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Purpose: Macular edema including cystoid macular edema is one of the main causes of unfavorable visual outcomes after cataract surgery. The macular thickness and the occurrence of macular edema after uncomplicated cataract surgery was evaluated using optical coherence tomography (OCT) in this study.Methods: Macular map images were taken by OCT before surgery and at 1 week, 1 month, and 2 months postsurgery. The subjects were classified into two groups (group 1, patients with no macular edema; group 2, patients with macular edema). Group 2 was defined as increase in central macular thickness (CMT) by 30% compared with that before surgery. The risk factors for macular edema were evaluated. Group 2 was divided into two subgroups: subclinical macular edema (group 2A) and cystoid macular edema (group 2B) and they were assessed in terms of the clinical course of best-corrected visual acuity and CMT.Results: A total of 376 patients were enrolled in this study, of which 36 (9.57%, group 2) showed macular edema measured by OCT after the surgery. Univariate analysis for group 1 and 2 revealed that intracameral injection of epinephrine during phacoemulsification was associated with the development of macular edema. In group 2, five patients (1.33%) developed cystoid macular edema. Statistically significant differences in the clinical course of CMT were observed at 2 months (201.2 ± 23.1, 250.0 ± 29.8, and 371.0 ± 160.3 in group 1, group 2A, and group 2B, respectively; p < 0.001) and 1 month postoperatively (198.5 ± 23.6, 237.8 ± 40.9, and 314.0 ± 104.5 in group 1, group 2A, and group 2B, respectively; p < 0.001). Group 2B required additional treatment and eventually achieved best-corrected visual acuity of >0.2 with CMT in the normal range.Conclusions: The intracameral injection of epinephrine may cause macular edema after uncomplicated cataract surgery. Examination of CMT using OCT is recommended for the early detection of macular edema.

Aim: To first explore the prognostic value of MMP11 and MMP15 in hepatocellular carcinoma. Methods: MMP11/MMP15 expression was immunohistochemically detected and correlated with clinicopathologic variables and survival and confirmed in publicly available databases. An MMP-based risk score (MMPRS) was established. Results: Tumoral MMP11/MMP15 expression was higher and univariately associated with crucial clinicopathologic parameters, overall survival and disease-free survival in all patients and/or many subsets. Multivariately, MMP11/MMP15 expression remained significant. Their overexpression and prognostic value were confirmed in the Ualcan and Kaplan–Meier plotter databases. Critically, the novel MMPRS integrating MMP11, MMP15 and tumor–node–metastasis stage identified subgroups with the best and worst prognoses, with much higher predictive power. Conclusion: MMP11 and MMP15 served as prognosticators in hepatocellular carcinoma. MMPRS might work more accurately.

Background Colorectal cancer (CRC) is the third most common type of diagnosed cancer in the world and has the second-highest mortality rate. Meanwhile, South Korea has the second-highest incidence rate for CRC in the world. Objective To assess the possible influence of ethnicity on the molecular profile of colorectal cancer, we compared genomic and transcriptomic features of South Korean CRCs with European CRCs. Methods We assembled a genomic and transcriptomic dataset of South Korean CRC patients (KOCRC; n = 126) from previous studies and European cases (EUCRC; n = 245) selected from The Cancer Genome Atlas (TCGA). Then, we compared the two datasets in terms of clinical data, driver genes, mutational signature, gene sets, consensus molecular subtype, and fusion genes. Results These two cohorts showed similar profiles in driver mutations but differences in the mutation frequencies of some driver genes (including APC, TP53, PABPC1, FAT4, MUC7, HSPG2, GNAS, DENND5B, and BRAF). Analysis of hallmark pathways using genomic data sets revealed further differences between these populations in the WNT, TP53, and NOTCH signaling pathways. In consensus molecular subtype (CMS) analyses of the study cases, no BRAF mutations were found in the CMS1 subtype of KOCRC, which contrasts with previous findings. Fusion gene analysis identified oncogenic fusion of PTPRK-RSPO3 in a subset of KOCRC patients without APC mutations. Conclusions This study presents insights into the genomic landscape of KOCRCs and reveals some similarities and differences with EUCRCs at the molecular level.

With the rapid development of endoscopic technology, endoscopic therapy (ET) has gradually become a new treatment choice for gastrointestinal stromal tumors (GISTs). However, due to the low incidence of duodenal GIST and the difficulty of ET, there is a lack of data to compare the long-term results of ET and surgical resection.Duodenal GIST patients from 2004 to 2015 were selected from the surveillance, epidemiology, and end result (SEER) database. We used the Kaplan-Meier method and log-rank test to describe the 5- and 10-year survival differences between the ET and the surgery groups. The multivariate Cox proportional hazard model was used for analyzing the risk factors influencing the prognosis of patients. We used a 1:1 propensity score-matched (PSM) to reduce confounding factors, and then we compared survival differences between the two groups again.A total of 294 patients with duodenal GIST were enrolled, including 41 (13.9%) patients with ET and 253 (86.1%) patients with surgical resection. Before PSM, the long-term survival of patients with duodenal GIST after ET and surgical resection was similar [5-year overall survival (OS) (79.7 vs. 79.3%, p = 0.876), 10-year OS (66.5 vs. 68.1%, p = 0.876)]. After adjusting the relevant variables using multivariate Cox analysis, we found that the ET and surgery groups were comparable in OS and cancer-specific survival (CSS). After PSM, there was also no significant difference between ET and surgical resection for long-term OS and CSS.Our study found no significant difference in long-term survival between ET and surgical resection in patients with duodenal GIST. However, to obtain high-quality evidence, more extensive sample size studies are needed in the future to evaluate the long-term effects of ET on patients.

Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC. Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins. IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer. Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.

Radiofrequency (RF) has been widely used as a noninvasive technique for skin tightening and rejuvenation. Moiré is a type of interference pattern corresponding to the shape of the face. We aimed to objectively evaluate the effect of RF on facial skin laxity using moiré. Ten subjects participated and were treated with a monopolar RF on the face. Clinical photographs and moiré images were obtained at the baseline and after treatment. The periorbital angle from the upper third of the face, zygomatic length ratio (L1/L2), angle from the middle third, perioral perpendicular length, and angle from the lower third were analyzed. After one session of RF treatment, the mean zygomatic length ratio (L1/L2) from the middle third of the face significantly increased in the 4th week (by 49.68%, P = .047). The L1/L2 ratio increased to nearly one, which were not significant after 8 weeks. The mean perioral perpendicular length decreased to 282.25 ± 84.069 pixels (px) after 4 weeks, and to 281.38 ± 76.03 px after 24 weeks; these differences were statistically significant. The parameters of zygomatic length ratio and perioral perpendicular length extracted from illuminated moiré images can be useful for objectively assessing various facial tightening treatments in clinical settings.

The occlusal force and occlusal contact area may be used to evaluate oral function following restoration of a missing tooth. This study aimed to monitor the initial changes in these factors after single molar implant restoration.Patients who underwent single implant restoration between December 2018 and September 2019 were recruited for this study. Occlusal force was measured before, immediately after, and 1 month after prosthesis placement. The occlusal contact area was evaluated immediately and 1 month after the placement. Data were grouped by sex, restored tooth, and restored side for analysis.In most groups, occlusal force was significantly increased 1 month after the placement compared with that before placement (P.05), and the change was more significant in the first molar group than in the second molar group. There was a significant difference in the occlusal contact area of the implant prosthesis immediately and 1 month after placement when a thickness of 9 μm was used. The occlusal contact area of the natural tooth in the mesial side was significantly increased 1 month after placement (P.05).Occlusal force was significantly increased 1 month after implant restoration, and restoration of the first molar had the most significant effect on the occlusal force. Occlusal contact areas may differ according to the occlusal indicator used in the clinical setting because the changes were significant with only 0 to 9 μm.

