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Hang-Tsung Liu,1,* Cheng-Shyuan Rau,2,* Yueh-Wei Liu,3 Ting-Min Hsieh,1 Chun-Ying Huang,1 Peng-Chen Chien,4 Hui-Ping Lin,4 Chia-Jung Wu,4 Pei-Chin Chuang,5 Ching-Hua Hsieh4 1Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 2Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 3Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 4Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 5Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan*These authors contributed equally to this workCorrespondence: Pei-Chin Chuang; Ching-Hua Hsieh, Tel +886-7-3454746, Email pcjchuang@gmail.com; m93chinghua@gmail.comIntroduction: RNA modifications mediated by the m6A, m1A, and m5C regulatory genes are crucial for the progression of malignancy. This study aimed to explore the expression of regulator genes for m6A/m5C/m1A methylation at the single-cell level and to validate their expression in cancerous and adjacent para-cancerous liver tissues of adult patients with HCC who underwent tumor resection.Methods: The bulk sequencing from The Cancer Genome Atlas (TCGA) database and the single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database were used to identify the dysregulated m6A/m5C/m1A genes for hepatocellular carcinoma (HCC). A real-time polymerase chain reaction (real-time PCR) was used to measure the expression of dysregulated m6A/m5C/m1A genes in collected human HCC tissues and compared with adjacent para-cancerous liver tissues. Immune cell infiltration with these significantly expressed methylation-related genes was evaluated using Timer2.0.Results: A discrepancy in m6A/m5C/m1A gene expression was observed between bulk sequencing and scRNA-seq. The clustered heatmap of the scRNA-seq-identified dysregulated m6A/m5C/m1A genes in TCGA cohort revealed heterogeneous expression of these methylation regulators within the cancer, whereas their expression in the adjacent liver tissues was more homogeneous. The real-time PCR validated the significant overexpression of DNMT1, NSUN5, TRMT6, IGF2BP1, and IGFBP3, which were identified using scRNA-seq, and IGFBP2, which was identified using bulk sequencing. These dysregulated methylation genes are mainly correlated with the infiltration of natural killer cells.Discussion: This study suggests that cellular diversity inside tumors contributes to the discrepancy in the expression of methylation regulator genes between traditional bulk sequencing and scRNA-seq. This study identified five regulatory genes that will be the focus of further studies regarding the function of m6A/m5C/m1A in HCC.Keywords: hepatocellular carcinoma, HCC, methylation, N6-methyladenosine, m6A, N1-methyladenosine, m1A, 5-methylcytidine, m5C, bulk sequencing, single-cell RNA sequencing, scRNA-seq

Ting-Min Hsieh,1 Po-Chun Chuang,2 Chun-Ting Liu,3 Bei-Yu Wu,3 Yueh-Wei Liu,4,&ast; Ching-Hua Hsieh5,&ast; 1Division of Trauma, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Emergency, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Division of Plastic Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yueh-Wei Liu; Ching-Hua Hsieh, Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, Tel +886-7-7317123 ext. 8002 ; +886-7-7317123 ext. 8001, Email anthony0612@adm.cgmh.org.tw; m93chinghua@gmail.comBackground: The “cushion effect” theory proposes that increased body mass index (BMI) is associated with less severe abdomen injury following blunt abdomen trauma, while the “obesity paradox” describes the protective effect of obesity against mortality. However, most previous studies used the abdominal abbreviated injury scale as the outcomes seemed to be inadequate owing to the injuries to the abdominal organs, such as the spleen and liver, which may be attributable to the force that caused the chest trauma. This study aimed to use adult trauma patients with surgical blunt bowel mesenteric injuries (BBMIs) to investigate the influence of obesity on the clinical outcomes and overall morbidities.Methods: This retrospective study reviewed the data of all hospitalized trauma patients between 2009 and 2019 and included all patients with surgically proven small bowel, colon, or mesenteric injuries due to a road traffic accident. Comparison of the outcomes was performed among 123 patients with surgically proven BBMI, who were categorized by BMI into the normal-weight (n = 73, BMI< 25 kg/m2), overweight (n = 37, 25≤BMI≤ 30 kg/m2), and obese groups (n = 13, BMI> 30 kg/m2).Results: The obese group had a significantly lower incidence of isolated bowel injury (0%) compared with the normal-weight (35.6%) and overweight (16.2%) groups (p=0.005), but with higher incidence of isolated mesenteric injury or combined injury, although this was not significant. The obese group (92.3%) had a significantly higher percentage of overall morbidity than the normal-weight (61.6%) and overweight (70.3%) groups (p = 0.047). No significant difference was observed in the in-hospital mortality and 24-hour mortality among the three study groups.Conclusion: The study findings do not support the existence of a cushion effect and obesity paradox of obesity in blunt abdominal trauma.Keywords: obesity, trauma, blunt bowel mesenteric injury, mortality

Here, a nanosheet-structured CuWO 4 (nanoCuWO 4 ) is demonstrated as a selective and stable photoanode for biomass valorization in neutral and near-neutral solutions. nanoCuWO 4 can be readily prepared by a solid phase reaction using nanosheet-structured WO 3 as the template. Several substrates, including glucose, fructose and glycerol, are investigated to reveal the wide applicability of nanoCuWO 4 . The activity and product distribution trends in biomass valorization are investigated at different pH by taking advantage of the promising stability of nanoCuWO 4 in a wide pH range. Product analyses confirm that formate production with a Faradaic efficiency (FE) of 76 ± 5% and glycolate production with an FE of 61 ± 8% can be achieved by glucose and fructose valorization at pH 10.2, respectively. On the other hand, glyceraldehyde and dihydroxyacetone (DHA) are the main products in the glycerol valorization, accounting for an FE of over 85% at pH 7. Notably, nanoCuWO 4 has the highest FE of DHA in photoelectrochemical (PEC) glycerol valorization compared to WO 3 and BiVO 4 at neutral pH. The oxidation routes and mechanism of glycerol valorization on nanoCuWO 4 are also under investigation. The co-production of H 2 and value-added chemicals is finally demonstrated using a photovoltaic cell connected to a nanoCuWO 4 -based PEC glycerol valorization system., (© 2024 Wiley‐VCH GmbH.)

Anterior open bite (AOB), characterized by the lack of vertical overlap between upper and lower anterior teeth, poses a considerable challenge in orthodontics. The condition depends on many factors that combine to render it difficult to achieve post treatment stability. AOB is commonly classified as dental, skeletal, or functional on the basis of the clinical presentation and causative factors. Traditionally, skeletal AOB necessitates surgical intervention, whereas nonsurgical approaches such as extrusion arches and the Multiloop Edgewise Archwire Technique (MEAW) can be employed in more straightforward cases. Functional appliances are reserved for situations in which a patient's growth potential offers the possibility of effectively addressing AOB. This review presents a strategic treatment approach for addressing AOB, taking into account the classification and severity of the condition. The proposed SHE framework describes the use of mini-screws (S) for anchorage and vertical control, encouragement to correct habits (H), and the utilization of extractions and elastics (E). By incorporating extra-radicular mini-screws, AOB closure is achieved through anterior retraction in extraction cases or whole arch distalization of dentition with elastics in non-extraction cases. This framework emphasizes habit correction through a regimen of oral myofunctional therapy (OMT) and habit-correcting appliances to enhance posttreatment stability. This review suggests that nonsurgical correction is viable in the majority of cases, whereas surgical intervention should be reserved for severe cases of skeletal vertical overgrowth or horizontal discrepancies., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Circadian rhythms are essential regulators of a multitude of physiological and behavioral processes, such as the metabolism and function of the liver. Circadian rhythms are crucial to liver homeostasis, as the liver is a key metabolic organ accountable for the systemic equilibrium of the body. Circadian rhythm disruption alone is sufficient to cause liver cancer through the maintenance of hepatic metabolic disorder. Although there is evidence linking CRD to hepatocarcinogenesis, the precise cellular and molecular mechanisms that underlie the circadian crosstalk that leads to hepatocellular carcinoma remain unknown. The expression of CRD-related genes in HCC was investigated in this study via bulk RNA transcriptomic analysis and single-cell sequencing. Dysregulated CRD-related genes are predominantly found in hepatocytes and fibroblasts, according to the findings. By using a combination of single-cell RNA sequencing and bulk RNA sequencing analyses, the dysregulated CRD-related genes ADAMTS13, BIRC5, IGFBP3, MARCO, MT2A, NNMT, and PGLYRP2 were identified. The survival analysis using the Kaplan-Meier method revealed a significant correlation between the expression levels of BIRC5 and IGFBP3 and the survival of patients diagnosed with HCC.

