines for sleep-wake identification within pediatric age groups. The scoring rules vary greatly and although sensitivity (sleep agreement with polysomnography) is usually high, a significant limitation remains in relation to specificity (wake agreement). Furthermore, accurate algorithm output and sleep-wake summaries usually require prior entry from daily logs of sleep–wake periods and artefact-related information (e.g. non-wear time), involving significant parent co-operation. Scoring criteria for daytime naps remains an unexplored area. Many of the problems facing accuracy of measurement are inherent within the field of actigraphy itself, particularly where sleep periods containing significant movements are erroneously classified as wake, and within quiet wakefulness when no movements are detected, erroneously classified as sleep. We discuss the challenges of actigraphy for pediatric sleep, briefly describe the technical basis and consider a number of technological approaches that may facilitate improved classification of errors in sleep-wake discrimination.

Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer’s disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n=16) and a control group (n=4) of healthy dogs with radioactively labeled PiB ([11C]PiB). Structural MRI brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PIB retention in brain. In the CCD group, dogs had significant retention of [11C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [11C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [11C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [11C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

MRI is widely used in the assessment of acute ischemic stroke. In particular, it identifies the mismatch between hypoperfused and the permanently damaged tissue, the PWI-DWI-mismatch volume. It is used to help triage patients into active or supportive treatment pathways. COMBAT Stroke is an automated software tool for estimating the mismatch volume and ratio based on MRI. Herein, we validate the decision made by the software with actual clinical decision rendered. Furthermore, we evaluate the association between treatment decisions (both automated and actual) and outcomes.COMBAT Stroke was used to determine PWI-DWI mismatch volume and ratio in 228 patients from two European multicenter stroke databases. We performed confusion matrix analysis to summarize the agreement between the automated selection and the clinical decision. Finally, we evaluated the clinical and imaging outcomes of the patients in the four entries of the confusion matrix (true positive, true negative, false negative, and false positive). 186 of 228 patients with acute stroke underwent thrombolytic treatment, with the remaining 42 receiving supportive treatment only. Selection based on radiographic criteria using COMBAT Stroke classified 142 patients as potential candidates for thrombolytic treatment and 86 for supportive treatment; 60% sensitivity and 29% specificity. The patients deemed eligible for thrombolytic treatment by COMBAT Stroke demonstrated significantly higher rates of compromised tissue salvage, less neurological deficit, and were more likely to experience thrombus dissolving and reestablishment of normal blood flow at 24-hour follow-up compared to those who were treated without substantial PWI-DWI mismatch. These results provide evidence that COMBAT Stroke, in addition to clinical assessment, may offer an optimal framework for a fast, efficient, and standardized clinical support tool to select patients for thrombolysis in acute ischemic stroke.

This paper reports an experiment intended to test a particular hypothesis derived from blindsight research, which we name the source misidentification hypothesis. According to this hypothesis, a subject may be correct about a stimulus without being correct about how she had access to this knowledge (whether the stimulus was visual, auditory, or something else). We test this hypothesis in healthy subjects, asking them to report whether a masked stimulus was presented auditorily or visually, what the stimulus was, and how clearly they experienced the stimulus using the Perceptual Awareness Scale (PAS). We conclude that knowledge about perceptual modality seems a necessary precondition in order to issue correct reports of which stimulus was presented. Furthermore, we find that PAS ratings correlate with correctness, and that subjects are at chance level when reporting no conscious experience of the stimulus. To demonstrate that particular levels of reporting accuracy are obtained, we employ a statistical strategy, which operationally tests the hypothesis of non-equality, such that the usual rejection of the null-hypothesis admits the conclusion of equivalence.