This study aimed to determine the equivalence between definitive chemoradiotherapy (DCRT) and radical esophagectomy in clinical T1bN0M0 esophageal squamous cell carcinoma (ESCC).Among 282 patients with cT1bN0M0 ESCC, 238 underwent radical esophagectomy and 44 underwent DCRT. Both treatments were retrospectively compared overall survival (OS), progression-free survival (PFS), and complications.The DCRT group exhibited poorer patient characteristics than the surgery group, especially with mean age (73 vs. 63 years), Eastern Cooperative Oncology Group (ECOG) status, and Charlson Comorbidity Index (p 0.001, each). The median follow-up duration was 49.5 (range, 0.4-97.0) and 45.5 months (range, 5.0-112.0) in the surgery and DCRT groups, respectively. In the DCRT group, clinical complete response was achieved in 43 patients (97.7%) at 1 month after treatment. The 5-year OS rates were 75.8% and 68.8% (p = 0.135) and the 5-year PFS were 63.8% and 57.8% (p = 0.637) for the surgery and DCRT groups, respectively. Local recurrence rates were identical between the two groups (11.4% and 11.4%), but the distant metastasis rate was lower in the DCRT group (n = 1, 2.27% vs. n = 29, 12.15%). Grade 3-4 hematologic toxicities were observed in 11 patients (25%) of the DCRT group, and 56 patients (23.5%) in the surgery group showed grade 3-5 surgical complications, including mortality (n = 5).Based on the non-inferior survival rates, recurrence patterns, and complication rates without critical surgical mortality, DCRT was comparable to esophagectomy for cT1bN0 esophageal squamous cell carcinoma.

Background/aim We evaluated the predictive value of candidate serum biomarkers for recurrence in stage II and III colorectal cancer (CRC) after curative surgery. Patients and methods A total of 33 and 120 patients with CRC with or without recurrence at 5 years after curative surgery were included in the training set and the validation set, respectively. Possible serum biomarkers were examined for associations with CRC recurrence using receiver operating characteristics (ROC) curve analysis. Results In the training set, the expression levels of the 14 biomarkers were compared according to recurrence. Among them, five biomarkers that had significantly different expression levels were validated in 60 patients with recurrence at 5 years after curative surgery and 60 patients without. Multivariate analysis showed that natural log-transformed values of carcinoembryonic antigen (CEA), cyclin-dependent kinase regulatory subunit 2 (CKS2), 2'-5'-oligoadenylate synthetase 2 (OAS2), and autophagy-related gene 5 (ATG5) in preoperative serum were significantly related to recurrence. ROC analysis showed that these biomarkers were able to discriminate patients with recurrence from those without (area under the curve=0.828, 95% confidence interval=0.755-0.990). Conclusion Preoperative serum levels of CEA, CKS2, OAS2 and ATG5 were independent risk factors for recurrence. A combination of serum CEA, CKS2, OAS2 and ATG5 predicted tumor recurrence well in patients with stage II and III CRC.

The role of B7‐H3 in acute myeloid leukemia (AML) is not fully understood. Two previous studies investigating its expression and significances in AML are partially different. In this study, we aimed to systematically characterize the genomic and immune landscape in AML patients with altered B7‐H3 expression using multi‐omics data in the public domain. We found significantly increased B7‐H3 expression in AML compared to either other hematological malignancies or healthy controls. Clinically, high B7‐H3 expression was associated with old age, TP53 mutations, wild‐type WT1 and CEBPA, and the M3 and M5 FAB subtypes. Moreover, we observed that increased B7‐H3 expression correlated significantly with a poor outcome of AML patients in four independent datasets. Gene set enrichment analysis (GSEA) revealed the enrichment of the “EMT” oncogenic gene signatures in high B7‐H3 expressers. Further investigation suggested that B7‐H3 was more likely to be associated with immune‐suppressive cells (macrophages, neutrophils, dendritic cells, and Th17 cells). B7‐H3 was also positively associated with a number of checkpoint genes, such as VISTA (B7‐H5), CD80 (B7‐1), CD86 (B7‐2), and CD70. In summary, we uncovered distinct genomic and immunologic features associated with B7‐H3 expression in AML. This may lead to a better understanding of the molecular mechanisms underlying B7‐H3 dysregulation in AML and to the development of novel therapeutic strategies., In this paper, we found significantly increased B7‐H3 expression in AML compared to either other hematological malignancies or healthy controls. Importantly, we observed that increased B7‐H3 expression correlated significantly with a poor outcome of AML patients in four independent datasets. We also uncovered distinct genomic and immunologic features associated with B7‐H3 expression in AML.

Nonalcoholic fatty liver disease (NAFLD) is characterized by high morbidity. Although long noncoding RNAs (lncRNAs) are known to have a role in NAFLD pathogenesis, the identified lncRNA types are limited. In this study, NAFLD models were established in vitro and in vivo using free fatty acid-treated LO2 cells and high-fat diet-fed mice, respectively. Microarray data were downloaded from the Gene Expression Omnibus database, and AC012668 was selected for further analysis. Cell viability and apoptosis were measured using Cell Counting Kit 8 and flow cytometry assays. RNA expression was detected using reverse transcription-quantitative polymerase chain reaction. Triglyceride (TG) content and lipid deposition were detected using enzyme-linked immunosorbent assay and Oil-Red O staining. Western blotting was used to visualize protein expression. Starbase and TargetScan were used to predict the target miRNA and gene, and the predictions were verified through RNA pull-down and luciferase reporter assays. AC012668 expression levels were significantly suppressed in NAFLD models, whereas AC012668 overexpression inhibited lipogenesis-related gene (SCD1, SREBP1, FAS) expression and TG/lipid accumulation in vitro. Subsequently, miR-380-5p was predicted and verified to target AC012668, and its expression was notably increased in the NAFLD cell model. Moreover, transfection of miR-380-5p antagonized the effects of AC012668 on lipid formation and accumulation. LRP2 was confirmed to be the target gene of miR-380-5p and was downregulated in the NAFLD cell model. Silencing LRP2 reversed the effects of the miR-380-5p inhibitor on lipid formation and accumulation. AC012668 inhibited NAFLD progression via the miR-380-5p/LRP2 axis. These findings may provide a novel strategy against NAFLD.

The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from a poor response rate, common side effects, and the need for lifelong treatment. Novel therapeutic targets are expected. Interestingly, non-canonical structures of nucleic acids play crucial roles in the regulation of gene expression. Especially the formation of G-quadruplexes (G4s) in G-rich strands has been demonstrated to affect many bioprocesses including replication, transcription, and translation, showing great potential as targets in anticancer and antiviral therapies. In this review, we summarize recent antiviral studies about G4s and discuss the potential roles of G4 structures in antiviral therapy for HBV.

