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Background/Purpose The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Plants and associated microorganisms are essential sources of natural products against human cancer diseases, partly exemplified by plant-derived anticancer drugs such as Taxol (paclitaxel). Natural products provide diverse mechanisms of action and can be used directly or as prodrugs for further anticancer optimization. Despite the success, major bottlenecks can delay anticancer lead discovery and implementation. Recent advances in sequencing and omics-related technology have provided a mine of information for developing new therapeutics from natural products. Artificial intelligence (AI), including machine learning (ML), has offered powerful techniques for extensive data analysis and prediction-making in anticancer leads discovery. This review presents an overview of current AI-guided solutions to discover anticancer lead compounds, focusing on natural products from plants and associated microorganisms.

Objective To observe the effect of the combined therapy of electroacupuncture (EA) and ginger-isolated moxibustion on endometrial receptivity in the patients with polycystic ovarian syndrome (PCOS). Methods A total of 70 subjects of PCOS were randomized into two groups, 35 cases in each one. In the western medication group, letrozole and human chorionic gonadotropin (HCG) were administered. In the combined therapy group, on the base of the treatment as the western medication group, the artificial cycle therapy with EA and ginger-isolated moxibustion was provided. The treatment duration was 3 menstrual cycles in two groups. After treated for 3 menstrual cycles, the symptom score of traditional Chinese medicine (TCM), endometrial thickness, the number of ovulation cycle, endometrial morphology, bilateral uterine artery pulsatility index (PI), resistance index (RI), the sum of peak systolic velocity/end diastolic velocity (S/D) and pregnancy were compared in the patients between two groups. Results (1) After treatment, the endometrial thickness was better (0.21 ± ± 0.13 vs 0.14 ± 0.08, P Conclusion The combined treatment of electroacupuncture and ginger-isolated moxibustion with western medication effectively improves endometrial receptivity, increases clinical pregnancy rate and reduces early abortion rate in the patients with PCOS.

Background/purpose To investigate the clinical characteristics of intraocular lymphoma and to evaluate two protocols of intravitreal methotrexate injection. Methods A retrospective chart review was conducted of newly-diagnosed intraocular lymphoma patients between January 2013 and January 2018 at National Taiwan University Hospital. Patients were divided into two groups. In Group A, intravitreal methotrexate was administered weekly for the initial 8 weeks, every 2 weeks for the following 12 weeks, and then monthly for 7 months. In Group B, intravitreal methotrexate was administered twice a week for the initial 2 weeks, weekly for the subsequent 2 weeks, once every 2 weeks for the next 1 month, and monthly for the last 10 months. Results A total of 12 patients were analyzed in the study; seven of these patients were allocated to Group A. Differences in the overall survival and progression-free survival between the two groups did not yield statistical significance. The median visual acuity was improved from LogMAR 0.46 to LogMAR 0.30 with borderline significance in Group A (p = 0.053). Two of seven patients in Group A and five of five patients in Group B developed punctate keratitis during intravitreal methotrexate injection treatment. Conclusion Intravitreal methotrexate is an effective and repeatable treatment for intraocular lymphoma. A new protocol with reduced frequency of intravitreal injections as shown in this study could potentially produce similar results without a worse prognosis, along with a decrease in the incidence of keratitis.

Light detection and ranging (LiDAR) sensors are promising for automated transportation to detect the surrounding environment. However, most LiDAR solutions are complex and bulky. By designing a MEMS-mirror-based LiDAR, we can improve the volume constraints, but MEMS mirrors could limit scanning angles. In this work, we simulated and demonstrated a MEMS LiDAR system to solve the current obstacles. Combining a MEMS mirror and a wide-angle lens into the system, small-volume and large field-of-view (FOV) LiDAR systems can be realized. We use ray tracing optical simulation software to design a pair of aspherical lenses to expand the scanning angle. After the laser beam passes through the wide-angle lens, the FOV can be increased to 104 degrees. The distortion of the wide-angle lens is controlled below 3%, making the scanned image precise to the actual situation. In order to experimentally demonstrate the small-volume MEMS scanning LiDAR, a modular laser rangefinder is used with a MEMS mirror. The entire system of the LiDAR scanner is around 15 cm × 5 cm × 2.5 cm. In the natural light environment for wide-angle LiDAR measurement, the maximum error is less than 2%. Finally, an image processing program is written to convert the scanned data into a 3D point cloud image, and the generated image proves the complete function of the proposed LiDAR.

Colorectal cancer has the second highest incidence of malignant tumors and is the fourth leading cause of cancer deaths in China. Early diagnosis and treatment of colorectal cancer will lead to an improvement in the 5-year survival rate, which will reduce medical costs. The current diagnostic methods for early colorectal cancer include excreta, blood, endoscopy, and computer-aided endoscopy. In this paper, research on image analysis and prediction of colorectal cancer lesions based on deep learning is reviewed with the goal of providing a reference for the early diagnosis of colorectal cancer lesions by combining computer technology, 3D modeling, 5G remote technology, endoscopic robot technology, and surgical navigation technology. The findings will supplement the research and provide insights to improve the cure rate and reduce the mortality of colorectal cancer.

Background: Tranexamic acid has been reported to benefit the treatment of postinflammatory hyperpigmentation (PIH). Laser-assisted drug delivery (LADD) could facilitate the efficacy of topically ap...

Background The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative‐intent surgery for colorectal liver metastases (CRLM). Patients and Methods Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative‐intent CRLM resection from Sun Yat‐sen University Cancer Center (434 patients) and Sun Yat‐sen University Sixth Affiliated Hospital (146 patients) in 2000–2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. Results At the median follow‐up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22–2.44; p, We retrospectively analyzed 580 patients with colorectal liver metastases (CRLM) who underwent curative‐intent hepatectomy. Our study implicated preoperative LDH level as a reliable and independent laboratory biomarker to predict the clinical outcome of curative‐intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection.

Background and ObjectivesThe GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy.MethodsThis cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed.ResultsOne hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21–55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID.DiscussionThe NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort.Classification of EvidenceThis study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently has no cure. The aged population is growing globally, creating an urgent need for more promising therapies for this debilitating disease. Much effort has been made in recent decades, and the field is highly dynamic, with numerous trials. The main focus of these trials includes disease modification and symptomatic treatment. Some have shown beneficial outcomes, while others have shown no significant benefits. Here, we cover the outcome of recently published AD clinical trials, as well as the mechanism of action of these therapeutical agents, to re-think drug development strategies and directions for future studies.