Snakebite envenomation is a significant global health issue that requires specific antivenom treatments. In Taiwan, available antivenoms target a variety of snakes, but none specifically target Trimeresurus gracilis, an endemic and protected species found in the high mountain areas of Taiwan. This study evaluated the effectiveness of existing antivenoms against T. gracilis venom, focusing on a bivalent antivenom developed for Trimeresurus stejnegeri and Protobothrops mucrosquamatus (TsPmAV), as well as monovalent antivenoms for Deinagkistrodon acutus (DaAV) and Gloydius brevicaudus (GbAV). Our research involved in vivo toxicity testing in mice and in vitro immunobinding experiments using (chaotropic) enzyme-linked immunosorbent assays, comparing venoms from four pit viper species (T. gracilis, T. stejnegeri, P. mucrosquamatus, and D. acutus) with three types of antivenoms. These findings indicate that TsPmAV partially neutralized T. gracilis venom, marginally surpassing the efficacy of DaAV. In vitro tests revealed that GbAV displayed higher binding capacities toward T. gracilis venom than TsPmAV or DaAV. Comparisons of electrophoretic profiles also reveal that T. gracilis venom has fewer snake venom C-type lectin like proteins than D. acutus, and has more P-I snake venom metalloproteases or fewer phospholipase A2 than G. brevicaudus, T. stejnegeri, or P. mucrosquamatus. This study highlights the need for antivenoms that specifically target T. gracilis, as current treatments using TsPmAV show limited effectiveness in neutralizing local effects in patients. These findings provide crucial insights into clinical treatment protocols and contribute to the understanding of the evolutionary adaptation of snake venom, aiding in the development of more effective antivenoms for human health., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chuang 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.)

The oral cavity of snakes serves as a habitat for various microorganisms, some of which may include potential zoonotic pathogens posing risks to hosts and causing wound infections in snakebite victims. Clinical studies on snakebite cases in Taiwan have identified specific pathogens, such as Enterococcus faecalis (Gram-positive), Morganella morganii , Aeromonas hydrophila , and Pseudomonas aeruginosa (Gram-negative). However, the prevalence of these bacteria in the oral cavity of wild snakes remains largely unknown. This study investigated the occurrence of these bacteria in six wild snake species ( Naja atra , Bungarus multicinctus , Trimeresurus stejnegeri , Protobothrops mucrosquamatus , Boiga kraepelini , and Elaphe taeniura friesi ) from southern Taiwan, along with factors influencing their presence. Oropharyngeal swab samples were collected from a substantial number of wild-caught snakes ( n = 1104), followed by DNA extraction, polymerase chain reaction, and gel electrophoresis. The band positions of samples were compared with positive and negative controls to determine the presence of target bacteria in each sample. The overall occurrence rates were 67.4% for E. faecalis , 31.5% for M. morganii , 8.2% for A. hydrophila , and 7.7% for P. aeruginosa . Among snake species, B. kraepelini exhibited dominance in E. faecalis (93.4%), A. hydrophila (17.1%), and P. aeruginosa (14.5%), while male N. atra showed dominance in M. morganii (51.3%). The occurrence of E. faecalis was lowest in winter. The results of multiple logistic regression analyses suggest that factors such as species, sex, temperature, season, and coexisting pathogens may have a significant impact on the occurrence of target bacteria. These findings have implications for wildlife medicine and snakebite management.

Many studies have been exploring the use of bone graft materials (BGMs) and mesenchymal stem cells in bone defect reconstruction. However, the regeneration potential of Algipore (highly purified hydroxyapatite) and Biphasic (hydroxyapatite/beta-tricalcium phosphate) BGMs combined with bone marrow-derived mesenchymal stem cells (BMSCs) remains unclear. Therefore, we evaluated their osseointegration capacities in reconstructing peri-implant bone defects. The cellular characteristics of BMSCs and the material properties of Algipore and Biphasic were assessed in vitro. Four experimental groups-Algipore, Biphasic, Algipore+BMSCs, and Biphasic+BMSCs-were designed in a rabbit tibia peri-implant defect model. Implant stability parameters were measured. After 4 and 8 weeks of healing, all samples were evaluated using micro-CT, histological, and histomorphometric analysis. In the energy-dispersive X-ray spectroscopy experiment, the Ca/P ratio was higher for Algipore (1.67) than for Biphasic (1.44). The ISQ values continuously increased, and the PTV values gradually decreased for all groups during the healing period. Both Algipore and Biphasic BGM promoted new bone regeneration. Higher implant stability and bone volume density were observed when Algipore and Biphasic BGMs were combined with BMSCs. Biphasic BGM exhibited a faster degradation rate than Algipore BGM. Notably, after eight weeks of healing, Algipore with BSMCs showed more bone-implant contact than Biphasic alone ( p < 0.05). Both Algipore and Biphasic are efficient in reconstructing peri-implant bone defects. In addition, Algipore BGM incorporation with BSMCs displayed the best performance in enhancing implant stability and osseointegration potential.

Background: The effect of alcohol consumption on trauma remains controversial. The effects of alcohol on hemorrhage and peritonitis after blunt abdominal trauma have rarely been discussed. This study aimed to explore the effects of acute alcohol intoxication on the clinical characteristics, injury patterns, and outcomes in a surgical blunt bowel mesenteric injury (BBMI) cohort., Methods: A retrospective data analysis was performed using trauma cases of patients who had been tested for alcohol and had surgically proven BBMI from a Trauma Registry System from 2009 to 2021. Patients were grouped according to their positive blood alcohol concentration (BAC; >0.5% vs. no BAC; less than 0.5% no BAC) upon arrival at the emergency department (ED). The injury characteristics, physiological parameters, and outcomes with respect to post-injury complications and mortality were assessed., Results: In total, 142 patients with surgical BBMI were included. Of these, 116 and 26 patients were assigned to the BAC-negative and BAC-positive groups, respectively. The overall injury severity, injury pattern, and age were comparable between the groups. The patients in the BAC-positive group had a significantly lower systolic blood pressure (99 mmHg vs. 119 mmHg; p = 0.046), worse shock index (0.96 vs. 0.82; p = 0.048), and lower percentage and number of packed red blood cells transfused (34.6% vs. 57.8%; p = 0.032 and 0 U vs. 2 U; p = 0.031) than those in the BAC-negative group. Additionally, although not statistically significant, patients in the BAC-positive group had lower leukocyte counts (9,700 cells/mm 3 vs. 11,600 cells/mm 3 ; p = 0.165 ) at the ED. However, significantly reduced percentages of leukocytes ≥ 12,000 cells/mm 3 (26.9% vs. 48.3%; p = 0.048) and ≥ 12,000 or ≤ 4,000 cells/mm 3 (26.9% vs. 50.9%; p = 0.027) were observed in the BAC-positive group at the ED. Furthermore, the 30-day mortality rate did not show statistically significant differences, and there was a higher incidence of bowel-related mortality in the BAC-positive group (11.5% vs. 1.7%, p = 0.043)., Conclusions: For patients with BBMI arriving alive to the hospital, acute alcohol consumption was associated with significantly worse hemodynamic parameters, interfered inflammation status, and higher bowel related mortality rate., (© 2024. The Author(s).)

The management of blunt abdominopelvic trauma with combined hemoperitoneum and pelvic fractures is challenging for trauma surgeons. Although angioembolization can achieve hemostasis in most visceral organ injuries and pelvic fractures after blunt abdominal trauma, it cannot effectively control hemorrhage in patients with blunt bowel mesenteric injury (BBMI). This study aimed to determine the risk factors associated with hemodynamically unstable patients with BBMI and to test the hypothesis that pelvic fracture is an independent risk factor for patients with unstable BBMI and concomitant pelvic fracture to guide the therapeutic sequence for difficult-to-manage patients. This retrospective study reviewed the data of hospitalized patients with trauma between 2009 and 2021 and included 158 adult patients with surgically proven BBMI. The patients were divided on the basis of the presence of a shock episode before emergency laparotomy. The shock group included 44.3% of all patients in the study (n = 70). Clinical injury severity and prognosis for patients in the shock group were poorer than those for patients in the non-shock group, and more invasive treatments and transfusions were performed for patients in the shock group than for those in the non-shock group. Pelvic fractures were more frequently associated with the shock group than with the non-shock group (21.4% vs. 5.7%; p = 0.003). In multivariate analysis, the presence of intracerebral hemorrhage (odds ratio [OR] = 10.87, 95% confidence intervals [CIs]: 1.70-69.75) and rib fracture (OR = 5.94, 95% CIs = 1.06-33.45) was identified as an independent predictor of shock, whereas the effect of pelvic fracture did not achieve statistical significance (OR = 2.94, 95% CIs = 0.66-13.13) after adjusting for confounding factors. For patients with BBMI, outcomes need to be improved during early diagnosis, and treatments should be expeditiously performed on the basis of the rapid identification of unstable hemodynamic status. Our results support the recommendation of emergency laparotomy in unstable patients with concomitant pelvic fractures, followed by damage control TAE if needed.