Twisted Gastrulation (TWSG1) is a conserved, secreted glycoprotein that modulates signaling of bone morphogenetic proteins (BMPs) in the extracellular space. Deletion of exon 4 of mouse Twsg1 (mTwsg1) is associated with significant craniofacial defects. However, little is understood about the biochemical properties of the corresponding region of the protein. We have uncovered a significant role for exon 4 sequences as encoding the only two glycosylation sites of the mTWSG1 protein. Deletion of the entire exon 4 or mutation of both glycosylation sites within exon 4 abolishes glycosylation of mTWSG1. Importantly, we find that constructs with mutated glycosylation sites have significantly reduced BMP binding activity. We further show that glycosylation and activity of TWSG1 recombinant proteins vary markedly by cellular source. Non-glycosylated mTWSG1 made in E. coli has both reduced affinity for BMPs, as shown by surface plasmon resonance analysis, and reduced BMP inhibitory activity in a mandibular explant culture system compared to glycosylated proteins made in insect cells or murine myeloma cells. This study highlights an essential role for glycosylation in Twisted gastrulation action.

Nghiên cứu này nhằm tìm ra giải pháp nâng cao vai trò phụ nữ trong tham gia tập huấn khoa học kỹ thuật lĩnh vực sản xuất lúa ở thành phố Cần Thơ, cụ thể là địa bàn quận Ô Môn và huyện Thới Lai. Nghiên cứu được thực hiện bằng cách phỏng vấn 120 nông dân trong và ngoài lớp tập huấn theo số liệu tách biệt giới. Kết quả phân tích cho thấy các yếu tố như người phụ nữ trình độ học vấn thấp, có ít năm kinh nghiệm sản xuất, bận rộn chăm sóc con cái và mất nhiều thời gian vào các hoạt động kinh tế khác thì thường ít được tham gia tập huấn. Nhằm nâng cao cơ hội tập huấn cho phụ nữ, các đoàn thể địa phương cần tăng cường liên kết tuyên truyền giới trong cộng đồng, các cơ quan khuyến nông cần gắn hiệu quả kinh tế với tập huấn, người phụ nữ cần chủ động nâng cao kiến thức và sự tự tin của bản thân là các giải pháp chính yếu đã được đề ra.

Alternative pre-mRNA splicing (AS) is a biological process that results in proteomic diversity. However, implications of AS alterations in cancer remain poorly understood. Herein, we performed a comprehensive AS analysis in cancer driver gene transcripts across fifteen cancer types and found global alterations in inclusion rates of the PBAF SWI/SNF chromatin remodeling complex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of cancer tissues compared with those in normal tissues. Further analysis confirmed that PBRM1 E27 is excluded by the direct binding of RBFOX2 to intronic UGCAUG elements. In addition, the E27-included PBRM1 isoform upregulated PD-L1 expression via enhanced PBAF complex recruitment to the PD-L1 promoter. PBRM1 wild-type patients with clear cell renal cell carcinoma were resistant to PD-1 blockade therapy when they expressed low RBFOX2 mRNA levels. Overall, our study suggests targeting of RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy for immune checkpoint blockade., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Laparoscopic colon surgery is now commonly used for colorectal cancer (CRC) resection. The objective of this study was to compare the oncologic outcomes between open conversion and laparoscopic surgery, and to identify risk factors for open conversion., Methods: We retrospectively reviewed the medical records of patients who underwent curative resection for stage 0-III CRC at five Hallym University-affiliated hospitals between January 2011 and June 2021. The patients were divided into the conversion and laparoscopic groups according to whether laparoscopic surgery was completed., Results: Out of 2231 patients, laparoscopic surgery was completed in 2131 patients and 100 (4.5 %) converted to open surgery. The operation time (P = 0.028) and postoperative hospital stay (P = 0.036) were longer in the conversion group than in the laparoscopic group. Overall (P = 0.022) and severe (Clavien-Dindo classification grade ≥3) (P = 0.048) complications were more frequent in the conversion group than in the laparoscopic group. The 5-year recurrence-free survival (RFS) rate was worse in the conversion group than in the laparoscopic group (P = 0.002). In the multivariable analysis, open conversion was not a prognostic factor for RFS (P = 0.082). Abdominal surgery history (P = 0.021), obstruction (P < 0.001), and T4 stage (P < 0.001) were independently associated with open conversion., Conclusion: The conversion group had worse perioperative and oncologic outcomes. History of abdominal surgery, obstruction, and T4 stage were associated with open conversion. However, conversion itself was not associated with RFS., Competing Interests: Declarations of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