In this study, the authors extended the perceived risk-value model to include customer involvement to conceptualize an adoption intention model in the context of internet-only bank services (IOBSs). Hypotheses were tested using survey data collected in China. A total of 252 valid questionnaires were returned. Structural equation modeling was used to test two models, an antecedent model, and moderating model, constructed by assuming that customer involvement affects the perceived risk-value model in different ways. The findings verified that the perceived value could explain customers' intention to adopt IOBSs, whereas the influences of perceived risk were discovered to be nonsignificant, reducing the fitness of the perceived risk-value model. However, the opposite result was obtained when customer involvement was considered to exert a moderating effect rather than an antecedent effect. The implications of this research for IOBS service operators are discussed, and suggestions for future research are provided.

Purpose To examine a screen model for detecting undergraduates with higher risk for developing psychosis (HRDP). Design and methods A cross-sectional design with convenience sampling was used. The screen model included exploration stage by self-report scales and confirmation stage by face-to-face interviews. Findings A total of 273 students were detected from 4744 surveys during 4 years. Of them, 120 students with HRDP were identified and 7 had been diagnosed as schizophrenia or bipolar disorders at 12-month follow-up. Practice implications This screen model can be used in early detection for undergraduates with HRDP from large general samples.

Purpose The aim of this study was to examine the association between obstructive sleep apnea (OSA) diagnosis and diverse types of injuries. Design This population-based retrospective cohort study compared records from 2000 to 2013 in the Taiwan National Health Insurance Research Database. Methods 3025 patients identified with OSA were compared against the control cohort consisting of 12,100 age- and sex-matched patients. Cox proportional hazards regression analysis was performed to estimate the effects of OSA on injury risk. Findings Patients with OSA exhibited a significantly higher overall incidence of injury of 2599 per 100,000 person-years compared to the control cohort (2248 per 100,000 person-years). After the confounding factors were considered, subjects with OSA showed a higher risk of injury than subjects in the control group (adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI] = 1.64-1.93). The risk of unintentional injury (traffic, poisoning, falls) and intentional injury (suicide) in the group of patients with OSA was higher than that in the controls. Conclusions Our study strongly supports the conclusion that adults with OSA are at increased risk of injury. Clinical relevance The present results indicate the significance of OSA as a predictor of injury risk, which will provide valuable information for clinical practice and injury prevention.

Background: The increasing use of platelet-rich plasma (PRP) to treat muscle injuries raises concerns because transforming growth factor–beta (TGF-β) in PRP may promote fibrosis in the injured muscle and thus impair muscle regeneration. Purpose: To investigate whether suramin (a TGF-β inhibitor) can reduce muscle fibrosis to improve healing of the injured muscle after PRP treatment and identify the underlying molecular mechanism. Study Design: Controlled laboratory study. Methods: Myoblasts isolated from the gastrocnemius muscle of Sprague Dawley rats were treated with PRP or PRP plus suramin. MTT assays were performed to evaluate cell viability. The expression of fibrosis-associated proteins (such as type I collagen and fibronectin), Smad2, and phosphorylated Smad2 was determined using Western blot analysis and immunofluorescent staining. An anti–TGF-β antibody was employed to verify the role of TGF-β in fibronectin expression. Gastrocnemius muscles were injured through a partial transverse incision and then treated using PRP or PRP plus suramin. Hematoxylin and eosin staining was conducted to evaluate the healing process 7 days after the injury. Immunofluorescent staining was performed to evaluate fibronectin expression. Muscle contractile properties—fast-twitch and tetanic strength—were evaluated through electric stimulation. Results: PRP plus 25 μg/mL of suramin promoted myoblast proliferation. PRP induced fibronectin expression in myoblasts, but suramin reduced this upregulation. The anti–TGF-β antibody also reduced the upregulation of fibronectin expression in the presence of PRP. The upregulation of phosphorylated Smad2 by PRP was reduced by either the anti–TGF-β antibody or suramin. In the animal study, no significant difference was discovered in muscle healing between the PRP versus PRP plus suramin groups. However, the PRP plus suramin group had reduced fibronectin expression at the injury site. Fast-twitch strength and tetanic strength were significantly higher in the injured muscle treated using PRP or PRP plus suramin. Conclusion: Simultaneous PRP and suramin use reduced fibrosis in the injured muscle and promoted healing without negatively affecting the muscle’s contractile properties. The underlying molecular mechanism may be associated with the phosphorylated Smad2 pathway. Clinical Relevance: Simultaneous PRP and suramin use may reduce muscle fibrosis without compromising muscle contractile properties and thus improve muscle healing.

In this study, we assessed the pharmacokinetics (PK), bioequivalence, and safety of 150 mg capecitabine compared to the branded reference formulation in colorectal or breast cancer patients receiving a high-fat diet. This was a multicenter, open, random, balanced, three-period, three-sequence and semi-repetitive cross study with 48 subjects. In each study period, the eligible subject received the test or reference formulation, followed by a 1-day washout period. Serial blood samples for pharmacokinetic assessment were collected at predose up to 8 h postdose. The plasma concentrations of capecitabine were analyzed by LC/MS–MS. Pharmacokinetic parameters (non-compartmental model) were assessed with WinNonlin software. The pharmacokinetic parameters assessed were the area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0–t), the AUC from time zero to infinity (AUC0–∞), the peak plasma concentration of the drug (Cmax), the time needed to reach maximum concentration (Tmax), the elimination half-life (t1/2), and the terminal elimination rate (λz). All were analyzed using an analysis of variance (ANOVA) model after logarithmic transformation of the data. To establish the bioequivalence (BE) for capecitabine, reference-scaled average bioequivalence (RSABE) acceptance criteria and average bioequivalence (ABE) acceptance criteria were used. Safety and tolerability were assessed during the entire study period. Reference scaled maximum plasma concentration (Cmax) was higher than 0.294, permitting use of RSABE. The within-subject SDs of the reference intervention (SWR) for AUC0–t and AUC0–∞ were < 0.294, meeting ABE criteria. The point estimate for the geometric least squares mean (GLSM) ratio for the point estimate of Cmax was 0.962, within the range of 0.80–1.25. The 90% upper confidence boundary for the test/reference of GLSM ratios was 97.84–105.40% for AUC0–t and 97.33–103.51% for AUC0–∞, all of which were within the prespecified limits. The 90% confidence intervals for AUC0–t and AUC0–∞ and 95% upper confidence limit for Cmax indicated bioequivalence. No serious adverse events were found among the subjects. According to the criteria for bioequivalence, the test formulation was bioequivalent to the reference formulation in terms of the rate and extent of absorption under fed conditions by measurement of total capecitabine and was safe and well tolerated. NCT04420871.