Snakebite envenomation is a neglected tropical disease. Taiwan, with its subtropical and Southeast Asian environment, provides suitable habitat for several venomous snake species. Trimeresurus stejnegeri, an arboreal pit viper, is the most common cause of venomous snakebite in Taiwan. Trimeresurus stejnegeri envenomation can cause local swelling, occasional ecchymosis, and wound infection. The primary treatment of T. stejnegeri envenomation is the binary antivenom, vacuum freeze-dried F(ab')2 fragments of equine antibodies, against T. stejnegeri and Protobothrops mucrosquamatus. This study aimed to analyze the incidence of post-envenomation wound infections caused by T. stejnegeri based on data collected over a decade from institutions affiliated with the Chang Gung Memorial Hospital in Taiwan. A total of 254 patients were enrolled in this study. Clinical and laboratory data, treatment information, and patient outcomes were extracted from electronic medical records. Wound infection was associated with delay in antivenom initiation (adjusted odds ratio: 3.987; 95% CI: 1.406-11.302). The infection rates were 20.5%, 12.5%, 31.3%, and 48.1% for antivenom administration within 2 hours, 2-4 hours, 4-6 hours, and > 6 hours, respectively. Therefore, early initiation of antivenom treatment (within 6 hours) is recommended. Morganella morganii was cultured from wounds of the patients, whereas Enterobacter cloacae and Enterococcus faecalis were cultured from both the oral cavity of snakes and the wounds of the patients. For post-envenomation patients who develop a local infection, empiric antibiotics such as third-generation cephalosporins, quinolones, and piperacillin/tazobactam are recommended because snakebite wound infections are often polymicrobial in nature.

Background/objectives: To propose a novel smart glasses device for recording eye movement and compare its results to the prism alternate cover test (PACT)., Subjects/methods: This method comparison study enrolled patients with strabismic conditions, who first underwent conventional strabismus evaluations (PACT in the primary position), followed by the smart glasses NeuroSpeed system (NSS) recording protocols. The video recordings were analysed using specialized software, to calculate the horizontal deviation from the primary position. The results were compared with those of the PACT using Passing‒Bablok regression and Bland‒Altman analysis., Results: This study included 70 individuals aged 4 to 80 years, of which 38 were men and 32 were women. The overall analysis of horizontal deviations using the Passing‒Bablok regression revealed a correlation coefficient (r) of 0.969, with a systemic bias of 0.00, a proportional bias of 0.809, and a perpendicular residual standard deviation of 4.134., Conclusions: The predictive values of eye movement examinations recorded by the NSS were comparable to those of the PACT. Thus, this new system can provide additional information for ophthalmologists to aid in the diagnosis and measurement of strabismus., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

During the coronavirus disease 2019 (COVID-19) pandemic, global vaccination efforts declined due to the burden on health systems and community resistance to epidemic control measures. Influenza and pneumococcal vaccines have been recommended for vulnerable populations to prevent severe pneumonia. We investigated community response towards influenza and pneumococcal vaccines (pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine) after the COVID-19 outbreak in Taiwan. We retrospectively included adults who visited Chang Gung Memorial Hospital (CGMH) institutions for influenza or pneumococcal vaccination from January 2018 to December 2021. The first case of COVID-19 in Taiwan was detected in January 2020; therefore, in this study, hospitalized cases from January 2018 to December 2019 were defined as "before COVID-19 outbreak," and hospitalized cases from January 2020 to December 2021 were defined as "after COVID-19 outbreak". A total of 105,386 adults were enrolled in the study. An increase in influenza vaccination ( n = 33,139 vs. n = 62,634) and pneumococcal vaccination ( n = 3035 vs. n = 4260) were observed after the COVID-19 outbreak. In addition, there was an increased willingness to receive both influenza and pneumococcal vaccinations among women, adults without underlying disease and younger adults. The COVID-19 pandemic may have increased awareness of the importance of vaccination in Taiwan.

This study reports a carboxymethyl cellulose (CMC)/polyvinyl alcohol (PVA) composite film that incorporates Calendula officinalis (CO) extract for biomedical applications. The morphological, physical, mechanical, hydrophilic, biological, and antibacterial properties of CMC/PVA composite films with various CO concentrations (0.1%, 1%, 2.5%, 4%, and 5%) are fully investigated using different experiments. The surface morphology and structure of the composite films are significantly affected by higher CO concentrations. X-ray diffraction (XRD) and Fourier transform infrared spectrometry (FTIR) analyses confirm the structural interactions among CMC, PVA, and CO. After CO is incorporated, the tensile strength and elongation upon the breaking of the films decrease significantly. The addition of CO significantly reduces the ultimate tensile strength of the composite films from 42.8 to 13.2 MPa. Furthermore, by increasing the concentration of CO to 0.75%, the contact angle is decreased from 15.8° to 10.9°. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay reveals that the CMC/PVA/CO-2.5% and CMC/PVA/CO-4% composite films are non-cytotoxic to human skin fibroblast cells, which is favorable for cell proliferation. Remarkably, 2.5% and 4% CO incorporation significantly improve the inhibition ability of the CMC/PVA composite films against Staphylococcus aureus and Escherichia coli. In summary, CMC/PVA composite films containing 2.5% CO exhibit the functional properties for wound healing and biomedical engineering applications.

Background: Carbon monoxide poisoning (COP), resulting from accidental and intentional exposure, is a leading cause of fatal poisoning worldwide. Except for early death, neurological sequelae are common and impose a large burden on patients, caregivers, and the society., Materials and Methods: This retrospective study included patients who visited the emergency departments (EDs) of the medical institutes of Chang Gung Memorial Hospital after COP with a carboxyhemoglobin level > 10% between January 2009 and October 2018. Patients who experienced out-of-hospital cardiac arrest (OHCA) were excluded. Poor outcome was defined as mortality or a Glasgow coma scale (GCS) <13 at discharge. Stepwise regression analysis was performed, and a receiver operating characteristic (ROC) curve was applied to analyze our newly created scoring system for prognosis prediction., Results: This study enrolled 1171 patients. Fire scene (F) (aOR, 20.635; 95% CI, 8.345-51.023), intentional CO exposure (I) (aOR, 2.634; 95% CI, 1.335-5.196), respiratory failure (R) (aOR, 9.944; 95% CI, 5.533-17.873), every point of reduced GCS (E) (aOR, 1.253; 95% CI, 1.186-1.323), and diabetes mellitus (D) (aOR, 2.749; 95% CI, 1.201-6.292) were identified as predictors of poor outcomes. The FIRED score was created., Conclusion: The FIRED score could predict the outcomes of non-OHCA patients with a carboxyhemoglobin level > 10% after COP using five factors that can be obtained by history taking and basic examination. An FIRED score ≥ 10 was associated with a poor outcome (sensitivity, 89.6%; specificity, 82.4%; AUC0.930)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

(1) Background: Surgical blunt bowel and/or mesenteric injuries (BBMIs) are rare but challenging for trauma surgeons. Surgical BBMI is associated with specific injury mechanisms, such as direct compression by the handlebar in motorcycle accidents or rapid acceleration and deceleration of the impact forces associated with seatbelt injuries in motor vehicle collisions. However, the discussions on the implications of BBMI and the mechanisms of road traffic accidents remain scarce. This retrospective study assessed the clinical and injury characteristics of surgically proven BBMI among motorcyclists and car occupants based on trauma-registered data obtained from a level I trauma center in Taiwan. (2) Methods: Medical data of 72 motorcyclists and 38 car occupants who had surgical BBMI between January 2009 and December 2020 were reviewed. Patient characteristics, injuries, and outcomes in both groups were compared and analyzed. (3) Results: Motorcyclists with surgical BBMI had a significantly higher Injury Severity Score (median [Q1-Q3], 18 (9-27) vs. 16 (9-18), p = 0.044) and lower Glasgow Coma Scale score (15 (11-15) vs. 15 (15-15), p = 0.034]) than car occupants. Motorcyclists with surgical BBMI had a higher incidence of pelvic fractures (18.1% vs. 2.6%, p = 0.032) and upper limb fractures (23.6% vs. 7.9%, p = 0.042) and a significantly higher rate of chest tube insertion than car occupants (29.2% vs. 10.5%, p = 0.027). However, there were no significant differences in the outcomes of morbidity and mortality between motorcyclists and car occupants with surgical BBMI. (4) Conclusions: This study demonstrated there were no significant differences in outcomes between motorcyclists and car occupants with surgical BBMI. However, motorcyclists with surgical BBMI were injured more severely, along with injuries to the head/neck and extremities, than car occupants.