A food exchange list is a tool developed to help diabetic patients control their energy intake and plan balanced meals. Korean food exchange lists were first developed in 1988, revised in 1995, and updated again in 2010. With rapidly changing dietary habits and increasing demand for diverse food cultures, the Korean Diabetes Association in cooperation with 4 related organizations established a Task Force Team (TFT) to revise food exchange lists in March 2022. Starting with a workshop, TFT held 11 official revision meetings, culminating in a public hearing in May 2023. The final revised version of Korean food exchange lists was published in December 2023. Key outcomes of the revision are summarized as follows: 1. Based on the National Standard Food Composition Table 10.0 database, the existing classification system and nutrient standards for each food group remain unchanged this time. 2. Based on a survey conducted among diabetes educators, the number of items on the food exchange lists has increased from 339 in 2010 to 435 this time. 3. Considering patients' usual eating habits, meal planning examples were developed distributing food group exchange units by energy level based on 3 types of proportions of carbohydrate energy (40%-45%, 50%-55%, 60%-65%). 4. Due to limitations in real-time updates for rapidly changing information, detailed guidance on how to access and interpret the data is provided. These revisions will help people with diabetes manage their blood sugar levels and facilitate the implementation of healthy meal planning in various other conditions, including obesity., Competing Interests: Conflict of Interest: The authors declare that they have no competing interests., (Copyright © 2024. The Korean Society of Clinical Nutrition.)

Gelatin methacryloyl (GelMA) hydrogels are used for stem cell encapsulation in bone tissue engineering due to their fast and stable photo-crosslinking. However, cell viability and ability to induce osteogenesis are reduced by reactive oxygen species (ROS) produced during the crosslinking reaction. In this study, we developed biomimetic nanoparticles (TMNs) by combining tannic acid (TA) and simulated body fluid (SBF) minerals, and used them to synthesize GelMA-based composite hydrogels for addressing those limitations. The optimal concentrations of TA and SBF were investigated to create nanoparticles that can effectively scavenge ROS and induce osteogenesis. The incorporation of TMNs into composite hydrogels (G-TMN) significantly enhanced the survival and proliferation of encapsulated human adipose-derived stem cells (hADSCs) by providing resistance to oxidative conditions. In addition, the ions that were released, such as Ca 2+ and PO 4 3- , stimulated stem cell differentiation into bone cells. The hADSCs encapsulated in G-TMN had 2.0 ± 0.8-fold greater viability and 1.3 ± 1.8 times greater calcium deposition than those encapsulated in the hydrogel without nanoparticles. Furthermore, the in vivo transplantation of G-TMN into a subcutaneous mouse model demonstrated the rapid degradation of the gel-network while retaining the osteoinductive particles and cells in the transplanted area. The increased cellular activity observed in our multifunctional composite hydrogel can serve as a foundation for novel and effective therapies for bone deformities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Exposure to adverse experiences during early life is associated with an increased risk of psychopathology during adolescence. In a previous study, we demonstrated that neonatal maternal separation (NMS) combined with social isolation led to impulsive and depressive-like behaviors in male adolescents. Additionally, it significantly reduced the expression of excitatory amino acid carrier 1 (EAAC1) in the hippocampus. Building upon this work, we investigated the effects of N-acetylcysteine (NAC), a precursor to glutathione, in early-life stress (ELS) model rats and in EAAC1 -/- mice. EAAC1 plays a dual role in transporting both glutamate and cysteine into neurons. Our findings revealed that female adolescents subjected to in the ELS model also exhibited behavioral defects similar to those of males. NAC injection rescued depressive-like behaviors in both male and female NMS models, but it improved impulsive behavior only in males. Furthermore, we observed increased reactive oxidative stress (ROS) and neuroinflammation in the ventral hippocampus (vHPC) and prefrontal cortex of NMS model rats, which were mitigated by NAC treatment. Notably, NAC reversed the reduced expression of EAAC1 in the vHPC of NMS model rats. In EAAC1 -/- mice, severe impulsive and depressive-like behaviors were evident, and the NAC intervention improved only depressive-like behaviors. Collectively, our results suggest that ELS contributes to depression and impulsive behaviors during adolescence. Moreover, the cysteine uptake function of EAAC1 in neurons may be specifically related to depression rather than impulsive behavior., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