2β,3α,19-Triacetoxy-17-hydroxyspongia-13(16),14-diene (1), a novel acetoxy diterpenoid, and 18-nor-2,17-hydroxyspongia-1,4,13(16),14-quaien-3-one (2), belonging to the rare 18-nor-spongian carbon skeleton, together with six related known metabolites (3‒8), were isolated from the aquaculture Spongia officinalis Linnaeus, 1759. Their structures were elucidated by comprehensive spectroscopic analysis, quantum chemical calculation of NMR parameters, and electronic circular dichroism (ECD). Compounds 3, 4, and 5 exhibited moderate inhibition against STAT3/NF-κB, HIF-1, Wnt signalling pathways. Compounds 1, 3, and 5 showed cytotoxicity activities against K562 cell line with IC50 values of 7.3, 3.5, and 6.4 μM, respectively.

BackgroundType D personality and depression are the independent psychological risk factors for adverse outcomes in cardiovascular patients. The aim of this study was to examine the combined effect of Type D personality and depression on clinical outcomes in patients suffering from acute myocardial infarction (AMI).MethodsThis prospective cohort study included 3568 patients diagnosed with AMI between February 2017 and September 2018. Type D personality and depression were assessed at baseline, while the major adverse cardiac event (MACE) rate (cardiac death, recurrent non-fatal myocardial infarction, revascularization, and stroke) and in-stent restenosis (ISR) rate were analyzed after a 2-year follow-up period.ResultsA total of 437 patients developed MACEs and 185 had ISR during the follow-up period. The Type D (+) depression (+) and Type D (+) depression (−) groups had a higher risk of MACE [95% confidence interval (CI) 1.74–6.07] (95% CI 1.25–2.96) and ISR (95% CI 3.09–8.28) (95% CI 1.85–6.22). Analysis of Type D and depression as continuous variables indicated that the main effect of Type D, depression and their combined effect were significantly associated with MACE and ISR. Moreover, Type D (+) depression (+) and Type D (+) depression (−) emerged as significant risk factors for MACE and ISR in males, while only Type D (+) depression (+) was associated with MACE and ISR in female patients.ConclusionsThese findings suggest that patients complicated with depression and Type D personality are at a higher risk of adverse cardiovascular outcomes. Individual assessments of Type D personality and depression, and comprehensive interventions are required.

Shao-Chun Wu,1,&ast; Cheng-Shyuan Rau,2,&ast; Pao-Jen Kuo,3 Fu-Yuan Shih,2 Hui-Ping Lin,3 Yi-Chan Wu,3 Ting-Min Hsieh,4 Hang-Tsung Liu,4 Ching-Hua Hsieh3 1Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Hua HsiehDepartment of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung, 833, TaiwanTel +886-7-7327476Fax +886-7-3450431Email m93chinghua@gmail.comPurpose: Severe trauma may lead to the systemic release of inflammatory mediators into the circulation with profound acute-phase responses; however, the understanding of the expression of these mediators remains limited. This study aimed to characterize the alterations in the expression of circulating acute-phase proteins, cytokines, and checkpoint proteins in patients with severe trauma injuries.Patients and Methods: The study population included trauma patients in the intensive care unit (ICU) with an injury severity score equal to or greater than 16 and who had used a ventilator for 48 hours. A total of 12 female and 28 male patients were recruited for the study; six patients died and 34 survived. Blood samples collected at acute stages were compared with those drawn at the subacute stage, the time when the patients were discharged from the ICU, or before the discharge of the patients from the hospital.Results: The study identified that the expression of acute-phase proteins, such as alpha-1-acid glycoprotein and C-reactive protein, and cytokines, including granulocyte colony-stimulating factor, interleukin-6, and interleukin-1 receptor antagonist, was elevated in the circulation after severe trauma. In contrast, the levels of acute-phase proteins, such as alpha-2-macroglobulin, serum amyloid P, and von Willebrand factor, and cytokines, including interleukin-4 and interferon gamma-induced protein 10, were reduced. However, there were no significant differences in the expression of checkpoint proteins in the circulation.Conclusion: The dysregulated proteins identified in this study may serve as potential therapeutic targets or biomarkers for treating patients with severe trauma. However, the related biological functions of these dysregulated factors require further investigation to validate their functions.Keywords: circulation, inflammatory reaction, biomarkers, severe trauma, critical illness

BACKGROUND Glycated hemoglobin (Hb) (HbA1c) is an indicator that is used to diagnose and monitor the treatment of diabetes. Many factors can affect the detection of HbA1c. One of the most important of these factors is the Hb variant. Here, we report a rare Hb variant and evaluate its effect on HbA1c. CASE SUMMARY A 35-year-old man was suspected of harboring an Hb variant following the measurement of HbA1c with the Variant II Turbo 2.0 Hb detection system during a routine examination. Subsequently, we used the Arkray HA-8160 and ARCHITECT c4000 system to reanalyze HbA1c. Finally, the Hb variant was detected with a Capillary2FP analyzer that operates on the principle of capillary electrophoresis. We also used gene sequencing to investigate the mutation site. The value of HbA1c detected with the Variant II Turbo 2.0 system was 52.7%. However, the Arkray HA-8160 system did not display a result while the ARCHITECT c16000 system showed a result of 5.4%. The Capillary2FP analyzer did not reveal any abnormal Hb zones. However, gene sequencing identified the presence of a mutation in the Hb β2 chain [CD2(CAC>TAC), His>Tyr, HBB: c.7C>T]; the genotype was Hb Fukuoka. CONCLUSION Hb variants could cause abnormal HbA1c results. For patients with Hb variants, different methods should be used to detect HbA1c.

Under the background of China’s continuous promotion of urbanization, urban underground integrated pipeline corridor has become an inevitable trend of future urban integrated management. After the completion of the pipeline corridor, how to effectively manage its risks in operation and maintenance management has become a topic at this stage. In this paper, through the combination of the classical AHP method and DSM method, based on a large number of literature studies, the risk relationship system of the integrated pipe corridor is constructed. AnyLogic software is applied to simulate the system dynamics, analyze the impact of dynamic changes of each risk factor on the risk accident of the integrated pipe corridor, carry out uncertainty reasoning from multiple perspectives, and realize the evaluation and analysis of the accident risk of the integrated pipe corridor. The results of the study could provide targeted support tools for integrated pipeline corridor risk operation and maintenance management.