The COVID-19 virus's rapid global spread has caused millions of illnesses and deaths. As a result, it has disastrous consequences for people's lives, public health, and the global economy. Clinical studies have revealed a link between the severity of COVID-19 cases and the amount of virus present in infected people's lungs. Imaging techniques such as computed tomography (CT) and chest x-rays can detect COVID-19 (CXR). Manual inspection of these images is a difficult process, so computerized techniques are widely used. Deep convolutional neural networks (DCNNs) are a type of machine learning that is frequently used in computer vision applications, particularly in medical imaging, to detect and classify infected regions. These techniques can assist medical personnel in the detection of patients with COVID-19. In this article, a Bayesian optimized DCNN and explainable AI-based framework is proposed for the classification of COVID-19 from the chest X-ray images. The proposed method starts with a multi-filter contrast enhancement technique that increases the visibility of the infected part. Two pre-trained deep models, namely, EfficientNet-B0 and MobileNet-V2, are fine-tuned according to the target classes and then trained by employing Bayesian optimization (BO). Through BO, hyperparameters have been selected instead of static initialization. Features are extracted from the trained model and fused using a slicing-based serial fusion approach. The fused features are classified using machine learning classifiers for the final classification. Moreover, visualization is performed using a Grad-CAM that highlights the infected part in the image. Three publically available COVID-19 datasets are used for the experimental process to obtain improved accuracies of 98.8, 97.9, and 99.4%, respectively.

Objective To investigate the efficacy and clinical application advantage of omental tamponade with vascular pedicle combined with Laparoscopic fenestration for the treatment of diaphragmatic hepatic cyst. Methods A total of 56 patients with diaphragmatic hepatic cysts underwent laparoscopic surgery in a single tertiary academic medical center from January 2010 to October 2020, including 21 patients (non-omental group) underwent laparoscopic fenestration of liver cysts, and 36 patients underwent laparoscopic liver cyst fenestration combined with vascular pedicle omentum tamponade (omental group). The general conditions and follow-up results of the two groups were compared and annalyzed. Results The operation time of the omental group was longer than that of the non-omental group (P = 1.358E-4). There was no significant difference in postoperative complications, postoperative laboratory values and hospital costs (P>0.05). The length of hospital stay in omental group was shorter than that in non-omental group (P = 0.034). In the omental group, recurrence occurred in 1 of 35 patients (4.65%) who were followeded up 12 months after surgery. In the non-omental group, of the 21 patients followed, 3 patients (14.28%) recurred 6 months after surgery, and 8 patients (38.10%) recurred 12 months after surgery. Conclusion It is an effective method to prevent the recurrence of diaphragmatic hepatic cyst after laparoscopic fenestration by packing the cyst with vascularized omentum.

We previously discovered that exogenously expressed GFP-tagged cytoplasmic human myxovirus resistance protein (MxA), a major antiviral effector of Type I and III interferons (IFNs) against several RNA- and DNA-containing viruses, existed in the cytoplasm in phase-separated membraneless biomolecular condensates of varying sizes and shapes with osmotically regulated disassembly and reassembly. In this study we investigated whether cytoplasmic IFN-α-induced endogenous human MxA structures were also biomolecular condensates, displayed hypotonic osmoregulation and the mechanisms involved. Both IFN-α-induced endogenous MxA and exogenously expressed GFP-MxA formed cytoplasmic condensates in A549 lung and Huh7 hepatoma cells which rapidly disassembled within 1–2 min when cells were exposed to 1,6-hexanediol or to hypotonic buffer (~40–50 mOsm). Both reassembled into new structures within 1–2 min of shifting cells to isotonic culture medium (~330 mOsm). Strikingly, MxA condensates in cells continuously exposed to culture medium of moderate hypotonicity (in the range one-fourth, one-third or one-half isotonicity; range 90–175 mOsm) first rapidly disassembled within 1–3 min, and then, in most cells, spontaneously reassembled 7–15 min later into new structures. This spontaneous reassembly was inhibited by 2-deoxyglucose (thus, was ATP-dependent) and by dynasore (thus, required membrane internalization). Indeed, condensate reassembly was preceded by crowding of the cytosolic space by large vacuole-like dilations (VLDs) derived from internalized plasma membrane. Remarkably, the antiviral activity of GFP-MxA against vesicular stomatitis virus survived hypoosmolar disassembly and subsequent reassembly. The data highlight the exquisite osmosensitivity of MxA condensates, and the preservation of antiviral activity in the face of hypotonic stress.

Exosomes, which are extracellular vesicles produced by endosomes, are important performers of intercellular communication functions. For more than three decades, there has been a growing awareness of exosomes as the contents of the tumor microenvironment and their intimate connection to the development of cancer. The composition, generation, and uptake of exosomes as well as their roles in tumor metastasis, angiogenesis, and immunosuppression are discussed in this paper. In order to stop the progression of cancer, it is crucial to find new diagnostic biomarkers and therapeutic targets for the disease. Knowing the biological characteristics of exosomes and their functions in tumor development helps in this endeavor.

Acute myeloid leukemia (AML) is the most common type of hematological malignancy. Recently, an increasing number of reports have shown that many circular RNAs can act as effective targets for AML. However, the roles of circ_0059707 in AML remain largely unclear. In this study, we found that the expression levels of circ_0059707 were significantly decreased in AML patients with respect to normal controls (p < 0.001). Low expression levels of circ_0059707 were also associated with a poor prognosis. Furthermore, circ_0059707 overexpression inhibited cell growth and promoted apoptosis in leukemia cells, compared with control cells. Circ_0059707- and empty plasmid-transfected cells were injected subcutaneously into BALB/c nude mice. We found that the tumor volume was significantly lower in mice in the circ_0059707 group than in control mice (p < 0.01). Nuclear pyknosis, nuclear fragmentation, nuclear dissolution, and cell necrosis were observed in the circ_0059707 group by HE staining. CircInteractome analysis showed that 25 microRNAs (miRNAs), including miR-1287-5p, ©-miR-1825, a©hsa-miR-326, may be potential targets for circ_0059707. The expression of these miRNAs was analyzed in both the GEO GSE51908 and the GSE142700 databases. miR-1287-5p expression was lower in AML patients compared with controls in both the GSE51908 and the GSE142700 datasets. Moreover, we demonstrated that miR-1287-5p expression was down-regulated in AML patients and up-regulated in circ_0059707-overexpressing cells. Collectively, our research demonstrated that the down-regulation of circ_0059707 was highly evident in de novo AML patients. Our analysis also demonstrated that circ_0059707 inhibited cell growth and promoted apoptosis by up-regulating miR-1287-5p.

Human hepatitis B virus (HBV) is a small enveloped DNA virus with a complex life cycle. It is the causative agent of acute and chronic hepatitis. HBV can resist immune system responses and often causes persistent chronic infections. HBV is the leading cause of liver cancer and cirrhosis. Interferons (IFNs) are cytokines with antiviral, immunomodulatory, and antitumor properties. IFNs are glycoproteins with a strong antiviral activity that plays an important role in adaptive and innate immune responses. They are classified into three categories (type I, II, and III) based on the structure of their cell-surface receptors. As an effective drug for controlling chronic viral infections, Type I IFNs are approved to be clinically used for the treatment of HBV infection. The therapeutic effect of interferon will be enhanced when combined with other drugs. IFNs play a biological function by inducing the expression of hundreds of IFN-stimulated genes (ISGs) in the host cells, which are responsible for the inhibiting of HBV replication, transcription, and other important processes. Animal models of HBV, such as chimpanzees, are also important tools for studying IFN treatment and ISG regulation. In the present review, we summarized the recent progress in IFN-HBV treatment and focused on its mechanism through the interaction between HBV and ISGs.