We present a case of a 13-year-old patient with a distinct tumor with both granular cell and perineurial elements, located on the lower lip. The patient presented with a long-standing lip mass that was clinically felt to most likely represent a mucocele. Following surgical excision, histopathological examination revealed a well-circumscribed tumor composed of granular cells with positive S100 protein staining and spindled cells positive for EMA and GLUT-1, confirming mixed neuroectodermal and perineurial origin. This is the first case documenting a perineurial-granular cell hybrid tumor in a patient under 18 years old, and the first to be reported in the head and neck. This case expands our understanding of hybrid PNSTs, emphasizing the importance of considering diverse clinical presentations, especially in the context of rare pediatric occurrences in atypical locations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This pilot study explored whether a socially assistive robot (SAR) would have positive effects on Korean American immigrant older adults' health behaviors and emotional well-being and whether the older adults would be receptive to the SAR. A total of 30 participants (age 65+) in a large metropolitan area participated in the study, and each participant was provided a SAR named Hyodol for 4 months and interacted with it in ways that they saw appropriate. We used one-group pre- and post-test design to assess changes between baseline and follow-up in medication adherence, depressive symptoms, loneliness, and disability. Additionally, we employed in-depth qualitative interviews to explore participants' perceptions about the SAR. At post-test, participants showed improved medication adherence, reduced depressive symptoms, and a slightly and statistically nonsignificant decrease in loneliness scores. Qualitative data suggested high adoptability of this particular SAR among the participants., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Inhibition of lipid synthesis in sebocytes is essential for acne treatments. The effects of natural product-derived substances on lipid synthesis are unknown. This study investigated the effects of water extract of Mangifera indica leaves (WEML) on lipid synthesis in human sebocytes. Sebocyte differentiation in low serum conditions increased lipid accumulation and proliferator-activated receptor γ expression. WEML treatment significantly inhibited lipid accumulation and adipogenic mRNA expression in sebocytes. Mangiferin, a bioactive compound in WEML, also reduced lipid accumulation and adipogenic mRNA expression via the AKT pathway. Thus, WEML and mangiferin effectively inhibit lipid synthesis in sebocytes, showing promise for acne treatment.

Previous studies have reported that amputation invokes body-wide responses in regenerative organisms, but most have not examined the implications of these changes beyond the region of tissue regrowth. Specifically, long-range epidermal responses to amputation are largely uncharacterized, with research on amputation-induced epidermal responses in regenerative organisms traditionally being restricted to the wound site. Here, we investigate the effect of amputation on long-range epidermal permeability in two evolutionarily distant, regenerative organisms: axolotls and planarians. We find that amputation triggers a long-range increase in epidermal permeability in axolotls, accompanied by a long-range epidermal downregulation in MAPK signaling. Additionally, we provide functional evidence that pharmacologically inhibiting MAPK signaling in regenerating planarians increases long-range epidermal permeability. These findings advance our knowledge of body-wide changes due to amputation in regenerative organisms and warrant further study on whether epidermal permeability dysregulation in the context of amputation may lead to pathology in both regenerative and non-regenerative organisms., Competing Interests: CONFLICT OF INTEREST J.L.W. is a co-founder of Matice Biosciences. Other authors declare no conflicts of interest.

Introduction: Nocardia farcinica is an opportunistic bacterium that causes bovine mastitis and pulmonary, cutaneous, and central nervous system infections in humans. Bovine abortion caused by N. farcinica has been sporadically reported. The purpose of this study was to analyze the pathological findings of bovine abortions caused by N. farcinica in the Republic of Korea and determine the antimicrobial resistance and genotypical characteristics of N. farcinica isolates., Case Presentation: Three cases of bovine abortions were submitted to the Animal and Plant Quarantine Agency for differential diagnosis. Grossly, one fetus showed severe lung consolidation following palpation of the entire lobes. Histologically, necrotizing granulomatous interstitial pneumonia was observed in all fetuses; a fetus with a gross lesion demonstrated necrotizing lymphadenitis in the mesenteric lymph nodes and necrotizing dermatitis in the ear. N. farcinica isolates were isolated from the abomasal contents and lungs of all fetuses. Finally, two cases were diagnosed as abortions due to N. farcinica , and one was diagnosed as an N. farcinica abortion coinfected with bovine viral diarrhea virus. According to the multilocus sequence analysis, all isolates were identified as N. farcinica and were determined to be genetically related to isolates from humans. Two N. farcinica isolates were resistant to trimethoprim-sulfamethoxazole, which is recommended as the first treatment for human nocardial infections., Conclusion: This is the first pathological report of bovine abortion caused by N. farcinica in the Republic of Korea. Further studies are needed to phenotypically and genotypically characterize N. farcinica isolates with various sources and continuously monitor antimicrobial resistance patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Yun, Bae, Lee, Moon, Lee, Jeoung, Ku and Kim.)