We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9 ± 9.8 years with mean duration from symptom-onset to diagnosis of 3.2 ± 2.5 years. Common presenting symptoms were sensory symptoms of upper limbs (43.3%), symmetric sensory symptoms of both lower limbs (16.7%) and autonomic symptoms (16.7%). Nerve conduction studies showed sensorimotor polyneuropathy in 25 (83.3%) patients (22, axonal). Abnormal echocardiograms were seen in 24 (80%) patients, although 15 were asymptomatic. Of six different TTR mutations found, Ala97Ser was the commonest, and found exclusively in 84.6% of Chinese patients. Other mutations among Chinese patients were Val30Met, Ala25Thr and Asp39Val. Our Malay and Tamil patients had Glu54Lys and Gly47Val mutations respectively. In conclusion, TTR Ala97Ser is the commonest mutation among ethnic Chinese Malaysians which presented with late-onset progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical cardiac involvement.

Background Prostate cancer (PCa) refers to malignant tumors derived from prostate epithelial cells, whose morbidity and mortality rates have been increasing every year. Although new drugs for treating prostate cancer continue to emerge, the unclear mechanism underlying drug targets limits this therapy, thereby constraining identification of effective therapeutic targets. Although GDP dissociation inhibitor 2(GDI2) is highly expressed and closely associated with occurrence and development of many tumors, its role in prostate cancer remains unclear. In this study, we investigated the role of GDI2 and elucidated its underlying mechanism of action in prostate cancer. Moreover, we screened chemotherapeutic drugs that affect GDI2 expression with a view of identifying novel targets for diagnosis and treatment of prostate cancer. Methods We performed sequence analyses and functional assays to precisely elucidate the GDI2 role in prostate cancer. Moreover, we induced tumorigenesis in nude mice to verify the role of GDI2 in vivo. Finally, we used the CCK8 assay to ascertain the most suitable IC50 across the three drugs and performed quantitative real time polymerase chain reaction (qRT-PCR) and Western Blot to analyze the effects of drugs on expression of GDI2, p75NTR, and p-NFκB. Results GDI2 was up-regulated in prostate cancer cells and tissues. Knocking down GDI2 suppressed cell proliferation but promoted cell apoptosis. Interestingly, knocking down GDI2 activated the p75NTR signaling pathway, indicating, for the first time, that p75NTR is negatively correlated with GDI2 expression. Conclusion Taken together, these results indicate that GDI2 is a therapeutic target of paclitaxel. Knocking down of GDI2 inhibits cell proliferation and promotes cell apoptosis via the p75NTR signaling pathway in prostate cancer. Notably, paclitaxel inhibits GDI2 expression, implying that GDI2 may be a promising therapeutic target in prostate cancer.

Background Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a currently widely used strategy for locally advanced esophageal cancer (EC). However, the conventional imaging methods have certain deficiencies in the evaluation and prediction of the efficacy of nCRT. This study aimed to explore the value of functional imaging in predicting the response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced esophageal squamous cell carcinoma (ESCC). Methods Fifty-four patients diagnosed with locally advanced ESCC from August 2017 to September 2019 and treated with nCRT were retrospectively analyzed. DW-MRI scanning was performed before nCRT, at 10–15 fractions of radiotherapy, and 4–6 weeks after the completion of nCRT. 18F-FDG PET/CT scans were performed before nCRT and 4–6 weeks after the completion of nCRT. These 18F-FDG PET/CT and DW-MRI parameters and relative changes were compared between patients with pathological complete response (pCR) and non-pCR. Results A total of 8 of 54 patients (14.8%) were evaluated as disease progression in the preoperative assessment. The remaining forty-six patients underwent operations, and the pathological assessments of the surgical resection specimens demonstrated pathological complete response (pCR) in 10 patients (21.7%) and complete response of primary tumor (pCR-T) in 16 patients (34.8%). The change of metabolic tumor volume (∆MTV) and change of total lesion glycolysis (∆TLG) were significantly different between patients with pCR and non-pCR. The SUVmax-Tpost, MTV-Tpost, and TLG-Tpost of esophageal tumors in 18F-FDG PET/CT scans after neoadjuvant chemoradiotherapy and the ∆ SUVmax-T and ∆MTV-T were significantly different between pCR-T versus non-pCR-T patients. The esophageal tumor apparent diffusion coefficient (ADC) increased after nCRT; the ADCduring, ADCpost and ∆ADCduring were significantly different between pCR-T and non-pCR-T groups. ROC analyses showed that the model that combined ADCduring with TLG-Tpost had the highest AUC (0.914) for pCR-T prediction, with 90.0% and 86.4% sensitivity and specificity, respectively. Conclusion 18F-FDG PET/CT is useful for re-staging after nCRT and for surgical decision. Integrating parameters of 18F-FDG PET/CT and DW-MRI can identify pathological response of primary tumor to nCRT more accurately in ESCC.

Summary Background Previous studies embracing digital technology and automated methods of scoring dental arch relationships have shown that such technology is valid and accurate. To date, however there is no published literature on artificial intelligence and machine learning to completely automate the process of dental landmark recognition. Objectives This study aimed to develop and evaluate a fully automated system and software tool for the identification of landmarks on human teeth using geometric computing, image segmenting, and machine learning technology. Methods Two hundred and thirty-nine digital models were used in the automated landmark recognition (ALR) validation phase, 161 of which were digital models from cleft palate subjects aged 5 years. These were manually annotated to facilitate qualitative validation. Additionally, landmarks were placed on 20 adult digital models manually by 3 independent observers. The same models were subjected to scoring using the ALR software and the differences (in mm) were calculated. All the teeth from the 239 models were evaluated for correct recognition by the ALR with a breakdown to find which stages of the process caused the errors. Results The results revealed that 1526 out of 1915 teeth (79.7%) were correctly identified, and the accuracy validation gave 95% confidence intervals for the geometric mean error of [0.285, 0.317] for the humans and [0.269, 0.325] for ALR—a negligible difference. Conclusions/implications It is anticipated that ALR software tool will have applications throughout clinical dentistry and anthropology, and in research will constitute an accurate and objective tool for handling large datasets without the need for time intensive employment of experts to place landmarks manually.