Strategies for stem cell-based cardiac regeneration and repair are key issues for the ischemic heart disease (IHD) patients with chronic complications related to ischemic necrosis. Cardiac stem cells (CSCs) have demonstrated high therapeutic efficacy for IHD treatment owing to their specific cardiac-lineage commitment. The therapeutic potential of CSCs could be further enhanced by designing a cellular spheroid formulation. The spheroid culture condition of CSCs was optimized to ensure regulated size and minimal core necrosis in the spheroids. The CSC spheroids revealed mRNA profiles of the factors related to cardiac regeneration, angiogenesis, anti-inflammatory, and cardiomyocyte differentiation with a higher expression level than the CSCs. Intramyocardially delivered CSC spheroids in the rat IHD model resulted in a significant increase in retention rate by 1.82-fold (day 3) and 1.98-fold (day 14) compared to CSCs. Endothelial cell differentiation and neovascularization of the engrafted CSC spheroids were noted in the infarcted myocardium. CSC spheroids significantly promoted cardiac regeneration: i.e., decreased infarction and fibrotic area (11.22% and 4.18%) and increased left ventricle thickness (0.62 mm) compared to the untreated group. Cardiac performance was also improved by 2.04-fold and 1.44-fold increase in the ejection fraction and fractional shortening, respectively. Intramyocardial administration of CSC spheroids might serve as an advanced therapeutic modality with enhanced cell engraftment and regenerative abilities for cardiac repair after myocardial infarction.

The aim of this study was to investigate the relationship between the concurrent use of benzodiazepines and opioids and the risk of fractures in older patients with chronic non-cancer pain. Patients with osteoarthritis or low back pain (≥ 65 years of age) included in the Korean National Health Insurance Service–National Sample Cohort database of Korea and with an incident diagnosis of hip, humeral, or forearm fracture between 2011 and 2015 were identified as cases. For each case, four controls were matched for age (within 5 years), sex, and year of cohort entry. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for fractures associated with concurrent use of benzodiazepines and opioids using a conditional logistic regression analysis, adjusting for comorbidities and comedications. The aOR (95% CI) for the concurrent use of benzodiazepines and opioids was 1.45 (1.22–1.71), compared with those of non-use within 30 days before the index date. The aOR was 1.65 (1.22–2.23) in patients who were continuously receiving benzodiazepines and were newly initiated with concurrent opioids. The aORs for concurrent use were 1.95 (1.39–2.74) and 1.27 (1.03–1.56) in the case of hip fracture and forearm fracture, respectively. The concurrent use of benzodiazepines and opioids was associated with an increased risk of fractures in older patients with chronic non-cancer pain. Therefore, patients continuously receiving benzodiazepines in whom opioids are newly initiated need careful monitoring, and such combined therapy should be limited to the shortest duration possible.

Sickness symptoms exerted via inflammatory responses occur in several infectious and chronic diseases. A growing body of evidence suggests that altered nutrient availability and metabolism are tightly coupled to inflammatory processes. However, the relationship between metabolic shifts and the development of the sickness response has not been explored fully. Therefore, we aimed to evaluate metabolic phenotypes with a mouse model showing sickness symptoms via systemic administration of lipopolysaccharide (LPS) in the present study. LPS injection elevated the lipid utilization and circulating levels of fatty acids. It also increased the levels of β-hydroxybutyric acid, a ketone body produced from fatty acids. We confirmed the functional connectivity between nutrient utilization and inflammatory responses and demonstrated enhanced lipid utilization in the hypothalamus providing insights into hypothalamic control of sickness responses. Collectively, these findings could help develop new therapeutic strategies to treat patients with severe sickness symptoms associated with infectious and chronic human diseases.

ImportanceFalls have become a major public health issue in China with population aging. Although falls prevention for older community-dwelling people has been included in the National Essential Public Health Service Package since 2009, there is limited understanding of the implementation of this program.ObjectiveTo identify the associated factors and provide recommendations to inform the better implementation of falls prevention in the Chinese primary health care system.Design, Setting, and ParticipantsThis qualitative study was conducted in 3 purposively selected cities in China from March 1 to June 7, 2021. Health administrators from the local health commission or bureau, staff members from local Centers for Disease Control and Prevention and primary health care facilities and community-dwelling older people were recruited, using a combination of purposive sampling and snowball sampling.Main Outcomes and MeasuresIn-depth interviews were conducted with health administrators and focus groups with other participants. Data analysis followed the guidance of the Consolidated Framework for Implementation Research. Study outcomes included facilitators and barriers of implementing falls prevention for older people in the Chinese primary health care settings. A framework with recommendations was developed to inform the future intervention implementation.ResultsAmong a total of 130 participants interviewed, 77 (59.2%) were female and the mean (SD) age was 47.4 (16.7) years. Clear recognition of the challenges and benefits of falls prevention, adaptive regionally tailored guidance plans, and continuous governmental policy and financial support were the major facilitators, whereas the major barriers consisted of insufficient confidence in delivering interventions and poor understanding of the falls burden, low recognition of the importance of falls prevention, limited multisectoral collaboration, and weak financial incentives. A 7-strategy embedded framework—including data-driven surveillance, audit and feedback, implementation strategy, workforce strengthening, community empowerment, internal services integration, and external enabling environment—was developed to foster successful implementation.Conclusions and RelevanceThis qualitative study identified major facilitators and barriers to the implementation of falls prevention for older people at the primary care level, which have the potential to contribute to better implementation of falls prevention for older people in the Chinese primary health care system.

Each novel SARS-CoV-2 variant renews concerns about decreased vaccine efficacy caused by evasion of vaccine induced neutralizing antibodies. However, accumulating epidemiological data show that while vaccine prevention of infection varies, protection from severe disease and death remains high. Thus, immune responses beyond neutralization could contribute to vaccine efficacy. Polyclonal antibodies function through their Fab domains that neutralize virus directly, and Fc domains that induce non-neutralizing host responses via engagement of Fc receptors on immune cells. To understand how vaccine induced neutralizing and non-neutralizing activities synergize to promote protection, we leverage sera from 51 SARS-CoV-2 uninfected health-care workers after two doses of the BNT162b2 mRNA vaccine. We show that BNT162b2 elicits antibodies that neutralize clinical isolates of wildtype and five variants of SARS-CoV-2, including Omicron BA.2, and, critically, induce Fc effector functions. FcγRIIIa/CD16 activity is linked to neutralizing activity and associated with post-translational afucosylation and sialylation of vaccine specific antibodies. Further, neutralizing and non-neutralizing functions diminish with age, with limited polyfunctional breadth, magnitude and coordination observed in those ≥65 years old compared to

This study aimed to estimate the level of underestimation of National Dose Registry (NDR) doses based on the workers’ dosimeter wearing compliance. In 2021, a nationwide survey of Korean medical radiation workers was conducted. A total of 989 medical workers who performed fluoroscopically-guided interventional procedures participated, and their NDR was compared with the adjusted doses by multiplying the correction factors based on the individual level of dosimeter compliance from the questionnaire. Ordinal logistic regression analysis was performed to identify the factors for low dosimeter wearing. Based on the data from the NDR, the average annual effective radiation dose was 0.95 mSv, while the compliance-adjusted dose was 1.79 mSv, yielding an 89% increase. The risks for low compliance with wearing a badge were significantly higher among doctors, professionals other than radiologists or cardiologists, workers not frequently involved in performing fluoroscopically-guided interventional procedures, and workers who did not frequently wear protective devices. This study provided quantitative information demonstrating that the NDR data may have underestimated the actual occupational radiation exposure. The underestimation of NDR doses may lead to biased risk estimates in epidemiological studies for radiation workers, and considerable attention on dosimetry wearing compliance is required to interpret and utilize NDR data.