Exposure to storage mite (SM) and house dust mite (HDM) allergens is a risk factor for sensitization and asthma development; however, the related immune responses and their pathology have not been fully investigated. The HDMs Dermatophagoides farinae and Dermatophagoides pteronyssinus and SM Tyrophagus putrescentiae are potent allergens that induce asthma. Most SM-related studies have focused on the allergic reactions of individuals by measuring their immunoglobulin (Ig)E expression. Considering the limited research on this topic, the present study aims to investigate the differences in the immune responses induced by HDMs and SMs and histologically analyze lung tissues in a mouse asthma model to understand the differential effects of HDM and SM. The results revealed that all mite species induced airway inflammation. Mice challenged with T. putrescentiae had the highest airway resistance and total cell, eosinophil, and neutrophil counts in the bronchoalveolar lavage fluid (BALF). The SM-sensitized groups showed more severe lesions and mucus hypersecretions than the HDM-sensitized groups. Although the degree of HDM and SM exposure was the same, the damage to the respiratory lung tissue was more severe in SM-exposed mice, which resulted in excessive mucin secretion and increased fibrosis. Furthermore, these findings suggest that SM sensitization induces a more significant hypersensitivity response in mucosal immunity than HDM sensitization in asthma models.

Acute stress caused by short-term exposure to deleterious chemicals can induce the aggregation of RNA-binding proteins (RBPs) in the cytosol and the formation of stress granules (SGs). The cytoplasmic RBP, Ras GTPase-activating protein-binding protein 1 (G3BP1) is a critical organizer of SG, and its aggregation is considered a hallmark of cellular stress. However, assembly of SG is a highly dynamic process that involves RBPs; hence, existing methods based on fixation processes or overexpression of RBPs exhibit limited efficacy in detecting the assembly of SG under stress conditions. In this study, we established a G3BP1- Green fluorescent protein (GFP) reporter protein in a human neuroblastoma cell line to overcome these limitations. GFP was introduced into the G3BP1 genomic sequence via homologous recombination to generate a G3BP1-GFP fusion protein and further analyze the aggregation processes. We validated the assembly of SG under stress conditions using the G3BP1-GFP reporter system. Additionally, this system supported the evaluation of bisphenol A-induced SG response in the established human neuroblastoma cell line. In conclusion, the established G3BP1-GFP reporter system enables us to monitor the assembly of the SG complex in a human neuroblastoma cell line in real time and can serve as an efficient tool for assessing potential neurotoxicity associated with short-term exposure to chemicals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The emergence of drug-resistant Mycobacterium tuberculosis (M.tb) has led to the development of novel anti-tuberculosis (anti-TB) drugs. Common methods for testing the efficacy of new drugs, including two-dimensional cell culture models or animal models, have several limitations. Therefore, an appropriate model representative of the human organism is required. Here, we developed an M.tb infection model using human lung organoids (hLOs) and demonstrated that M.tb H37Rv can infect lung epithelial cells and human macrophages (hMφs) in hLOs. This novel M.tb infection model can be cultured long-term and split several times while maintaining a similar number of M.tb H37Rv inside the hLOs. Anti-TB drugs reduced the intracellular survival of M.tb in hLOs. Notably, M.tb growth in hLOs was effectively suppressed at each passage by rifampicin and bedaquiline. Furthermore, a reduction in inflammatory cytokine production and intracellular survival of M.tb were observed upon knockdown of MFN2 and HERPUD1 (host-directed therapeutic targets for TB) in our M.tb H37Rv-infected hLO model. Thus, the incorporation of hMφs and M.tb into hLOs provides a powerful strategy for generating an M.tb infection model. This model can effectively reflect host-pathogen interactions and be utilized to test the efficacy of anti-TB drugs and host-directed therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study presents a deep learning model to predict phlebitis in patients with peripheral intravenous catheter (PIVC) insertions. Leveraging electronic health record data from 27,532 admissions and 70,293 PIVC events at a hospital in Seoul, South Korea, the study involved analyzing patient demographics, PIVC-specific features, and drug-related information. The developed deep learning model was benchmarked against various machine learning models, demonstrating superior performance with an accuracy of 0.93 and an AUC of 0.89. This highlights its potential as an effective tool for early detection of phlebitis, promising enhanced patient outcomes and healthcare efficiency.