Background: The objective of this study was to analyze the association between tooth loss and uncontrolled diabetes among US adults., Methods: The authors used National Health and Nutrition Examination Survey data from 2011 through 2018. The sample included 16,635 participants 20 years and older who represent 187,596,215 people in the United States in a probability weighted sample. The authors used bivariate analysis and multiple regressions to analyze factors associated with edentulism and number of missing teeth., Results: The multiple logistic regression model significantly predicted edentulism using diabetes status (adjusted odds ratio controlled diabetes, 1.44 [95% CI, 1.12 to 1.86]; adjusted odds ratio uncontrolled diabetes, 2.26 [95% CI, 1.33 to 3.85]), missing annual dental visits, seeing a dentist only for treatment, family income below 200% of the federal poverty guideline, being female, being 65 years or older, tobacco smoking, and no college education. After controlling for the same covariates, multiple Poisson regression analysis showed that dentate adults with controlled and uncontrolled diabetes had higher relative risk of tooth loss than those without diabetes (adjusted risk ratio controlled diabetes, 1.52 [95% CI, 1.35 to 1.71]; adjusted risk ratio uncontrolled diabetes, 1.57 [95% CI, 1.35 to 1.83])., Conclusions: US adults with uncontrolled (glycated hemoglobin ≥ 9%) and controlled diabetes (glycated hemoglobin < 9%) were more likely to be edentulous and experience tooth loss than adults without diabetes., Practical Implications: US health policy officials should adopt benefits policies to provide regular dental examinations to people who have diabetes, have low income (< 200% of the federal poverty guideline), or are 65 years or older to reduce tooth loss and improve their quality of life. Dentists should work with physicians to help patients control glycemic levels., (Copyright © 2022 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Radioresistance remains a major clinical challenge in cervical cancer therapy and results in tumor relapse and metastasis. Nevertheless, the detailed mechanisms are still largely enigmatic. This study was conducted to elucidate the prospective impacts of microRNA-29a ( miR-29a ) on the modulation of radioresistance-associated cervical cancer progression. Herein, we established two pairs of parental wild-type (WT) and radioresistant (RR) cervical cancer cells (CaSki and C33A), and we found that constant suppressed miR-29a, but not miR-29b/c, was exhibited in RR-clones that underwent a dose of 6-Gy radiation treatment. Remarkably, radioresistant clones displayed low radiosensitivity, and the reduced apoptosis rate resulted in augmented surviving fractions, measured by the clonogenic survival curve assay and the Annexin V/Propidium Iodide apoptosis assay, respectively. Overexpression of miR-29a effectively intensified the radiosensitivity and triggered the cell apoptosis in RR-clones. In contrast, suppressed miR-29a modestly abridged the radiosensitivity and abolished the cell apoptosis in WT-clones. Hence, ectopically introduced miR-29a into RR-clones notably attenuated the wound-healing rate and cell migration, whereas reduced miR-29a aggravated cell mobilities of WT-clones estimated via the in vitro wound-healing assay and time-lapse recording assay. Notably, we further established the in vivo short-term lung locomotion metastasis model in BALB/c nude mice, and we found that increased lung localization was shown after tail-vein injection of RR-CaSki cells compared to those of WT-CaSki cells. Amplified miR-29a significantly eliminated the radioresistance-enhanced lung locomotion. Our data provide evidence suggesting that miR-29a is a promising microRNA signature in radioresistance of cervical cancer cells and displays multifaceted innovative roles involved in anti-radioresistance, escalated apoptosis, and anti-cell migration/metastasis. Amalgamation of a nucleoid-based strategy ( miR-29a ) together with conventional radiotherapy may be an innovative and eminent strategy to intensify the radiosensitivity and further protect against the subsequent radioresistance and the potential metastasis in cervical cancer treatment.

Wound infections after venomous snakebites are clinically important. Information regarding the nature and antibiotic susceptibilities of snake oral bacterial flora could support empiric antibiotic therapy. Wild venomous snakes were collected from southern Taiwan: a total of 30 each of Bungarus multicinctus, Naja atra, Protobothrops mucrosquamatus, and Trimeresurus stejnegeri; 3 Deinagkistrodon acutus; and 4 Daboia siamensis. The species and antibiotic susceptibilities of their oral bacteria were determined. Aerobic gram-negative bacteria, especially Pseudomonas aeruginosa and Proteus vulgaris, were the most abundant. Proteus vulgaris were more abundant in B. multicinctus, N. atra, and P. mucrosquamatus than in T. stejnegeri (40%, 43.3%, and 40% vs. 13.3%, respectively). The gram-negative species were less susceptible to first- and second-generation cephalosporins and ampicillin-sulbactam than to third-generation cephalosporins, fluoroquinolones, carbapenems, or piperacillin-tazobactam. The most abundant aerobic gram-positive species cultured was Enterococcus faecalis, which was more abundant in N. atra than in other snakes (p < 0.001) and was highly susceptible to ampicillin, high-level gentamicin, penicillin, teicoplanin, and vancomycin. Bacteroides fragilis and Clostridium species were the most common anaerobic bacteria. The anaerobic organisms were highly susceptible to metronidazole and piperacillin. As a reference for empiric antimicrobial therapy, third-generation cephalosporins, fluoroquinolones, carbapenems, or piperacillin-tazobactam can be initiated in venomous snakebites wound infections.

(1) Background: It has been hypothesized that a discrepancy exists in the understanding of a do-not-resuscitate (DNR) order among physicians. We hypothesized that a DNR order signed in the emergency department (ED) could influence the patients’ prognosis after intensive care unit (ICU) admission. (2) Methods: We included patients older than 17 years, who visited the emergency department for non-traumatic disease, who had respiratory failure, required ventilator support, and were admitted to the ICU between January 2010 and December 2016. The associations between DNR and mortality, hospital length of stay (LOS), and medical fees were analyzed. Prolonged hospital LOS was defined as hospital stay ≥75th percentile (≥26 days for the study). Patients were classified as those who did and did not sign a DNR order. A 1:4 propensity score matching was conducted for demographics, comorbidities, and etiology. (3) Results: The study enrolled a total of 1510 patients who signed a DNR and 6040 patients who did not sign a DNR. The 30-day mortality rates were 47.4% and 28.0% among patients who did and did not sign a DNR, respectively. A DNR order was associated with mortality after adjusting for confounding factors (hazard ratio, 1.9; confidence interval, 1.70−2.03). It was also a risk factor for prolonged hospital LOS in survivors (odds ratio, 1.2; confidence interval, 1.02−1.44). Survivors who signed a DNR order were charged higher medical fees than those who did not sign a DNR (217,159 vs. 245,795 New Taiwan Dollars, p < 0.001). (4) Conclusions: Signing a DNR order in the ED increased the ICU mortality rate among patients who had respiratory failure and needed ventilator support. It increased the risk of prolonged hospital LOS among survivors. Finally, signing a DNR order was associated with high medical fees among survivors.

Background: Mesenchymal stem cell (MSC)-based tissue engineering plays a major role in regenerative medicine. However, the efficiency of MSC transplantation and survival of engrafted stem cells remain challenging. Melatonin can regulate MSC biology. However, its function in the osteogenic differentiation of dental pulp-derived MSCs (DPSCs) remains unclear. We investigated the effects and mechanisms of melatonin on the osteogenic differentiation and bone regeneration capacities of DPSCs., Methods: The biological effects and signaling mechanisms of melatonin with different concentrations on DPSCs were evaluated using a proliferation assay, the quantitative alkaline phosphatase (ALP) activity, Alizarin red staining, a real-time polymerase chain reaction, and a western blot in vitro cell culture model. The in vivo bone regeneration capacities were assessed among empty control, MBCP, MBCP + DPSCs, and MBCP + DPSCs + melatonin preconditioning in four-created calvarial bone defects by using micro-computed tomographic, histological, histomorphometric, and immunohistochemical analyses after 4 and 8 weeks of healing., Results: In vitro experiments revealed that melatonin (1, 10, and 100 μM) significantly and concentration-dependently promoted proliferation, surface marker expression (CD 146), ALP activity and extracellular calcium deposition, and osteogenic gene expression of DPSCs (p < 0.05). Melatonin activated the protein expression of ALP, OCN, and RUNX-2 and inhibited COX-2/NF-κB expression. Furthermore, the phosphorylation of mitogen-activated protein kinase (MAPK) p38/ERK signaling was significantly increased in DPSCs treated with 100 μM melatonin, and their inhibitors significantly decreased osteogenic differentiation. In vivo experiments demonstrated that bone defects implanted with MBCP bone-grafting materials and melatonin-preconditioned DPSCs exhibited significantly greater bone volume fraction, trabecular bone structural modeling, new bone formation, and osteogenesis-related protein expression than the other three groups at 4 and 8 weeks postoperatively (p < 0.05)., Conclusions: These results suggest that melatonin promotes the proliferation and osteogenic differentiation of DPSCs by regulating COX-2/NF-κB and p38/ERK MAPK signaling pathways. Preconditioning DPSCs with melatonin before transplantation can efficiently enhance MSCs function and regenerative capacities., (© 2022. The Author(s).)

Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with Parkinson's disease (PD). In this study, a smartwatch-based sensor is utilized as a convenient tool to detect the abnormal RBD phenomenon in PD patients. Instead, a questionnaire with sleep quality assessment and sleep physiological indices, such as sleep stage, activity level, and heart rate, were measured in the smartwatch sensors. Therefore, this device can record comprehensive sleep physiological data, offering several advantages such as ubiquity, long-term monitoring, and wearable convenience. In addition, it can provide the clinical doctor with sufficient information on the patient's sleeping patterns with individualized treatment. In this study, a three-stage sleep staging method (i.e., comprising sleep/awake detection, sleep-stage detection, and REM-stage detection) based on an accelerometer and heart-rate data is implemented using machine learning (ML) techniques. The ML-based algorithms used here for sleep/awake detection, sleep-stage detection, and REM-stage detection were a Cole-Kripke algorithm, a stepwise clustering algorithm, and a k-means clustering algorithm with predefined criteria, respectively. The sleep staging method was validated in a clinical trial. The results showed a statistically significant difference in the percentage of abnormal REM between the control group (1.6 ± 1.3; n = 18) and the PD group (3.8 ± 5.0; n = 20) ( p = 0.04). The percentage of deep sleep stage in our results presented a significant difference between the control group (38.1 ± 24.3; n = 18) and PD group (22.0 ± 15.0, n = 20) ( p = 0.011) as well. Further, our results suggested that the smartwatch-based sensor was able to detect the difference of an abnormal REM percentage in the control group (1.6 ± 1.3; n = 18), PD patient with clonazepam (2.0 ± 1.7; n = 10), and without clonazepam (5.7 ± 7.1; n = 10) ( p = 0.007). Our results confirmed the effectiveness of our sensor in investigating the sleep stage in PD patients. The sensor also successfully determined the effect of clonazepam on reducing abnormal REM in PD patients. In conclusion, our smartwatch sensor is a convenient and effective tool for sleep quantification analysis in PD patients.

This article presents a retrospective case series of implant site development using titanium mesh (Ti-mesh) in the maxilla. A total of 58 mesh procedures in combination with several different bone grafts (allograft, cellular allograft, and bovine xenograft) and biologics (including recombinant human platelet-derived growth factor, autogenous platelet-rich growth factor, and recombinant human bone morphogenetic protein-2) were performed in 48 patients. Ti-mesh guided bone regeneration procedures were performed 2 to 3 months after extraction of nonrestorable/hopeless teeth, and the implants were placed 6 to 8 months postaugmentation. The mean initial ridge width was 2.0 ± 1.0 mm, and the mean horizontal gain after Ti-mesh procedures was 4.7 ± 1.6 mm. The ridge width was first measured on the cross-sectional presurgical CBCT image and then confirmed clinically during surgical procedures. No statistical difference in the horizontal gain was found among different combinations of bone grafts and biomaterials. Ti-mesh exposure occurred 22% of the time. The middle-aged adults (odds ratio [OR] = 8.59; P = .046) and older adults (OR = 16.66; P = .02) had significantly higher chances of mesh exposure compared to young adults. While all implants were successfully placed, about 56% of the implants had < 2 mm of bone to the facial aspect of the osteotomy and received additional contour augmentation when placed in a prosthetically appropriate position for a screw-retained restoration. This study demonstrates that although Ti-mesh procedures result in significant bone regeneration in narrow alveolar ridges to predictably allow implant placement, the age-related mesh exposure rate and frequency of need for additional contour grafting should be discussed with patients.

Background: Exposure to glufosinate ammonium, an herbicide used worldwide, can cause CNS and respiratory toxicities. This study aimed to analyze acute human glufosinate ammonium poisoning., Materials and Methods: This multicenter retrospective cohort study involved five medical institutes affiliated with the Chang Gung Memorial Hospital system. Patients with glufosinate ammonium exposure visiting the emergency department (ED) between January 2008 and December 2020 were included., Results: In total, 95 patients were enrolled. Compared to exposure via the non-oral route, patients exposed orally (n = 61) had lower GCS scores, higher mortality rates, and longer hospital lengths of stay (P-value: <0.001, 0.002, and < 0.001, respectively). In the subgroup analysis among oral exposure patients, the survival group had a lower amount of estimated glufosinate ingestion than the non-survival group (10.5 [3.4-27] vs. 40.5 [27-47.3] g, P-value: 0.022), lower rate of substance co-exposure (9 [19.6%] vs. 10 [66.7%] P-value: 0.001), and lower rate of paraquat co-exposure (0 [0%] vs. 7 [46.7%] P < 0.001) compared with the mortality group. In the orally-exposed and non-paraquat co-exposure patients (n = 54), age > 70 years and GCS score < 9 at triage presented a high sensitivity (100.00%, 95% CI: 63.06-100.00%) and medium specificity (58.70%, 95% CI: 43.23-73.00%) in predicting mortality., Conclusion: Old age, change in consciousness, and paraquat co-exposure were associated with higher mortality in human glufosinate poisoning. Age > 70 years and GCS score < 9 at triage could be predictors of mortality in patients with acute oral glufosinate poisoning., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pneumonia, one of the important causes of death in children, may be induced or aggravated by particulate matter (PM). Limited research has examined the association between PM and its constituents and pediatric pneumonia-related emergency department (ED) visits. Measurements of PM 2.5 , PM 10 , and four PM 2.5 constituents, including elemental carbon (EC), organic carbon (OC), nitrate, and sulfate, were extracted from 2007 to 2010 from one core station and two satellite stations in Kaohsiung City, Taiwan. Furthermore, the medical records of patients under 17 years old who had visited the ED in a medical center and had a diagnosis of pneumonia were collected. We used a time-stratified, case-crossover study design to estimate the effect of PM. The single-pollutant model demonstrated interquartile range increase in PM 2.5 , PM 10 , nitrate, OC, and EC on lag 3, which increased the risk of pediatric pneumonia by 18.2% (95% confidence interval (Cl), 8.8-28.4%), 13.1% (95% CI, 5.1-21.7%), 29.7% (95% CI, 16.4-44.5%), 16.8% (95% CI, 4.6-30.4%), and 14.4% (95% Cl, 6.5-22.9%), respectively. After PM 2.5 , PM 10 , and OC were adjusted for, nitrate and EC remained significant in two-pollutant models. Subgroup analyses revealed that nitrate had a greater effect on children during the warm season (April to September, interaction p = 0.035). In conclusion, pediatric pneumonia ED visit was related to PM 2.5 and its constituents. Moreover, PM 2.5 constituents, nitrate and EC, were more closely associated with ED visits for pediatric pneumonia, and children seemed to be more susceptible to nitrate during the warm season.

Background: Three-dimensional (3D) culture of mesenchymal stem cells has become an important research and development topic. However, comprehensive analysis of human dental pulp-derived mesenchymal stem cells (DPSCs) in 3D-spheroid culture remains unexplored. Thus, we evaluated the cellular characteristics, multipotent differentiation, gene expression, and related-signal transduction pathways of DPSCs in 3D-spheroid culture via magnetic levitation (3DM), compared with 2D-monolayer (2D) and 3D-aggregate (3D) cultures., Methods: The gross morphology and cellular ultrastructure were observed in the 2D, 3D, and 3DM experimental groups using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Surface markers and trilineage differentiation were evaluated using flow cytometry and staining analysis. Quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining (IF) were performed to investigate the expression of differentiation and stemness markers. Signaling transduction pathways were evaluated using western blot analysis., Results: The morphology of cell aggregates and spheroids was largely influenced by the types of cell culture plates and initial cell seeding density. SEM and TEM experiments confirmed that the solid and firm structure of spheroids was quickly formed in the 3DM-medium without damaging cells. In addition, these three groups all expressed multilineage differentiation capabilities and surface marker expression. The trilineage differentiation capacities of the 3DM-group were significantly superior to the 2D and 3D-groups. The osteogenesis, angiogenesis, adipogenesis, and stemness-related genes were significantly enhanced in the 3D and 3DM-groups. The IF analysis showed that the extracellular matrix expression, osteogenesis, and angiogenesis proteins of the 3DM-group were significantly higher than those in the 2D and 3D-groups. Finally, 3DM-culture significantly activated the MAPK and NF-kB signaling transduction pathways and ameliorated the apoptosis effects of 3D-culture., Conclusions: This study confirmed that 3DM-spheroids efficiently enhanced the therapeutic efficiency of DPSCs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The shock index, pediatric age-adjusted (SIPA), defined as the maximum normal heart rate divided by the minimum normal systolic blood pressure by age, can help predict the risk of morbidity and mortality after pediatric trauma. This study investigated whether the SIPA can be used as an early index of prognosis for non-traumatic children visiting the pediatric emergency department (ED) and were directly admitted to the intensive care unit (ICU). We hypothesized that an increase in SIPA values in the first 24 h of ICU admission would correlate with mortality and adverse outcomes. Methods: This multicenter retrospective study enrolled non-traumatic patients aged 1-17 years who presented to the pediatric ED and were directly admitted to the ICU from January 1, 2016, to December 31, 2018, in Taiwan. The SIPA value was calculated at the time of arrival at the ED and 24 h after ICU admission. Cutoffs included SIPA values >1.2 (patient age: 1-6), >1.0 (patient age: 7-12), and >0.9 (patient age: 12-17). The utility of the SIPA and the trends in the SIPA during the first 24 h of ICU admission were analyzed to predict outcomes. Results: In total, 1,732 patients were included. Of these, 1,050 (60.6%) were under 6 years old, and the median Pediatric Risk of Mortality score was 7 (5-10). In total, 4.7% of the patients died, 12.9% received mechanical ventilator (MV) support, and 11.1% received inotropic support. The SIPA value at 24 h after admission was associated with increased mortality [odds ratio (OR): 4.366, 95% confidence interval (CI): 2.392-7.969, p < 0.001], MV support (OR: 1.826, 95% CI: 1.322-2.521, p < 0.001), inotropic support (OR: 2.306, 95% CI: 1.599-3.326, p < 0.001), and a long hospital length of stay (HLOS) (2.903 days, 95% CI: 1.734-4.271, p < 0.001). Persistent abnormal SIPA value was associated with increased mortality (OR: 2.799, 95% CI: 1.566-5.001, p = 0.001), MV support (OR: 1.457, 95% CI: 1.015-2.092, p = 0.041), inotropic support (OR: 1.875, 95% CI: 1.287-2.833, p = 0.001), and a long HLOS (3.2 days, 95% CI: 1.9-4.6, p < 0.001). Patients with abnormal to normal SIPA values were associated with decreased mortality (OR: 0.258, 95% CI: 0.106-0.627, p = 0.003), while patients with normal to abnormal SIPA values were associated with increased mortality (OR: 3.055, 95% CI: 1.472-5.930, p = 0.002). Conclusions: In non-traumatic children admitted to the ICU from the ED, increased SIPA values at 24 h after ICU admission predicted high mortality and bad outcomes. Monitoring the trends in the SIPA could help with prognostication and optimize early management., 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 © 2021 Huang, Yang, Li, Cheng, Huang, Chuang and Chiu.)