To establish the droplet digital PCR (ddPCR) assay for the detection of NPM1 type A mutation in patients with acute myeloid leukemia (AML), and to evaluate its specificity, sensitivity and its value in clinical application.NPM1 mutant and wildtype plasmids were used to verify the performance of ddPCR. Both ddPCR and Sanger sequencing were used to detect the bone marrow samples of 87 AML patients, which were confirmed by next generation sequencing (NGS). Moreover, NPM1 mutation burden was dynamically monitored in five patients by ddPCR.The limit of blank (LOB) of ddPCR established for NPM1 mutation detection was 1.1 copies/μl, and the limit of detection (LOD) was 2.43 copies/μl, which had good linearity. Among the 87 newly diagnosed AML patients, ddPCR identified seventeen cases positive for NPM1 mutation (19.5%)， which was consistent with Sanger sequencing. NGS confirmed 12 positive cases, including 8 of type A mutations, 2 of type D mutations, and 2 of rare type mutations. The results of dynamic monitoring of NPM1 mutation burden in 5 patients showed that the NPM1 mutation burden decreased obviously even close to 0, when patients achieve complete remission after chemotherapy. However, the mutation burden was increased again at the time of relapse.In this study, we established a ddPCR method for detection of NPM1 mutation with good sensitivity and repeatability, which can be used for screening NPM1 mutation in newly diagnosed AML patients and for minimal residual disease monitoring after remission in positive AML patients to guide treatment.微滴式数字PCR检测急性髓系白血病NPM1基因突变及其临床应用价值.建立微滴式数字PCR（ddPCR）检测急性髓系白血病（AML）患者NPM1基因A型突变的方法，评价该方法的特异性、灵敏度及其临床应用价值.使用NPM1突变型及野生型质粒对该方法进行性能验证；ddPCR及Sanger测序法检测87例初诊AML患者骨髓标本，用二代测序验证；ddPCR动态监测5例NPM1 A型突变患者化疗后突变负荷水平.检测NPM1基因A型突变的ddPCR方法，空白限（LOB）为1.1拷贝/微升，最低检测下限（LOD）为2.43拷贝/微升，且线性良好；ddPCR及Sanger测序法检测87例初诊标本NPM1突变结果完全一致，阳性17例（19.5%）；二代测序验证12例突变阳性样本，结果显示，NPM1 A型突变8例、D型突变2例、罕见型突变2例。5例患者NPM1突变水平动态监测结果显示，化疗达完全缓解时NPM1突变水平明显下降甚至接近于0，但复发时再次明显增高.本研究建立了一个检测NPM1突变的ddPCR方法，具有良好的灵敏度和重复性，可用于AML初诊患者的NPM1突变筛选和阳性患者的缓解后微小残留病监测以指导治疗.

Objective: To identify the expression and methylation patterns of lncRNA CASC15 in bone marrow (BM) samples of acute myeloid leukemia (AML) patients, and further explore its clinical significance.Eighty-two de novo AML patients and 18 healthy donors were included in the study. Meanwhile, seven public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were included to confirm the expression and methylation data of CASC15. Receiver operating characteristic (ROC) curve analysis was applied to determine the discriminative capacity of CASC15 expression to identify AML. The patients were divided into CASC15high group and CASC15low group by X-tile method, and the prognostic value of CASC15 was identified by Kaplan-Meier method and univariate and multivariate Cox regression analysis.The expression level of CASC15 was significantly decreased in BM cells of AML patients compared with healthy donors (P0.001). ROC curve analysis suggested that CASC15 expression might be a potential biomarker to discriminate AML from controls. The expression of CASC15 was high at the early stage of hematopoiesis, and reached a peak at the stage of multipotent progenitors differentiation, then decreased rapidly, and was at a range of low level fluctuations in the subsequent process. Among FAB subtypes, CASC15 expression in M0 was significantly higher than that in M1-M7. Clinically, CASC15low patients were more likely to have NPM1 mutations than CASC15high patients (P=0.048), while CASC15high patients had a significantly higher frequency of IDH1 and RUNX1 mutations (P=0.021 and 0.014, respectively). Moreover, CASC15low group had a shorter overall survival (OS) in patients with NPM1 mutations. Furthermore, multivariate analysis confirmed that CASC15 expression was a significant independent risk factor for OS in NPM1 mutated AML patients. In addition, CASC15 methylation level in BM samples of AML patients was significantly decreased compared with healthy donors. Patients with CASC15 high methylation had poor OS and disease-free survival.The expression of CASC15 is decreased in AML, and low CASC15 expression may predict adverse prognosis in AML patients with NPM1 mutations. Moreover, CASC15 methylation level in AML is significantly decreased, and high CASC15 methylation may predict poor prognosis in AML.长链非编码RNA CASC15低表达在伴NPM1基因突变的急性髓系白血病中的临床意义.确定急性髓系白血病（AML）患者骨髓样本中长链非编码RNA CASC15的表达水平及甲基化水平，并进一步探讨其在AML中的临床意义.纳入82例初治AML患者和18例健康对照者，同时分析了来自GEO和TCGA等7个公共数据集中的CASC15表达和甲基化数据。应用ROC曲线分析确定CASC15表达对AML患者的鉴别意义；使用X-tile方法将患者分为CASC15高表达组和CASC15低表达组，并采用Kaplan-Meier法及单因素和多因素Cox回归分析确定CASC15的预后价值.与健康对照者相比，CASC15在AML患者骨髓细胞中表达显著降低（P0.001）。ROC曲线分析结果表明，CASC15表达可能是鉴别AML的潜在生物标志物。CASC15在造血过程的早期阶段表达水平较高，在多能祖细胞分化阶段达到峰值，然后迅速下降至低值波动。在FAB亚型中，CASC15在M0中的表达水平显著高于M1-M7。CASC15低表达患者更有可能发生NPM1突变（P=0.048），而高表达患者更易发生IDH1（P=0.021）和RUNX1（P=0.014）突变。在伴NPM1突变的AML患者中，CASC15低表达患者的总体生存时间更短，多因素分析也证实CASC15表达是伴NPM1突变的AML患者总体生存时间的独立影响因素。此外，CASC15在AML患者骨髓样本中的甲基化水平较健康对照者显著降低，高甲基化患者总体生存时间和无病生存时间更短.CASC15在AML中表达降低，并且CASC15低表达提示伴NPM1基因突变的AML预后不良。CASC15在AML中甲基化水平显著降低，高甲基化可能预示患者预后不良.

Background We screened out several hypermethylated solute carrier (SLC) family genes in acute myeloid leukemia by reduced representation bisulfite sequencing. SLC22A3 encodes an organic cation transport protein, which is critical for drug transportation and cellular detoxification. SLC22A3 is significantly downregulated and associated with tumor progression and worse prognosis in a variety of solid tumors. However, there are no data available regarding the role of SLC22 in AML. This study aimed to explore the regulatory mechanism of DNA methylation on SLC22A3 expression, as well as its clinical significance in AML prognosis. Results SLC22A3 was identified as the sole prognosis-associated gene among SLCs based on TCGA and Beat AML databases. Bone marrow mononuclear cells (BMMNCs) from AML, MDS patients, and healthy donors were enrolled in this study. SLC22A3 methylation was significantly increased in AML compared with controls and MDS patients; meanwhile, the expression level of SLC22A3 was decreased. SLC22A3 hypermethylation presented an obvious association with some specific clinical characteristics and affected the survival time of AML patients as an independent risk indicator. SLC22A3 expression changed regularly as the disease complete remissions and relapses. Demethylation drug 5-aza-2′-deoxycytidine (DAC) activated transcription and increased mRNA expression of SLC22A3 in leukemia cell lines and AML fresh BMMNCs. Knockdown of SLC22A3 in leukemia cells enhanced cell proliferation and suppressed cell apoptosis. Data from public programs were used for auxiliary screening of probable molecular mechanisms of SLC22A3 in the antileukemia effect. Conclusions Our results showed that increased methylation and decreased expression of SLC22A3 may be indicators of poor prognosis in AML. Methylation-silenced SLC22A3 expression may have potential guiding significance on antileukemia effect of DAC.