Objectives: This study aimed to determine the risk of ischemic heart disease (IHD) and stroke among male couriers in Korea by linking the data from the National Health Insurance (NHI) and National Employee Insurance (NEI) databases., Methods: As of 2015, the NHI and NEI databases were linked using individual IDs. A cohort of male couriers, aged between 20 and 64 years, ( N = 5,012) was constructed using the Korean Employment Insurance Occupational Classification (KECO-2007). For comparison, a cohort of male total wage workers ( N = 5,429,176) and a cohort of office workers ( N = 632,848) within the same age group were also constructed. The follow-up was conducted until 31 December 2020 to confirm the occurrence of IHD and stroke. The diagnoses were defined using the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes. The criteria included medical services for more than 1 day of hospitalization or more than 2 outpatient visits. The age-standardized incidence ratio (SIR) was calculated to evaluate the risk of occurrence. The hazard ratio (HR) was calculated using the Cox model after adjusting for age, alcohol consumption, smoking, obesity, income level, and employment duration as confounding variables., Results: The SIR of IHD for couriers was 1.54 (95% CI 1.31-1.78), while for office workers, it was 1.08 (95% CI 1.06-1.10), compared to male total wage workers. The SIR for stroke was higher for couriers at 1.84 (95% CI 1.40-2.28) and lower for office workers at 0.86, compared to male total wage workers. Couriers had a higher SIR for stroke at 1.84 (95% CI 1.40-2.28) and lower for office workers at 0.86 (0.83-0.89). Compared to total wage workers, couriers had a significantly higher adjusted HR for IHD at 1.60 (95% CI 1.37-1.87) and a higher HR for stroke at 1.39 (95% CI 1.07-1.79). Compared to office workers, couriers had a significantly higher HR for IHD at 1.34 (95% CI 1.13-1.59) as well as for for stroke at 1.43 (95% CI 1.08-1.88)., Conclusion: The incidence of IHD and stroke was higher among male couriers compared to male office workers and total wage workers, highlighting the need for implementing public health interventions to prevent IHD and stroke among couriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yoon, Min, Kim, Kim and Kim.)

Exposure to toxic molecules from food or oral medications induces toxicity in colon cells that cause various human diseases; however, in vitro monitoring systems for colon cell toxicity are not well established. Stress granules are nonmembranous foci that form in cells exposed to cellular stress. When cells sense toxic environments, they acutely and systemically promote stress granule formation, with Ras GTPase-activating protein-binding protein 1 (G3BP1) acting as a core component to protect their mRNA from abnormal degradation. Here, we knocked in green fluorescent protein (GFP)-coding sequences into the C-terminal region of the G3BP1 gene in a human colon cell line through CRISPR-Cas9-mediated homologous recombination and confirmed the formation of stress granules with the G3BP1-GFP protein in these cells under cellular stress exposure. We demonstrated the formation and dissociation of stress granules in G3BP1-GFP expressing colon cells through real-time monitoring using a fluorescence microscope. Furthermore, we validated the toxicity monitoring system in the established colon cell line by observing stress granule formation following exposure to dihydrocapsaicin, bisphenol A, and sorbitol. Taken together, we established a stress granule reporter system in a colon cell line, providing a novel assessment for the real-time monitoring of colon toxicity in response to various chemicals., Competing Interests: The authors report no declarations of interest., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The skin, the organ with the largest surface area in the body, is the most susceptible to chemical exposure from the external environment. In this study, we aimed to establish an in vitro skin toxicity monitoring system that utilizes the mechanism of stress granule (SG) formation induced by various cellular stresses. In HaCaT cells, a keratinocyte cell line that comprises the human skin, a green fluorescent protein (GFP) was knocked in at the C-terminal genomic locus of Ras GTPase-activating protein-binding protein 1 (G3BP1), a representative component of SGs. The G3BP1-GFP knock-in HaCaT cells and wild-type (WT) HaCaT cells formed SGs containing G3BP1-GFP upon exposure to arsenite and household chemicals, such as bisphenol A (BPA) and benzalkonium chloride (BAC), in real-time. In addition, the exposure of G3BP1-GFP knock-in HaCaT cells to BPA and BAC promoted the phosphorylation of eukaryotic initiation factor 2 alpha and protein kinase R-like endoplasmic reticulum kinase, which are cell signaling factors involved in SG formation, similar to WT HaCaT cells. In conclusion, this novel G3BP1-GFP knock-in human skin cell system can monitor SG formation in real-time and be utilized to assess skin toxicity to various substances., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.