Purpose Management of peptic ulcer bleeding is clinically challenging. Accurate characterization of the bleeding during endoscopy is key for endoscopic therapy. This study aimed to assess whether a deep learning model can aid in the classification of bleeding peptic ulcer disease. Methods Endoscopic still images of patients (n = 1694) with peptic ulcer bleeding for the last 5 years were retrieved and reviewed. Overall, 2289 images were collected for deep learning model training, and 449 images were validated for the performance test. Two expert endoscopists classified the images into different classes based on their appearance. Four deep learning models, including Mobile Net V2, VGG16, Inception V4, and ResNet50, were proposed and pre-trained by ImageNet with the established convolutional neural network algorithm. A comparison of the endoscopists and trained deep learning model was performed to evaluate the model’s performance on a dataset of 449 testing images. Results The results first presented the performance comparisons of four deep learning models. The Mobile Net V2 presented the optimal performance of the proposal models. The Mobile Net V2 was chosen for further comparing the performance with the diagnostic results obtained by one senior and one novice endoscopists. The sensitivity and specificity were acceptable for the prediction of “normal” lesions in both 3-class and 4-class classifications. For the 3-class category, the sensitivity and specificity were 94.83% and 92.36%, respectively. For the 4-class category, the sensitivity and specificity were 95.40% and 92.70%, respectively. The interobserver agreement of the testing dataset of the model was moderate to substantial with the senior endoscopist. The accuracy of the determination of endoscopic therapy required and high-risk endoscopic therapy of the deep learning model was higher than that of the novice endoscopist. Conclusions In this study, the deep learning model performed better than inexperienced endoscopists. Further improvement of the model may aid in clinical decision-making during clinical practice, especially for trainee endoscopist.

Objective To observe and compare the therapeutic effect on shoulder periarthritis between Fu's subcutaneous needling (FSN) and electroacupuncture (EA). Methods A total of 68 patients with periarthritis of shoulder were divided into a FSN group and an EA group according to the random number table, 34 cases in each one. In the FSN group, FSN was adopted, once every two days, totally for 10 times. In the EA group, EA was used once daily, consecutively for 20 times. Shoulder pain score and shoulder function score (Constant-Murley score) before and after treatment were compared between the two groups. The clinical therapeutic effect was analyzed and evaluated statistically. Results After 20-day treatment, shoulder pain score was reduced obviously as compared with that before treatment in the patients of either group (both P Conclusion Both FSN and EA are effective in treatment of periarthritis of shoulder, but FSN obtains a much higher remarkably effective rate in treatment of periarthritis of shoulder and its effects for relieving shoulder pain and improving shoulder function are superior to EA. Because of its effective treatment and simple operation, FSN deserves to be promoted in clinical practice for periarthritis of shoulder.

Background Few prognostic factors have been proposed for patients with locally advanced renal cell carcinoma (RCC). This study aimed to investigate the possible predictive factors for disease-free survival (DFS) after curative surgery for RCC stage T3 or higher. Methods Patients with locally advanced RCC who underwent cure-intended partial or radical nephrectomy, with or without tumor thrombectomy, at our institution from April 1 st , 2005 to October 31 st , 2013 were retrospectively reviewed. Those undergoing cytoreductive nephrectomy were excluded. Preoperative data, including surgical and pathologic characteristics, were assessed for correlation with DFS. Chi-squared tests, multivariate Cox regression analysis, and Kaplan-Meier survival curve analyses were performed to determine potential predictive factors. A P-value less than 0.05 was considered statistically significant. Results A total of 159 patients were included for analysis. One hundred and nineteen (74.8%) patients remained disease-free during follow-up. Disease recurrence was found in 40 (25.2%) patients, and pathological T stage, capsule penetration, Fuhrman grade, thrombocytosis, and elevated serum alkaline phosphatase and γ-glutamyl transpeptidase levels were significantly associated with disease recurrence on univariate analysis. On multivariate analysis, capsule penetration (hazard ratio [HR] = 2.25, p = 0.038, 95% confidence interval [CI] = 1.05–4.85) and Fuhrman grade 3 or 4 (HR = 8.06, p = 0.003, 95% CI = 2.59–25.02) showed significant associations with DFS. Conclusions In patients with locally advanced RCC, capsule penetration and Fuhrman grade were associated with worse DFS after curative surgery. Urologists should closely monitor patients with capsule penetration and high Fuhrman grades, and adjuvant systemic treatments, other than targeted agents, should be considered.

While coformulated ledipasvir (90 mg)/sofosbuvir (400 mg) (LDV/SOF) is approved for the treatment of hepatitis C virus (HCV) genotype 2 (GT2) infection in Taiwan, Japan, and New Zealand, data regarding its use for HIV (Human Immunodeficiency Virus)-positive patients infected with HCV GT2 are sparse. We aimed to assess the effectiveness and tolerability of LDV/SOF for HIV-positive patients with HCV GT2 coinfection. From January 2019 to July 2020, consecutive HIV-positive Taiwanese patients infected with HCV GT2 who received LDV/SOF were retrospectively included for analysis. The effectiveness was determined by sustained virologic response 12 weeks off-therapy (SVR12). Of the 114 patients (mean age, 38.6 years) initiating LDV/SOF during the study period, 0.9% had liver cirrhosis and 4.4% were HCV treatment-experienced. All patients had estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m2 and were receiving antiretroviral therapy with 98.2% having CD4 counts ≥ 200 cells/mm3 and 93.9% plasma HIV RNA load

Objective To report a case series of calcaneal fracture–dislocations, which have not been described previously in China, and to provide a systematic review to explore the clinic manifestations, methods for diagnoses, and treatments. Methods Between January 2018 and December 2019, 4 patients (4 men; average age, 33.0 ± 16.67 years; range, 15–50 years) were diagnosed with fracture–dislocation of the calcaneus and treated by surgery. We also reviewed published cases and studies of calcaneal fracture–dislocations through the databases of PubMed and Web of Science between January 1977 and December 2019. Results Between January 2018 and December 2019, 4 cases were identified as calcaneal fracture–dislocations in our hospital. The main clinical manifestations include hindfoot pain, swelling, and deformity. The diagnoses were confirmed via radiographic examination. Two patients underwent open reduction and internal fixation (ORIF) and two were treated with a minimally invasive approach. Diagnosis had been missed in one patient and, consequently, presented with early signs of post‐traumatic arthritis, which may require extra subtalar arthrodesis in the future. Two patients were diagnosed inaccurately but achieved satisfactory outcomes through open reduction and internal fixation. The average follow‐up period was 9.75 ± 5.19 months. Except for the 1 misdiagnosed patient, the other 3 patients showed functional improvement. Only 23 fracture–dislocations of calcaneus cases were reported in the literature between January 1977 and December 2019. There were 15 Sanders type II fractures (65.22%) and 7 (30.43%) Sanders type III fractures, and there was 1 grade II open calcaneal fracture. Among them, 1 was a medial dislocation and 2 were “joint‐elevation” dislocations; the rest of them (20/23, 86.96%) were lateral dislocations. A total of 11 patients (47.83%) exhibited the double‐density sign, and varus tilt of the talus was revealed on plain radiographs for 9 patients (39.13%). Increased Bohler's angle was evident in lateral X‐ray films for 2 patients (2/23, 8.70%). A total of 21 cases (86.96%) were treated with surgical intervention and achieved satisfactory outcomes. Only 1 patient was treated with external fixation. Another 2 patients were treated conservatively and had poor clinic outcomes. Conclusion Calcaneal fracture–dislocation is a rare injury that is challenging to treat. Clinical manifestations such as fibular tendon dislocation, the double‐density sign on profile radiography, and abnormal talar tilt in the distal talofibular joint are important signs that may indicate this rare injury pattern. Timely surgical intervention is essential for satisfactory clinic outcomes. Orthopaedic surgeons should be aware of this uncommon injury to avoid misdiagnosis or inappropriate treatment., Fracture‐dislocation of calcaneus is a rare injury. The mechanism involves axial compression on an inverted foot. Fibular tendon dislocation, the double‐density sign, and abnormal talar tilt on profile radiography are important clinical signs that may indicate this rare injury pattern. Timely surgical interventions are essential to treat this injury.