Background: Global asthma-related mortality tallies at around 2.5 million annually. Although asthma may be triggered or exacerbated by particulate matter (PM) exposure, studies investigating the relationship of PM and its components with emergency department (ED) visits for pediatric asthma are limited. This study aimed to estimate the impact of short-term exposure to PM constituents on ED visits for pediatric asthma., Methods: We retrospectively evaluated non-trauma patients aged younger than 17 years who visited the ED with a primary diagnosis of asthma. Further, measurements of PM with aerodynamic diameter of < 10 μm (PM 10 ), PM with aerodynamic diameter of < 10 μm (PM 2.5 ), and four PM 2.5 components (i.e., nitrate (NO 3- ), sulfate (SO 4 2- ), organic carbon (OC), and elemental carbon (EC)) were collected between 2007 and 2010 from southern particulate matter supersites. These included one core station and two satellite stations in Kaohsiung City, Taiwan. A time-stratified case-crossover study was conducted to analyze the hazard effect of PM., Results: Overall, 1597 patients were enrolled in our study. In the single-pollutant model, the estimated risk increase for pediatric asthma incidence on lag 3 were 14.7% [95% confidence interval (CI), 3.2-27.4%], 13.5% (95% CI, 3.3-24.6%), 14.8% (95% CI, 2.5-28.6%), and 19.8% (95% CI, 7.6-33.3%) per interquartile range increments in PM 2.5 , PM 10 , nitrate, and OC, respectively. In the two-pollutant models, OC remained significant after adjusting for PM 2.5 , PM 10 , and nitrate. During subgroup analysis, children were more vulnerable to PM 2.5 and OC during cold days (< 26 °C, interaction p = 0.008 and 0.012, respectively)., Conclusions: Both PM 2.5 concentrations and its chemical constituents OC and nitrate are associated with ED visits for pediatric asthma. Among PM 2.5 constituents, OC was most closely related to ED visits for pediatric asthma, and children are more vulnerable to PM 2.5 and OC during cold days., (© 2021. The Author(s).)

This study evaluated the new bone formation potential of micro-macro biphasic calcium phosphate (MBCP) and Bio-Oss grafting materials with and without dental pulp-derived mesenchymal stem cells (DPSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in a rabbit calvarial bone defect model. The surface structure of the grafting materials was evaluated using a scanning electron microscope (SEM). The multipotent differentiation characteristics of the DPSCs and BMSCs were assessed. Four circular bone defects were created in the calvarium of 24 rabbits and randomly allocated to eight experimental groups: empty control, MBCP, MBCP+DPSCs, MBCP+BMSCs, Bio-Oss+DPSCs, Bio-Oss+BMSCs, and autogenous bone. A three-dimensional analysis of the new bone formation was performed using micro-computed tomography (micro-CT) and a histological study after 2, 4, and 8 weeks of healing. Homogenously porous structures were observed in both grafting materials. The BMSCs revealed higher osteogenic differentiation capacities, whereas the DPSCs exhibited higher colony-forming units. The micro-CT and histological analysis findings for the new bone formation were consistent. In general, the empty control showed the lowest bone regeneration capacity throughout the experimental period. By contrast, the percentage of new bone formation was the highest in the autogenous bone group after 2 (39.4% ± 4.7%) and 4 weeks (49.7% ± 1.5%) of healing ( p < 0.05). MBCP and Bio-Oss could provide osteoconductive support and prevent the collapse of the defect space for new bone formation. In addition, more osteoblastic cells lining the surface of the newly formed bone and bone grafting materials were observed after incorporating the DPSCs and BMSCs. After 8 weeks of healing, the autogenous bone group (54.9% ± 6.1%) showed a higher percentage of new bone formation than the empty control (35.3% ± 0.5%), MBCP (38.3% ± 6.0%), MBCP+DPSC (39.8% ± 5.7%), Bio-Oss (41.3% ± 3.5%), and Bio-Oss+DPSC (42.1% ± 2.7%) groups. Nevertheless, the percentage of new bone formation did not significantly differ between the MBCP+BMSC (47.2% ± 8.3%) and Bio-Oss+BMSC (51.2% ± 9.9%) groups and the autogenous bone group. Our study results demonstrated that autogenous bone is the gold standard. Both the DPSCs and BMSCs enhanced the osteoconductive capacities of MBCP and Bio-Oss. In addition, the efficiency of the BMSCs combined with MBCP and Bio-Oss was comparable to that of the autogenous bone after 8 weeks of healing. These findings provide effective strategies for the improvement of biomaterials and MSC-based bone tissue regeneration.

Background: PM 2.5 exposure is associated with pulmonary and airway inflammation, and the health impact might vary by PM 2.5 constitutes. This study evaluated the effects of increased short-term exposure to PM 2.5 constituents on chronic obstructive pulmonary disease (COPD)-related emergency department (ED) visits and determined the susceptible groups., Methods: This retrospective observational study performed in a medical center from 2007 to 2010, and enrolled non-trauma patients aged >20 years who visited the emergency department (ED) and were diagnosed as COPD. Concentrations of PM 2.5 , PM 10 , and the four PM 2.5 components, including organic carbon (OC), elemental carbon (EC), nitrate (NO 3 - ), and sulfate (SO 4 2- ), were collected by three PM supersites in Kaohsiung City. We used an alternative design of the Poisson time series regression models called a time-stratified and case-crossover design to analyze the data., Results: Per interquartile range (IQR) increment in PM 2.5 level on lag 2 were associated with increments of 6.6% (95% confidence interval (CI), 0.5-13.0%) in risk of COPD exacerbation. An IQR increase in elemental carbon (EC) was significantly associated with an increment of 3.0% (95% CI, 0.1-5.9%) in risk of COPD exacerbation on lag 0. Meanwhile, an IQR increase in sulfate, nitrate, and OC levels was not significantly associated with COPD. Patients were more sensitive to the harmful effects of EC on COPD during the warm season (interaction p = 0.019). The risk of COPD exacerbation after exposure to PM 2.5 was higher in individuals who are currently smoking, with malignancy, or during cold season, but the differences did not achieve statistical significance., Conclusion: PM 2.5 and EC may play an important role in COPD events in Kaohsiung, Taiwan. Patients were more susceptible to the adverse effects of EC on COPD on warm days.

Background: Liberal oxygen therapy might increase the mortality rate of patients. Non-rebreathing masks (NRM) are a high-flow, non-invasive oxygen device that can provide oxygen concentration up to 95%. This study aimed to determine the impact of using NRM in patients with respiratory failure., Methods: This retrospective cohort study was conducted in four medical institutions in Taiwan from January 2010 to December 2016. The association between mortality and NRM use before receiving ventilator support in patients with respiratory failure in the emergency department was analyzed. Patients were divided into the NRM treatment and no NRM treatment groups. A 1:4 propensity score matching was conducted. Regarding the duration of NRM use, treatments were grouped as 0 h, 0-1 h, 1-2 h, and >2 h., Results: A total of 18,749 patients were included, with 1074 using NRM. After propensity score matching, 1028 patients using NRM (0-1 h: 508, 1-2 h: 193, and >2 h: 327) and 4112 patients not using NRM were analyzed. The 30-day mortality rates were 29.1%, 28.5%, 27.5%, and 35.5% in the 0 h, 0-1 h, 1-2 h, and >2 h treatment groups, respectively. Patients with respiratory failure due to pulmonary disease using NRM over 2 h had a higher mortality rate than patients not using NRM (hazard ratio: 1.3, 95% CI: 1.01-1.66)., Conclusions: Prolonged use of NRM in patients with respiratory failure due to pulmonary disease possibly increases mortality., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Few studies quantify a cascade of dynamic transitions on the detailed components of metabolic syndrome (MetS) and subsequent progressions to cardiovascular disease (CVD) and its death. A total of 47,495 subjects repeatedly attending a community-based integrated screening program in Taiwan were recruited. The refined MetS-related classification (RMRC) in relation to five criteria of MetS was defined as free of metabolic disorder (FMD, none of any criteria), mild metabolic disorder (MMD, 1-2 criteria) and MetS. A multistate Markov model was used for modelling such a multistate process. The estimated progression rate from FMD to MMD was 44.82% (95% CI 42.95-46.70%) whereas the regression rate was estimated as 29.11% (95% CI 27.77-30.45%). The progression rate from MMD to MetS was estimated as 6.15% (95% CI 5.89-6.42%). The estimated annual incidence rates of CVD increased with the severity of RMRC, being 1.62% (95% CI 1.46-1.79%) for FMD, 4.74% (95% CI 4.52-4.96%) for MMD, to 20.22% (95% CI 19.52-20.92%) for MetS. The estimated hazard rate of CVD death was 6.1 (95% CI 4.6-7.7) per thousand. Elucidating the dynamics of MetS-related transition and quantifying the incidence and prognosis of CVD provide a new insight into the design and the evaluation of intervention programs for CVD.