Objectives: To evaluate if there is a difference in International Normalized Ratio (INR) readings taken within the 15 second time frame after lancing the finger vs 30-60 seconds of obtaining a blood drop utilizing a CoaguChek ® XS Plus point-of-care (POC) INR machine in patients on warfarin therapy. Methods: All adult patients on anticoagulation therapy with warfarin who were managed in a pharmacist-run anticoagulation clinic were considered for inclusion in the study. The mean difference of INR readings taken less than 15 seconds vs between 30-60 seconds after the blood drop was obtained from the finger was assessed. Results: A total of 62 pairs of INR results were included in the study. There was a mean difference in INR of .076 (95% CI 0.011-.140; P = .0217) when comparing INR readings taken less than 15 seconds and between 30-60 seconds after the blood drop was obtained from the finger. Conclusions: There was a significant difference in INR readings taken less than 15 seconds vs 30-60 seconds after obtaining the blood drop when utilizing a POC INR machine. INR readings taken 30-60 seconds after obtaining a blood drop with the CoaguChek ® XS Plus POC INR machine is not acceptable for use to monitor patients on warfarin., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The objective of standard guideline for utilization of human lung organoids is to provide the basic guidelines required for the manufacture, culture, and quality control of the lung organoids for use in non-clinical efficacy and inhalation toxicity assessments of the respiratory system. As a first step towards the utilization of human lung organoids, the current guideline provides basic, minimal standards that can promote development of alternative testing methods, and can be referenced not only for research, clinical, or commercial uses, but also by experts and researchers at regulatory institutions when assessing safety and efficacy.

Accurate simulation of different cell type interactions is crucial for physiological and precise in vitro drug testing. Human tissue-resident macrophages are critical for modulating disease conditions and drug-induced injuries in various tissues; however, their limited availability has hindered their use in in vitro modeling. Therefore, this study aimed to create macrophage-containing organoid co-culture models by directly incorporating human-induced pluripotent stem cell (hiPSC)-derived pre-macrophages into organoid and scaffold cell models. The fully differentiated cells in these organoids exhibited functional characteristics of tissue-resident macrophages with enriched pan-macrophage markers and the potential for M1/M2 subtype specialization upon cytokine stimulation. In a hepatic organoid model, the integrated macrophages replicated typical intrinsic properties, including cytokine release, polarization, and phagocytosis, and the co-culture model was more responsive to drug-induced liver injury than a macrophage-free model. Furthermore, alveolar organoid models containing these hiPSC-derived macrophages also showed increased drug and chemical sensitivity to pulmonary toxicants. Moreover, 3D adipocyte scaffold models incorporating macrophages effectively simulated in vivo insulin resistance observed in adipose tissue and showed improved insulin sensitivity on exposure to anti-diabetic drugs. Overall, the findings demonstrated that incorporating hiPSC-derived macrophages into organoid culture models resulted in more physiological and sensitive in vitro drug evaluation and screening systems., (Creative Commons Attribution license.)