ObjectivesWe investigated the association between protracted low-dose ionising radiation and the risk of cancer in medical radiation workers, the largest group of workers with occupational radiation exposures.MethodsData of all South Korean diagnostic medical radiation workers enrolled at the National Dose Registry during 1996–2011 were merged with the death and cancer incidence data until 31 December 2017. SIRs, relative risks and excess relative risks (ERRs) for cancer were calculated to quantify the radiation dose–response relationship using Poisson regression models.ResultsA total of 3392 first primary cancer cases were identified among 93 920 diagnostic medical radiation workers. The mean cumulative badge dose in the cohort was 7.20 mSv. The ERRs for solid cancer with a 5-year lag and haematopoietic cancers with a 2-year lag for all workers were 0.15 per 100 mGy (95% CI −0.20 to 0.51) and 0.09 per 100 mGy (95% CI −2.02 to 2.20), respectively. The ERRs for cancers did not significantly vary by job title, different lag years or after excluding thyroid and lung cancers. Sensitivity analyses restricted to workers employed for at least 1 year, or who were employed in or after 1996, or who had exposure to a cumulative badge dose of 1 mSv or more showed similar results.ConclusionsOccupational radiation doses were not significantly associated with cancer incidence among South Korean diagnostic medical radiation workers. However, cautious interpretation of ERRs is needed due to the limitations of short follow-up and low cumulative radiation doses.

CDR1as is a well‐identified circular RNA with regulatory roles in a variety of physiological processes. However, the effects of CDR1as on stemness of periodontal ligament stem cells (PDLSCs) and the underlying mechanisms remain unclear. In this study, we detect CDR1as in human PDLSCs, and subsequently demonstrate that CDR1as maintains PDLSC stemness. Knockdown of CDR1as decreases the expression levels of stemness‐related genes and impairs the cell's multi‐differentiation and cell migration abilities, while overexpression of CDR1as increases the expression levels of stemness‐related genes and enhances these abilities. Furthermore, our results indicate that the RNA‐binding protein hnRNPM directly interacts with CDR1as and regulates its expression in PDLSCs. In addition, we show that CDR1as promotes the expression of stemness‐related genes in PDLSCs by inhibiting miR‐7‐mediated suppression of KLF4 expression. Collectively, our results demonstrate that CDR1as participates in the molecular circuitry that regulates PDLSC stemness.

Background To analyse structural characteristics and perifoveal/peripapillary vasculature by OCT in children with peripapillary hyperreflective ovoid mass-like structures (PHOMS) and compare the results with those of normal subjects. Methods Forty-five patients (84 eyes) under 18 years old with blurry disc margin were evaluated with spectral domain-OCT and swept course-OCT. Patients were divided into four groups, according to presence of PHOMS and then the size of the existing PHOMS. Eyes with visible optic disc drusen (ODD) were not included. Foveal avascular zone (FAZ) and vessel densities from macula and optic disc area were assessed and potential associations between vessel density and structural parameters, such as peripapillary retinal nerve fibre layer (pRNFL), and macular ganglion cell and inner plexiform layer (mGCIPL) thickness, were analysed. Results Among 45 patients (eighty-four eyes), coexisting buried ODD were found only in eyes with PHOMS. The scleral canal diameter was significantly smaller in PHOMS positive eyes compared to control eyes. Vessel density measurements from the papillary, peripapillary and optic nerve head (ONH) regions in the large PHOMS group were significantly lower compared to the control group (papillary; P = 0.014, peripapillary; P = 0.001, ONH; P = 0.046). FAZ area and macular vessel densities showed no difference compared to normal eyes in all three PHOMS groups. pRNFL and mGCIPL thickness did not differ among four groups and correlations were also not significant. Conclusions Children with PHOMS have smaller scleral canal and can entail buried ODD. Vessel densities of optic disc area in large PHOMS eyes are significantly lower than in normal eyes.

ST59 is the predominant pathotype of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in China. As a variant of ST59, there is relatively little known about the detailed information of ST338. To address this issue, here, we described thirteen ST338 CA-MRSA strains isolated from severe bloodstream infection cases, and focused on their epidemiology, genetic features and virulence potential. Phylogenetic analysis showed the earliest isolated strain of this study is likely a predecessor of recent ST338 lineage (after year of 2014). Furthermore, the phylogenetic reconstruction and time estimation suggested that ST338 evolved from ST59 in 1991. Notably, the carrying patten of virulence factors of all ST338 strains were similar, and the genomic islands νSaα, νSaγ and SaPI and the core virulence factors like hla and psm were detected in ST338 isolates. However, all ST338 isolates lacked some adhesion factors such as clfA, clfB, eap, cna and icaD. Additionally, among these ST338 strains, one PVL-negative ST338 isolate was detected. Experiment on mice nose and human alveolar epithelial cell showed that the nasal colonization ability of ST338 was weaker than that of CA-MRSA MW2. In a mouse bloodstream infection model and skin infection model, PVL+ and PVL− strains had the similar virulence, which was dependent on upregulation of toxin genes rather than the presence of mobile genetic elements such as ΦSa2 carrying PVL. Our findings provide important insight into the epidemiology and pathogenicity of the novel and highly virulent ST338-SCCmec Vb clone.

The threat of COVID-19 outbreak in South Korea and around the globe challenged not only physical health but also mental health, increasing the chances of disorders such as posttraumatic stress disorder (PTSD). Such pandemic situation can be referred to a traumatic event for citizens. The present study aims to examine the psychometric properties of the PTSD Checklist (PCL-5), which is named the K-COVID-related-PTSD. The scale measures PTSD symptomology in the context of the COVID-19 pandemic in South Korea. A total of 1434 South Korean citizens were included in this study. The data were statistically analyzed using SPSS 21.0 and Mplus 8.0. The results of confirmatory factor analysis demonstrated a superior fit for the seven-factor hybrid model (x2 = 1425.445 (df = 149), CFI = 0.950, TLI = 0.937, SRMR = 0.033, RMSEA = 0.077) consisting of re-experiencing, negative affect, anxious arousal, dysphoric arousal, avoidance, anhedonia, and externalizing behaviors. Furthermore, the K-COVID-related-PTSD showed a satisfactory level of internal consistency (α = 0.793 to α = 0.939) with good convergent and discriminant validity. Finally, concurrent validity was confirmed by the significant correlations with all the negative mental health outcomes, such as PTSD symptoms, somatization, depression, anxiety, anger, negative affect, job burnout, and suicidal ideation. Overall, the current results demonstrate the K-COVID-related-PTSD is a valid scale and therefore has important implications for future pandemic-related studies.