Paraquat (N, N'-dimethyl-4, 4'-bipyridinium dichloride, PQ) intoxication is a common cause of lethal poisoning. This study aimed to identify the risk of using liberal oxygen therapy in patients with PQ poisoning. This was a multi-center retrospective cohort study involving four medical institutions in Taiwan. Data were extracted from the Chang Gung Research Database (CGRD) from January 2004 to December 2016. Patients confirmed to have PQ intoxication with a urine PQ concentration ≥ 5 ppm were analyzed. Patients who received oxygen therapy before marked hypoxia (SpO2 ≥ 90%) were defined as receiving liberal oxygen therapy. The association between mortality and patient demographics, blood paraquat concentration (ppm), and liberal oxygen therapy were analyzed. A total of 416 patients were enrolled. The mortality rate was higher in the liberal oxygen therapy group (87.8% vs. 73.7%, P = 0.007), especially in 28-day mortality (adjusted odds ratio [aOR]: 4.71, 95% confidence interval [CI]: 1.533-14.471) and overall mortality (aOR: 5.97, 95% CI: 1.692-21.049) groups. Mortality in patients with PQ poisoning was also associated with age (aOR: 1.04, 95% CI: 1.015-1.073), blood creatinine level (aOR: 1.49, 95% CI: 1.124-1.978), and blood paraquat concentration (ppm) (aOR, 1.51; 95% CI: 1.298-1.766). Unless the evidence of hypoxia (SpO2 < 90%) is clear, oxygen therapy should be avoided because it is associated with increased mortality., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this prospective study was to evaluate the success rates and prosthetic complications of implants with a modified sandblasted and acid-etched (SLA) surface inserted for posterior single-implant crown restorations. Final crowns were placed 3 to 4 weeks after surgery, and patient follow-up spanned 10 years in a private practice setting. A total of 22 patients (8 women, 14 men) with 25 posterior implants placed (16 mandible, 9 maxilla) were selected, including only implants for posterior single-implant crowns with insertion torque values of ≥ 35 Ncm at placement. Twenty-one implants passed the reverse torque test at 3 to 4 weeks after implant placement, and final restorations were placed. Three patients (4 implants) had "spinners," and there was one patient dropout after completion of the final restoration. All patients were recalled for clinical exams, digital periapical radiographs, and clinical photos at short-term (≤ 5 years) and long-term (> 5 years) follow-up appointments. The Community Periodontal Index of Treatment Needs was also determined at the initial and follow-up visits. Crestal bone level was measured at crown placement (T1), short-term follow-up (T2; mean: 29.4 months), and long-term follow-up appointments (T3; mean: 114.4 months). Twenty patients (23 implants) returned for examination at T2, and 15 (18 implants) were available at T3. For the 17 implants available at all evaluations, statistically significant bone loss was found from T1 to T2 (0.23 ± 0.30 mm), and the mean crestal bone level appeared stable from T2 to T3. Based on clinical and radiographic findings, the success rate for the implants and restorations at T2 and T3 was graded as 100%. Therefore, it can be stated that an early loading protocol of 3 to 4 weeks using a modified SLA surface at premolar/molar single-tooth locations can result in favorable clinical and radiographic long-term results.

Protobothrops mucrosquamatus is one of the common venomous snakes in Southeast Asia. This retrospective cohort study conducted in six medical institutions in Taiwan aimed to obtain information on the optimal management strategies for P. mucrosquamatus snakebite envenomation. Data were extracted from the Chang Gung Research Database from January 2006 to December 2016. The association between early antivenom administration and patient demographics, pain requiring treatment with analgesic injections, and hospital length of stay was analyzed. A total of 195 patients were enrolled; 130 were administered antivenom within 1 hour after emergency department arrival (early group), whereas 65 were treated later than 1 hour after arrival (late group). No in-hospital mortality was identified. The difference in surgical intervention rates between the early and late groups was statistically insignificant ( P = 0.417). Compared with the early group, the late group showed a higher rate of antivenom skin test performance (46.9% versus 63.1%, respectively, P = 0.033), longer hospital stay (42 ± 62 hours versus 99 ± 70 hours, respectively, P = 0.016), and higher rate of incidences of pain requiring treatment with analgesic injections (29.2% versus 46.2%, respectively, P = 0.019). After adjusting for confounding factors, early antivenom administration was associated with decreased pain requiring treatment with analgesic injections (adjusted odds ratio: 0.51, 95% CI: 0.260-0.985). Antivenom administration within 1 hour of arrival was associated with a decreased likelihood of experiencing pain and hospital length of stay in patients with P. mucrosquamatus snakebites. Antivenom skin testing was associated with delays in antivenom administration.

Despite the distant metastasis of cervical cancer cells being a prominent cause of mortality, neither the metastasis capacity nor the in vitro conditions mimicking adhesion of cervical cancer cells to endothelial cells have been fully elucidated. Circulating metastatic cancer cells undergo transendothelial migration and invade normal organs in distant metastasis; however, the putative molecular mechanism remains largely uncertain. In this study, we describe the use of an in vitro parallel-plate flow chamber to simulate the dynamic circulation stress on cervical cancer cells and elucidate their vascular adhesion and metastasis. We isolate the viable and shear stress-resistant (SSR) cervical cancer cells for mechanistic studies. Remarkably, the identified SSR-HeLa and SSR-CaSki exhibited high in vitro adhesive and metastatic activities. Hence, a consistently suppressed miR-128 level was revealed in SSR cell clones compared to those of parental wild-type (WT) cells. Overexpressed miR-128 attenuated SSR-HeLa cells' adherence to human umbilical cord vein endothelial cells (HUVECs); in contrast, suppressed miR-128 efficiently augmented the static adhesion capacity in WT-HeLa and WT-CaSki cells. Hence, amplified miR-128 modestly abolished in vitro SSR-augmented HeLa and CaSki cell movement, whereas reduced miR-128 aggravated the migration speed in a time-lapse recording assay in WT groups. Consistently, the force expression of miR-128 alleviated the SSR-enhanced HeLa and CaSki cell mobility in a wound healing assay. Notably, miR-128 mediated SSR-enhanced HeLa and CaSki cells' adhesion and metastasis through suppressed ITGA5 , ITGB5 , sLex , CEACAM-6 , MMP9 , and MMP23 transcript levels. Our data provide evidence suggesting that miR-128 is a promising microRNA that prevented endothelial cells' adhesion and transendothelial migration to contribute to the SSR-enhanced adhesion and metastasis progression under a parallel-plate flow chamber system. This indicates that the nucleoid-based miR-128 strategy may be an attractive therapeutic strategy to eliminate tumor cells resistant to circulation shear flow, prevent vascular adhesion, and preclude subsequent transendothelial metastasis.