Lei Sheng,1,* Wei Cao,2,* Pingping Lin,3 Weili Chen,1 Hongrong Xu,1 Chunjiu Zhong,4 Fei Yuan,1 Hanjing Chen,1 Hui Li,1 Chao Liu,1 Mengjie Yang,1 Xuening Li1 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People’s Republic of China; 3Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Shandong, 266071, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuening LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, 200032, People’s Republic of ChinaTel +86 21 3158 7860Fax +86 21 6443 7963Email li.xuening@zs-hospital.sh.cnPurpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials.Methods: Healthy subjects were sequentially enrolled into one of five SAD (150– 1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4– 9, followed by a single morning dose on day 10.Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.Keywords: Alzheimer’s disease, benfotiamine, thiamine, thiamine diphosphate, pharmacokinetics

Objective This article aimed to validate and compare the prognostic performance of generic scores (Pulmonary Embolism Severity Index [PESI] and Hestia) and cancer-specific pulmonary embolism (PE)/venous thromboembolism (VTE) scales (Registro Informatizado de la Enfermedad TromboEmbólica [RIETE], POMPE-C, and modified Ottawa) in PE patients with active cancer. Methods A retrospective study was conducted among 460 patients with PE and active cancer. The primary outcome was 30-day overall mortality. Secondary outcomes were 30-day PE-related death and overall adverse outcomes. The prognostic accuracy of clinical scores was determined using receiver operating characteristic (ROC) curve analysis. Results Within 30 days, 18.0% of patients died, 2.0% suffered major bleeding, and 0.2% presented recurrence of VTE. All scales showed a high area under the ROC curve (AUC) for predicting 30-day overall mortality except modified Ottawa (0.74 [0.70–0.78] for PESI, Hestia, and RIETE; 0.78 (0.74–0.81) for POMPE-C; 0.64 (0.59–0.68) for modified Ottawa]. PESI divided the least patients (9.1%) into low risk, followed by modified Ottawa (17.0%). Hestia stratified the most patients (65.4%) as low risk. But overall mortality of low-risk patients based on these three scales is high (>5%). RIETE and POMPE-C both classified 30.9% of patients as low risk, and low-risk patients stratified by these two scales presented a low overall mortality (1.4 and 3.5%). Similar predictive performance was found for 30-day PE-related death and overall adverse outcomes in these scores. Conclusion Cancer-specific PE prognostic scores (RIETE and POMPE-C) performed better than generic scales (PESI and Hestia) and a cancer-specific VTE prognostic scale (modified Ottawa) in identifying low-risk PE patients with active cancer who may be suitable for outpatient treatment.

According to cancer statistics reported in 2020, breast cancer constitutes 30% of new cancer cases diagnosed in American women. Histological markers of breast cancer are expressions of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2. Up to 80% of breast cancers are grouped as ER-positive, which implies a crucial role for estrogen in breast cancer development. Therefore, identifying potential therapeutic targets and investigating their downstream pathways and networks are extremely important for drug development in these patients. Through high-throughput technology and bioinformatics screening, we revealed that coiled-coil domain-containing protein 167 (CCDC167) was upregulated in different types of tumors; however, the role of CCDC167 in the development of breast cancer still remains unclear. Integrating many kinds of databases including ONCOMINE, MetaCore, IPA, and Kaplan-Meier Plotter, we found that high expression levels of CCDC167 predicted poor prognoses of breast cancer patients. Knockdown of CCDC167 attenuated aggressive breast cancer growth and proliferation. We also demonstrated that treatment with fluorouracil, carboplatin, paclitaxel, and doxorubicin resulted in decreased expression of CCDC167 and suppressed growth of MCF-7 cells. Collectively, these findings suggest that CCDC167 has high potential as a therapeutic target for breast cancer.

Sighing is a common symptom in children and adolescents. In this study, we explored the clinical characteristics and hemodynamic responses to head-up tilt test (HUTT) in children and adolescents with unexplained sighing.One hundred ninety-two children and adolescents complaining of unexplained sighing were enrolled as study group after excluding chest wall, lung, heart diseases, and psychogenic disorders. Sixty-nine healthy individuals were enrolled as control group. All the subjects underwent HUTT.Nitroglycerin-stimulated HUTT positive rate was higher in the study group than the control group (24.0% vs 10.1%, P = 0.014). In total, 32.3% of patients with sighing had positive responses to HUTT, which was higher than that of healthy individuals (32.3% vs 15.9%, P = 0.009). Among 62 cases with positive responses to HUTT in the study group, 48 cases were vasoinhibitory type vasovagal syncope (VVS), 5 cases were mixed type VVS, 3 cases were cardioinhibitory type VVS, 5 cases were postural tachycardia syndrome, and one case was orthostatic hypertension. Sighing patients with positive responses to HUTT had female dominance (54.8% vs39.2%, P = 0.045), older mean age (9.6 ± 2.8 vs 8.1 ± 2.7 years old, P = 0.001), higher basic systolic blood pressure (104.8 ± 10.4 vs 101.1 ± 9.9 mmHg, P = 0.019), and higher diastolic blood pressure (66.0 ± 7.5 vs 62.9 ± 9.2 mmHg, P = 0.021) compared with those of negative responses. CONCLUSIONS : Nearly one-third of children and adolescents with unexplained sighing had positive responses to HUTT, demonstrating that sighing was related to dysfunction of the autonomic nervous system. Elder female patients with higher systolic and diastolic blood pressure were more likely to have positive responses to HUTT.