Under ER stress conditions, the ER form of transmembrane proteins can reach the plasma membrane via a Golgi-independent unconventional protein secretion (UPS) pathway. However, the targeting mechanisms of membrane proteins for UPS are unknown. Here, this study reports that TMED proteins play a critical role in the ER stress-associated UPS of transmembrane proteins. The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS-CoV-2 Spike. Subsequent mechanistic analyses indicate that TMED3 recognizes the ER core-glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. Co-expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking-deficient ΔF508-CFTR and p.H723R-pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. In contrast, TMED2/3/9/10 silencing reduces SARS-CoV-2 viral release. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress-associated, Golgi-independent secretion of transmembrane proteins.

Recent studies have demonstrated that the oral microbiome in patients with Sjögren’s syndrome (SS) is significantly different from that in healthy individuals. However, the potential role of the oral microbiome in SS pathogenesis has not been determined. In this study, stimulated intraductal saliva samples were collected from the parotid glands (PGs) of 23 SS and nine non-SS subjects through PG lavage and subjected to 16S ribosomal RNA amplicon sequencing. The correlation between the oral microbiome and clinical features, such as biological markers, clinical manifestations, and functional and radiological characteristics was investigated. The salivary microbial composition was examined using bioinformatic analysis to identify potential diagnostic biomarkers for SS. Oral microbial composition was significantly different between the anti-SSA-positive and SSA-negative groups. The microbial diversity in SS subjects was lower than that in non-SS sicca subjects. Furthermore, SS subjects with sialectasis exhibited decreased microbial diversity and Firmicutes abundance. The abundance of Bacteroidetes was positively correlated with the salivary flow rate. Bioinformatics analysis revealed several potential microbial biomarkers for SS at the genus level, such as decreased Lactobacillus abundance or increased Streptococcus abundance. These results suggest that microbiota composition is correlated with the clinical features of SS, especially the ductal structures and salivary flow, and that the oral microbiome is a potential diagnostic biomarker for SS.

To determine the clinical effects of ocular surface and Meibomian gland parameters on tear film stability among individuals with Meibomian gland dysfunction (MGD), those with aqueous deficient dry eye (ADDE), individuals with both conditions and normal controls.Patients were divided into four groups: normal controls, patients with ADDE, patients with MGD, and patients who fulfilled diagnostic criteria for ADDE and MGD (Mixed Group). Data for ocular symptom score, lid margin abnormality, ocular staining, tear break-up time, meiboscore, and lipid layer thickness (LLT) measured by a Lipiview interferometer, Schirmer test, and MGD severity score were collected.A total of 109 patients (109 eyes) were evaluated. In patients with MGD, LLT was significantly lower than the ADDE patients. However, the Schirmer test value was the highest in the MGD group. The LLT negatively correlated with meiboscore and MGD severity score in the MGD group. Significant correlation between Schirmer test value and meiboscore was definite in the MGD group.Tear fluid secretion is more increased and lipid layer thickness is more decreased in MGD patients than in ADDE patients. Decreased lipid layer thickness caused by MGD-related tear film instability may stimulate reflex tear secretion. The obstructive MGD is more prevalent than hypersecretary MGD.Key messagesThe tear film stability is affected by Mebomian gland dysfunction (MGD). The measurement of the tear film parameters including lipid layer thickness suggests that the obstructive MGD is more prevalent than hypersecretary MGD and the aqueous layer compensates the decreased lipid layer caused by MGD.

Resistant starch (RS) is a complex prebiotic carbohydrate beneficial to the human gut. In the present study, four genes encoding for putative amylolytic enzymes, likely to be responsible for RS-degradation, were identified in the genome of Bifidobacterium adolescentis P2P3 by comparative genomic analysis. Our results showed that only three enzymes (RSD1, RSD2, and RSD3) exhibited non-gelatinized high amylose corn starch (HACS)-degrading activity in addition to typical α-amylase activity. These three RS-degrading enzymes (RSD) were composed of multiple domains, including signal peptide, catalytic domain, carbohydrate binding domains, and putative cell wall-anchoring domains. Typical catalytic domains were conserved by exhibiting seven typical conserved regions (I-VII) found mostly in α-amylases. Analysis of enzymatic activity revealed that RSD2 displayed stronger activity toward HACS-granules than RSD1 and RSD3. Comparative genomics in combination with enzymatic experiments confirmed that RSDs might be the key enzymes used by RS-degrading bifidobacteria to degrade RS in a particular ecological niche, such as the human gut.

Interventional medical radiation workers represent an under-studied population worldwide, although they receive relatively high occupational radiation doses. This study aimed to estimate the lifetime cancer risk from occupational radiation exposure among workers at interventional radiology departments. A field survey of interventional medical workers in nationwide branches of the Korean Society of Interventional Radiology was conducted in 2017. Organ-specific radiation doses were estimated using national dose registry data and conversion coefficients provided by the International Commission on Radiological Protection. Lifetime attributable risk (LAR) and lifetime fractional risk (LFR) were calculated based on realistic exposure scenarios using a radiation risk assessment tool. LARs from occupational radiation exposure until the age of retirement for all cancers combined were 338 (90.3–796.1), 121 (33.5–288.7), and 156 (41.1–390.6) per 100,000 individuals for male radiologists, male radiologic technologists, and female nurses, respectively. LFR for all cancers combined ranged from 0.22% (0.06–0.53) to 0.63% (0.17–1.47). Regarding the organ site, the highest LAR and LFR among all groups were observed for thyroid cancer. This study provides timely evidence of potential cancer burden from the current levels of occupational radiation exposure among workers at interventional radiology departments. The risks varied by occupational groups, and workers, particularly interventional radiologists, need to be carefully monitored for radiation.

γ-Glutamyl transpeptidase (GGT), a cell surface-bound protease, is associated with various diseases including cancer. The detection of the enzyme activity is an important subject, leading to about 40 activatable fluorescent probes so far. All of them, however, lack the membrane-localizing ability, raising a reliability issue in the quantitative analysis. Disclosed is the first fluorescent probe that senses the cell surface-bound enzyme, which, furthermore, is capable of ratiometric as well as two-photon imaging with desirable features. Ratiometric imaging of cancer cell lines reveals a 6.4-8.4-fold higher GGT levels than those in normal cell lines. A comparison of the enzyme activity in organ tissues of normal and tumor xenograft mice reveals notably different levels of enzyme activity depending on the kind of tissue. Normal tissues exhibited comparable levels of enzyme activity, except the kidney that has significantly higher GGT activity (2.7-4.0-fold) than the other organs. Compared with the normal tissues, considerably higher enzyme activity was observed in the tumor tissues of the thigh (4.0-fold), colon (2.5-fold), lung (3.6-fold), and liver (2.1-fold), but essentially no enhanced activity in the tumor tissues of the spleen, stomach, and pancreas and a comparable level in both the tumor and normal kidney tissues were observed. The probe offers practical means for studying GGT-associated biology in cells and tissues by one- as well as two-photon ratiometric imaging.

ObjectivesSuicide is a leading cause of death in the working-age population. We investigated suicide mortality among diagnostic medical radiation workers in relation to their demographic and occupational factors in South Korea.MethodsThe study population consisted of all diagnostic medical radiation workers enrolled in the National Dosimetry Registry from 1996 to 2011. The registry data were linked with mortality data through the end of 2017. We calculated age-standardised suicide rates, standardised mortality ratios (SMRs) and rate ratios (RRs) by demographic and occupational factors.ResultsA total of 207 suicides were identified among 94 367 medical radiation workers, exhibiting a suicide rate of 14.0 per 100 000 person-years. Compared with the general population, suicide rates were lower for both male and female workers (SMR 0.49, 95% confidence interval (CI) 0.42 to 0.57; SMR 0.54, 95% CI 0.41 to 0.70, respectively). Similarly, decreased SMRs were observed across job titles and other work-related factors. However, a shorter duration of employment was positively associated with RRs for suicide; risks were 2.74 (95% CI 1.56 to 4.81) and 4.66 (95% CI 1.53 to 14.20) times higher in male and female workers with less than 1 year of employment, respectively, than in those with at least 10 years of employment.ConclusionsDiagnostic medical radiation workers in South Korea showed lower suicide rates than in the general population. However, a shorter duration of employment was associated with higher risk of suicide. Suicide prevention efforts could target workers engaged in short-term employment.