Background/purpose: Early identification of pathogens causing bloodstream infection (BSI) is critical for prompt administration of appropriate antimicrobial therapy., Methods: We used an in-house saponin-based extraction method to evaluate the performance of Bruker Biotyper MALDI-TOF MS system (MALDI Biotyper) for bacterial and fungal identification in 2013 positively-flagged VersaTREK blood culture bottles., Results: A total of 180 monomicrobial and 23 polymicrobial positive blood cultures were investigated. Among monomicrobial positive blood cultures, the MALDI Biotyper recognized 90.6% and 81.7% of organisms directly from the flagged blood culture bottles to the genus and species levels, respectively. The MALDI Biotyper also correctly characterized one of the polymicrobial organisms to the species level in 20 (87%) bottles and to the genus level in 21 (91.3%) bottles. The overall identification rate using our protocol was 90.6% (184/203) and 82.3% (167/203) for genus and species levels, respectively. Identification accuracy was higher for Gram-positive than Gram-negative organisms and was the lowest for yeasts. Score values of identification were ≥1.500 for 200 (98.5%) bottles, ≥1.700 for 195 (96.1%) bottles and ≥2.000 for 182 (89.7%) bottles. Moreover, 83.5% and 92% of the isolates were identified precisely to species and genus level with the lower cutoff score of 1.500. Using our protocol also helped identifying BSI pathogens 18-24 h earlier compared to the sub-cultured colonies., Conclusion: Using Bruker MALDI Biotyper for identification of isolates directly from positive VersaTREK blood culture bottles, our in-house saponin-based protocol provided a more rapid turn-around time for correct identification of BSI pathogens than the conventional methods., Competing Interests: Declaration of Competing Interest We declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

In patients experiencing out-of-hospital cardiac arrest (OHCA), hypotension is common after return of spontaneous circulation (ROSC). Both dopamine and norepinephrine are recommended as inotropic therapeutic agents. This study aimed to determine the impact of the use of these two medications on hypotension. This is a multicenter retrospective cohort study. OHCA patients with ROSC were divided into three groups according to the post resuscitation inotropic agent used for treatment in the emergency department, namely, dopamine, norepinephrine, and dopamine and norepinephrine combined therapy. Thirty-day survival and favorable neurologic performance were analyzed among the three study groups. The 30-day survival and favorable neurologic performance rates in the three study groups were 12.5%, 13.0%, and 6.8% as well as 4.9%, 4.3%, and 1.2%, respectively. On controlling the potential confounding factors by logistic regression, there was no difference between dopamine and norepinephrine treatment in survival and neurologic performance (adjusted odds ratio (aOR): 1.0, 95% confidence interval (CI) 0.48-2.06; aOR: 0.8, 95% CI: 0.28-2.53). The dopamine and norepinephrine combined treatment group had worse outcome (aOR: 0.6, 95% CI: 0.35-1.18; aOR: 0.2, 95% CI: 0.05-0.89). In conclusion, there was no significant difference in post-ROSC hypotension treatment between dopamine and norepinephrine in 30-day survival and favorable neurologic performance rates., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Chao-Jui Li et al.)

The short isoform of human TIAM2 has been shown to promote proliferation and invasion in various cancer cells. However, the roles of TIAM2S in immune cells in relation to tumor development have not been investigated. To characterize the effects of TIAM2S, we generated TIAM2S-overexpressing mouse lines and found that aged TIAM2S-transgenic (TIAM2S-TG) developed significantly higher occurrence of lymphocytic infiltration and tumorigenesis in various organs, including colon. In addition, TIAM2S-TG is more sensitized to AOM-induced colon tumor development, suggesting a priming effect toward tumorigenesis. In the light of our recent findings that TIAM2S functions as a novel regulator of cellular serotonin level, we found that serotonin, in addition to Cox2, is a unique inflammation marker presented in the colonic lesion sites in the aged TG animals. Furthermore, our results demonstrated that ectopic TIAM2S altered immunity via the expansion of T lymphocytes; this was especially pronounced in CD8 + T cells in combination with CXCL13/BCA-1 pro-inflammatory chemokine in the serum of TIAM2S-TG mice. Consequently, T lymphocytes and B cells were recruited to the lesion sites and stimulated IL-23/IL17A expression to form the tertiary lymphoid organs. Collectively, our research suggests that TIAM2S provokes a pro-inflammatory immune microenvironment permissive to colorectal tumorigenesis through the serotonin-induced immunomodulatory effects.

Objective: By analyzing closed criminal malpractice claims involving resident physicians, we aimed to clarify the characteristics of litigations and examine the litigious errors leading to guilty verdicts., Design: A retrospective descriptive study. Setting/Study Participants . The verdicts pertaining to physicians recorded on the national database of the Taiwan justice system were reviewed. Main Outcome Measures . The characteristics of litigations were documented. Negligence and guilty verdicts were further analyzed to identify litigious errors., Results: Between January 1, 2000, and December 31, 2014, from a total of 436 closed criminal malpractice cases, 40 included resident physicians. Five (12.5%) cases received guilty verdicts with mean imprisonment sentences of 5.4 ± 4.1 months. An average of 77.2 months was required for the final adjudication, and surgery residents were involved most frequently (38.9%). Attending physicians were codefendants in 82.5% of cases and were declared guilty in 60% of them. Sepsis (37.5%) was the most common disease in the 40 cases examined, followed by operation/procedure complications (25%). Performance errors (70%) were more than twice as common than diagnostic errors (30%), but the percentage of guilty verdicts in performance error cases was much lower (7.1% vs. 25%). Four negligence cases received nonguilty verdicts, which were mostly due to lack of causation., Conclusion: Closed criminal malpractice cases involving residents took on average 6.22 years to conclude. Performance errors accounted for 70% of cases, with treatment of sepsis and operation/procedure complications predominant. To reduce medicolegal risk, residents should learn experiences from analyzing malpractice cases to avoid similar litigious pitfalls., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Kuan-Han Wu et al.)

The role of ventilation in preventing tuberculosis (TB) transmission has been widely proposed in infection control guidance. However, conclusive evidence is lacking. Modeling suggested the threshold of ventilation rate to reduce effective reproductive ratio (ratio between new secondary infectious cases and source cases) of TB to below 1 is corresponding to a carbon dioxide (CO 2 ) level of 1000 parts per million (ppm). Here, we measured the effect of improving ventilation rate on a TB outbreak involving 27 TB cases and 1665 contacts in underventilated university buildings. Ventilation engineering decreased the maximum CO 2 levels from 3204 ± 50 ppm to 591-603 ppm. Thereafter, the secondary attack rate of new contacts in university dropped to zero (mean follow-up duration: 5.9 years). Exposure to source TB cases under CO 2 >1000 ppm indoor environment was a significant risk factor for contacts to become new infectious TB cases (P < .001). After adjusting for effects of contact investigation and latent TB infection treatment, improving ventilation rate to levels with CO 2 <1000 ppm was independently associated with a 97% decrease (95% CI: 50%-99.9%) in the incidence of TB among contacts. These results show that maintaining adequate indoor ventilation could be a highly effective strategy for controlling TB outbreaks., (© 2019 The Authors. Indoor Air published by John Wiley & Sons Ltd.)

Antivenom reactions are a common complication of snake antivenom. This study aimed to identify predicators of antivenom reaction and the involvement of antivenom skin test in antivenom reaction development. This retrospective cohort study was conducted in six medical institutions in Taiwan. Data were extracted from the Chang Gung Research Database (CGRD) from January 2006 to December 2016. The association between antivenom reaction and patient demographics, type and dose of antivenom, and skin test results was analyzed. The study enrolled 799 patients, including 219 who developed antivenom reactions. Compared to patients receiving both freeze-dried hemorrhagic (FH) and freeze-dried neurotoxic (FN) antivenom, those administered a single type had a lower antivenom reaction risk (adjusted odds ratios [aORs]: 0.5 and 0.4, 95% confidence interval [CI]: 0.35-0.74 and 0.24-0.69, FH and FN respectively). Patients administered a higher antivenom dose (≥ 5 vials) had higher antivenom reaction risk (aOR: 1.8, 95% CI: 1.23-2.76). A positive skin test result was also associated with antivenom reaction (aOR: 16.7, 95% CI: 5.42-51.22). The skin test showed high specificity (98.5%, 95% CI: 97.49%-99.83%) but low sensitivity (17.5%, 95% CI: 10.74%-24.18%). The antivenom skin test should be abolished because of the extremely low sensitivity and possible misinterpretation of results because of the limitation of this examination., 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 © 2019 Elsevier B.V. All rights reserved.)

TIAM2S, the short form of human T-cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non-neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1-derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S-TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well-differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole-transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S-knockdown (TIAM2S-KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin-related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S-KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the non-oncogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior., (© 2020 Federation of American Societies for Experimental Biology.)

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, kills over 1 million people worldwide annually. Development of drug resistance (DR) in the pathogen is a major challenge for TB control. We conducted whole-genome analysis of seven Taiwan M. tuberculosis isolates: One drug susceptible (DS) and five DR Beijing lineage isolates and one DR Euro-American lineage isolate. Developing a new method for DR mutation identification and applying it to the next-generation sequencing (NGS) data from the 6 Beijing lineage isolates, we identified 13 known and 6 candidate DR mutations and provided experimental support for 4 of them. We assembled the genomes of one DS and two DR Beijing lineage isolates and the Euro-American lineage isolate using NGS data. Moreover, using both PacBio and NGS sequencing data, we obtained a high-quality assembly of an extensive DR Beijing lineage isolate. Comparative analysis of these five newly assembled genomes and two published complete genomes revealed a large number of genetic changes, including gene gains and losses, indels and translocations, suggesting rapid evolution of M. tuberculosis. We found the MazEF toxin-antitoxin system in all the seven isolates studied and several interesting mutations in MazEF proteins. Finally, we used the four assembled Beijing lineage genomes to construct a high-quality Beijing lineage reference genome that is DS and contains all the genes in the four genomes. It contains 212 genes not found in the standard reference H37Rv, which is Euro-American. It is therefore a better reference than H37Rv for the Beijing lineage, the predominant lineage in Asia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)