Rationale: With increasing incidence and prevalence of inflammatory bowel disease (IBD), it has become one of the major public health threats, and there is an urgent need to develop new therapeutic agents. Although the pathogenesis of IBD is still unclear, previous research has provided evidence for complex interplays between genetic, immune, microbial, and environmental factors. Here, we constructed a gene-microbiota interaction-based framework to discover IBD biomarkers and therapeutics. Methods: We identified candidate biomarkers for IBD by analyzing the publicly available transcriptomic and microbiome data from IBD cohorts. Animal models of IBD and diarrhea were established. The inflammation-correlated microbial and genetic variants in gene knockout mice were identified by 16S rRNA sequences and PCR array. We performed bioinformatic analysis of microbiome functional prediction and drug repurposing. Our validation experiments with cells and animals confirmed anti-inflammatory properties of a drug candidate. Results: We identified the DNA-sensing enzyme cyclic GMP-AMP synthase (cGAS) as a potential biomarker for IBD in both patients and murine models. cGAS knockout mice were less susceptible to DSS-induced colitis. cGAS-associated gut microbiota and host genetic factors relating to IBD pathogenesis were also identified. Using a computational drug repurposing approach, we predicted 43 candidate drugs with high potency to reverse colitis-associated gene expression and validated that brefeldin-a mitigates inflammatory response in colitis mouse model and colon cancer cell lines. Conclusions: By integrating computational screening, microbiota interference, gene knockout techniques, and in vitro and in vivo validation, we built a framework for predicting biomarkers and host-microbe interaction targets and identifying repurposing drugs for IBD, which may be tested further for clinical application. This approach may also be a tool for repurposing drugs for treating other diseases.

This study provides a novel viewpoint of environmental economics by connecting CO2 emissions (CO2e) and commercial policies. Using a newly developed conceptual framework, this study tested the impact of commercial policies on CO2e in Australia considering control variables, including income, contractionary and expansionary monetary policies, remittances, and fossil fuels for the period 1972Q1-2014Q4. The long-run coefficients were estimated through fully modified ordinary least squares (FMOLS), dynamic ordinary least squares (DOLS), and a correlated component regression (CCR). The results showed a significant long-term positive relationship between expansionary commercial policy and CO2e. The empirical results further suggested that contractionary commercial and monetary policies can effectively mitigate CO2e, while remittances and fossil fuels contribute to CO2e. This study highlights the policy implications of the estimated results for policymakers seeking to reduce CO2e.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Intermediate-length CAG repeats in ATXN2 have been well recognized as a genetic risk factor for amyotrophic lateral sclerosis (ALS). However, the role of similar trinucleotide repeat expansions in ...

Cefprozil, an oral second-generation semi-synthetic cephalosporin, possesses a broad spectrum of antimicrobial activity. A granule formulation has been developed to improve medication adherence of the patients. This study was conducted to assess the bioequivalence of the granule formulation to a dry suspension in healthy Chinese volunteers and estimate the pharmacokinetic (PK) profiles of cefprozil. An open-label, randomized, single-dose, two-period, two-group, crossover study was conducted in 60 healthy Chinese volunteers under fasted or fed conditions (30 volunteers for each condition) to assess the bioequivalence between two formulations of cefprozil. Blood samples were collected at specified time intervals, and the plasma concentrations of cis- and trans-cefprozil were determined by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events (AEs) were also recorded. Under fasted conditions, the mean Cmax was (3534.70 ± 634.67) ng/ml, Tmax was (0.98 ± 0.25) h, t1/2 was (1.37 ± 0.13) h and AUC0-t was (9302.86 ± 1618.39) ng·h/ml, respectively, after a single dose of 125 mg cefprozil for suspension. Under fed conditions, the mean Cmax was (2438.80 ± 493.78) ng/ml, Tmax was (1.66 ± 0.76) h, t1/2 was (1.36 ± 0.24) h and AUC0-t was (9332.36 ± 1373.61) ng·h/ml, respectively. The PK parameters of the granule formulation of cefprozil were similar to those of the suspension. The 90% CI values of the GMRs of Cmax, AUC0-t and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence range (80.00–125.00%). According to the criteria for bioequivalence, the test granule formulations of cefprozil and "Cefprozil for Suspension®" were determined to be bioequivalent whether under fasted or fed conditions by measurement of cis-, trans- and total cefprozil. ClinicalTrials.gov identifier, NCT04414254.

This paper presents a pulse-stimulus sensor readout circuit for use in cardiovascular disease examinations. The sensor is based on a gold nanoparticle plate with an antibody post-modification. The proposed system utilizes gated pulses to detect the biomarker Cardiac Troponin I in an ionic solution. The characteristic of the electrostatic double-layer capacitor generated by the analyte is related to the concentration of Cardiac Troponin I in the solvent. After sensing by the transistor, a current-to-frequency converter (I-to-F) and delay-line-based time-to-digital converter (TDC) convert the information into a series of digital codes for further analysis. The design is fabricated in a 0.18-μm standard CMOS process. The chip occupies an area of 0.92 mm2 and consumes 125 μW. In the measurements, the proposed circuit achieved a 1.77 Hz/pg-mL sensitivity and 72.43 dB dynamic range.

The China-Europe Freight Train (CEFT) serves as an important carrier and platform for international economic cooperation and international trade circulation between China and Europe. Since it worked, its actual operation and development have been affected by many factors, but the level of its actual operating efficiency and the main affecting factors of CEFT have been difficult to find, which has severely limited its sustainable development. Therefore, this paper scientifically selected the operation efficiency evaluation indicator system of CEFT and combined grey system theory, cross-efficiency method, and DEA to construct a new DEA evaluation model based on grey cross-efficiency, which can not only overcome the problem of ignoring the relative importance ratings of the evaluation indicator in the general DEA evaluation model and the traditional cross-efficiency DEA evaluation model but also more accurately evaluate the actual operation efficiency of CEFT. At the same time, based on the actual operating data of CEFT from 2011 to 2018 and the above new evaluation models, the CEFT’s operation efficiency was evaluated and tested by examples, showing that on the one hand, the grey cross-efficiency DEA evaluation model can more accurately evaluate the actual operation efficiency of CEFT than other traditional evaluation models; on the other hand, it is found that the “overseas cities,” “operating lines,” and “entry-exit nodes” are currently the main factors that limit the actual operation efficiency of CEFT and indicating improvement direction for the future efficient and sustainable development of CEFT.