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.

Matrix metalloproteinase 14 (MMP14) has been found to play multiple biological roles in cancers, including hepatocellular carcinoma (HCC). Up to now, its expression, clinicopathological and prognostic implications in HCC have not been comprehensively investigated. In the present study, MMP14 expression was detected, using tissue microarray-based immunohistochemical staining, in paired HCC and adjacent liver (AL) samples from 260 patients who underwent radical hepatectomy. The associations of MMP14 staining H-scores with clinicopathological parameters, overall and disease-free survival were then evaluated. Finally, its expression and prognostic value were confirmed in some online publicly available databases. It was shown that MMP14 expression was significantly higher in HCC than in AL tissues (p=0.035). Furthermore, MMP14 expression correlated positively with tumour size, Edmondson-Steiner grade and α-fetoprotein level (p

Objectives Thus far, biological roles of plasminogen activator inhibitor 1 (PAI1) in hepatocellular carcinoma (HCC) remain controversial. Moreover, its expression, clinicopathologic and prognostic significance in HCC have not been comprehensively investigated, therefore needing further evidence. Methods PAI1 expression was measured, using tissue microarray-based immunohistochemical staining, in matched HCC and adjacent liver samples from 178 patients with HCC after curative resection. The correlations of PAI1 H-scores with clinicopathologic variables and survival were further evaluated. Its prognostic value was finally confirmed in some public databases. Results It was found that PAI1 expression was significantly higher in HCC than in adjacent liver tissues. Moreover, high PAI1 expression was more frequent in those with multiple lesions. Univariate analyses showed that PAI1 expression was negatively associated with both overall and relapse-free survival. Although PAI1 expression was not statistically significant in multivariate Cox regression test, combination of it with TNM stage effectively distinguished survival and relapse, and served as an independent prognostic factor. In the online available datasets of HCC and liver cancer used, SERPINE1, the gene encoding PAI1, was also revealed to be prognostic. Conclusions Our data suggested that high PAI1 expression was predictive for unfavorable biological behavior and long-term prognosis in HCC.

The benzocoumarin dyes fluoresce negligibly in aqueous media but very strongly in cells, whereas representative conventional dyes display contrasting behaviour; the distinct emission behaviour of the fluorophores in organic solutions, in aqueous media, and in cell convinces the uniqueness of the cellular environment. The in cellulo superbright benzocoumarins also reveal an environment-insensitive emission behaviour, which is required for the reliable analysis via ratiometric imaging.

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.

Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone

The gut microbiota has an important role in the pathogenesis of hepatic encephalopathy(HE). Rifaximin, an intestinal non-absorbable antibacterial agent, is effective in the treatment of HE. However, whether long-term prophylactic use induces antibacterial resistance and its mechanism for treating HE remains unclear. This prospective study assessed the impact of 12 weeks rifaximin administration on the gut microbiota and resistome in cirrhotic patients. Fecal sampling was conducted 1 day before the first rifaximin administration and at Weeks 1, 2, 4, 6, 8, 10, 12 of the study. Thirty cirrhotic patients who were in remission from recurrent HE was enrolled to receive rifaximin (400mg TID for 12 weeks). Rifaximin improved hyperammonemia and cognitive function in the 21 patients who completed rifaximin treatment. The dynamic observations showed the gut microbiota diversity, composition and the number of resistance genes, plasmids, insertion sequences did not change significantly during the period(P>0.05). Metabolic pathways such as aromatic amino acids, tryptophan synthesis, urea cycle, and LPS synthesis reduced. No new antimicrobial resistance genes was emergenced. However, the number of aminoglycosides, rifamycin and phenolic resistance genes increased, whereas tetracycline, fosfomycin and cephamycin decreased (PE. coli, K. pneumoniae, and B. longum strains correlated with changes of resistance genes. Prophylactic use of rifaximin for 12 weeks improved hyperammonemia and neurophysiological function, maintained gut microbiota diversity, composition and did not change the overall resistome. Rifaximin altered expression of HE-related metabolic pathways. All of these effects could play a key role in preventing HE. Clinical Trial Registration: ChiCTR1900022234 (registered at the Chinese Clinical Trial Registry).

The cell membrane regulates the flux of materials in and out of cell, cell adhesion, and signaling. Fluorophores that selectively localize on it are in demand for investigations of the molecular events occurring on the outer cell membrane. Commercial membrane trackers based on phospholipids are structurally complex and difficult to modify further. We disclose the zwitterionic (naphthylvinyl)pyridinium dyes that selectively localize on the outer cell membrane and emit blue, green, and red fluorescence, respectively. Notably, they are structurally compact and provide bright fluorescence images of the cell membrane. By comparing with control compounds, we identified minimal structural elements for the "robust" localization of dye on the outer cell membrane. Further, the dyes are two-photon active, enabling high-resolution, deep-tissue imaging. One of the dyes was used to image a spleen tissue, which provided high-resolution fluorescent images with a distinct morphology. In addition, the materials and results disclosed are valuable for the development of membrane-targeting probes and structurally compact fluorophores.

Many countries have reported increasing rates of penicillin-susceptible methicillin-sensitive Staphylococcus aureus (MSSA-PENS). To date, there is relatively little known about the current situation and molecular characteristics of MSSA-PENS in China. In this study, we carried out a laboratory-based multi-region retrospective study to investigate the genomic epidemiology and characterisation of MSSA-PENS isolated from invasive bloodstream infections (BSIs) across 17 provinces. The prevalence of MSSA-PENS isolates increased significantly over the 6-year period, with the proportion increasing from 3.51% in 2014–8.80% in 2019, an average relative increase of 22.14% per year (95% confidence interval 9.67%-34.61%, P for trend

At present, it has been controversial whether primary tumor resection (PTR) can bring survival advantage to patients with metastatic small intestine neuroendocrine tumors (SI-NETs). To answer this question, we conducted a retrospective cohort study to evaluate the effect of PTR on the survival of patients with metastatic SI-NETs.Information on SI-NETs patients from 2004 to 2015 was extracted from Surveillance, Epidemiology, and End Results (SEER) databases. Demographics, tumor characteristics, treatment, and survival were compared. Propensity score-matched (PSM) was used 1:1 in the filtered queue. Cox proportional hazard regression model was used to evaluate the correlation between PTR and treatment results.Before PSM, survival analysis showed that PTR significantly prolonged the survival of metastatic SI-NETs patients. After PSM, there was no significant difference in overall survival (OS) and cancer-specific survival (CSS) between the PTR group and the non-PTR group. Multivariate analysis showed no significant difference in OS and CSS between the two groups (p 0.05).Our study shows that OS and CSS are comparable between the PTR group and the non-PTR group. Thus, we believe that PTR should not be actively performed on such patients. Meanwhile, it is undeniable that properly selected patients may also benefit from PTR. Therefore, prospective randomized controlled trials are still needed to verify the effect of PTR on patients in the future.