Bone scan image (BSI) is the most widely available technique for detecting cancer that has spread (metastasized) from the original location, such as breast or prostate cancer. One benefit of this process is as strong prognostic indicator of survival longevity for cancer patient. However, some challenging issues should be considered, i.e. variability in image brightness, abnormal bone shape or structure, asymmetry gesture position, and image noise due to muscle and fat tissue make the process to determine the region of interest (ROI) become more difficult, not to mention the required-time when inspecting the ROI of each bone part manually. The purposes of this study are to provide an effortless and meticulous ROI labeling as prerequired in clinical application. Finally, to propose a novel framework for determination of multiple ROI automatically by utilizing specific bone landmarks, in the hope of that could contribute to clinical observation in metastasis analysis. The results show that the proposed framework is promising method with high sensitivity (0.96), specificity (0.97), precision (0.94), Sorensen-Dice Index (0.96) and image content index (0.96).

Robotic endovascular technology may offer advantages over conventional manual catheter techniques. Our aim was to compare the endovascular catheter path-length (PL) for robotic versus manual contralateral gate cannulation during endovascular aneurysm repair (EVAR), using video motion analysis (VMA). This was a multicentre retrospective cohort study with fluoroscopic video recordings of 24 EVAR cases (14 robotic, 10 manual) performed by experienced operators (> 50 procedures), obtained from four leading European centres. Groups were comparable with no statistically significant differences in aneurysm size (p = 0.47) or vessel tortuosity (p = 0.68). Two trained assessors used VMA to calculate the catheter PL during contralateral gate cannulation for robotic versus manual approaches. There was a high degree of inter-observer reliability (Cronbach’s α > 0.99) for VMA. Median robotic PL was 35.7 cm [interquartile range, IQR (30.8–51.0)] versus 74.1 cm [IQR (44.3–170.4)] for manual cannulation, p = 0.019. Robotic cases had a median cannulation time of 5.33 min [IQR (4.58–6.49)] versus 1.24 min [IQR (1.13–1.35)] in manual cases (p = 0.0083). Generated efficiency ratios (PL/aorto-iliac centrelines) was 1.6 (1.2–2.1) in robotic cases versus 2.6 (1.7–7.0) in manual, p = 0.031. Robot-assisted contralateral gate cannulation in EVAR leads to decreased navigation path lengths and increased economy of movement compared with manual catheter techniques. The benefit could be maximised by prioritising robotic catheter shaping over habituated reliance on guidewire manipulation. Robotic technology has the potential to reduce the endovascular footprint during manipulations even for experienced operators with the added advantage of zero radiation exposure.

High-voltage amorphous indium–gallium–zinc oxide thin-film transistors can be monolithically integrated into the system-on-chip platform as input–output bridges. However, a transient instability showing substantial ON-current degradation under high drain bias is discovered. This drain-bias transient instability depends on the stress time of less than 10 s and both drain and gate stress voltages. It is attributed to the charge trapping in local oxygen vacancies with shallow energy levels and the migration of oxygen ions near the drain. We found that oxygen vacancies are induced by metal contacts. An elevated-metal structure suppresses the transient instability by separating the metal contact region farther away from the channel compared with the conventional top-contact structure.

BACKGROUND: To analyze the efficacy of computed tomography (CT)-guided implantation of (125)I radioactive particles in treatment of early lung cancer. METHODS: Six patients were analyzed, including 4 squamous cell carcinoma, 1 adenocarcinoma, and 1 small cell lung cancer. TPS software was used to calculate the therapeutic dose amount of particles implanted, and the spacing and distribution of seeds in the target area and adjacent tissues. Under the guidance of CT, 20–55 particles were implanted at each site, with the total number of radioactive particles being 226, the particle spacing being 0.5–1.0 cm, and the implantation being performed in accordance with the principle of uniform implantation. The patients were each followed up with repeated pulmonary CT scans at 1, 3, 6, 12, 18, 24, 30 and 36 months after the procedure. In accordance with the response evaluation criteria in solid tumors (RECIST), the following definitions for responses were used: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). RESULTS: There were 2 CRs and 4 PRs one month after procedure; six patients were followed up 3 months after procedure, including 2 CRs and 4 PRs; one patient was lost in follow-up, and 5 patients were followed up 6 months after procedure, including 3 CRs and 2 PRs; five patients were followed up 12 months after procedure, including 3 CRs, 1 PR and 1 PD. The single PD patient was again given CT-guided implantation of (125)I radioactive particles for the treatment of recurrent lesions. The pulmonary CT was repeated 6 months after procedure, and the response was evaluated as SD. Four patients were followed up 18 months after procedure, including 3 CRs and 1 PR; one patient was lost in follow-up and 3 patients were followed up 24 months after the procedure with the response being evaluated as CR for all of them; one patient was followed up 36 months after procedure, and the response was evaluated as PD. During the follow-up, no serious complications occurred in any of the patients. CONCLUSIONS: The preliminary clinical observation showed that (125)I radioactive particle implantation was a safe, reliable and effective therapeutic method for early lung cancer.

Objectives Renal replacement therapy-requiring acute kidney injury frequently occurs in ICUs, which require evidence-based medical attention. However, in the postacute kidney injury patient population, the evidence regarding effective therapies to improve patient outcomes is lacking. Therefore, we aimed to examine whether the renin-angiotensin-aldosterone system blockade is effective in improving renal outcomes in postacute kidney injury patients who experienced temporary renal replacement therapy and have hypertension. Design A retrospective cohort study. Setting A nationwide database in Taiwan. Patients From January 1, 2000, to December 31, 2013, we identified 8,558 acute kidney injury patients with hypertension in the national registry database. All these patients experienced an acute kidney injury episode, which required temporary renal replacement therapy for at least once. Interventions Users (n = 3,885) and nonusers (n = 4,673) of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Measurements and main results We used Cox proportional hazards regression models to analyze hazard ratios for the commencement of end-stage renal disease and all-cause mortality for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users (n = 3,885) and nonusers (n = 4,673). In a median follow-up of 4.3 years, 5,880 patients (68.7%) required long-term dialysis, and 4,841 patients (56.6%) died. Compared with postacute kidney injury patients who did not use angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users are marginally less likely to progress to end-stage renal disease (adjusted hazard ratio 0.95; 95% CI 0.90-1.01; p = 0.06) and significantly less likely to suffer from all-cause mortality (adjusted hazard ratio 0.93; 95% CI 0.87-0.98; p = 0.011). Conclusions In patients who experienced renal replacement therapy-requiring acute kidney injury and have hypertension, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use is associated with better survival outcomes compared with nonuser.

OBJECTIVES This study aimed to evaluate the optimal risk assessment model (RAM) to stratify the risk of venous thromboembolism (VTE) in hospitalized patients with cancer. We examined and compared the VTE predictive ability of the Khorana score (KS) and the Caprini RAM in hospitalized cancer patients. METHODS We performed a retrospective case–control study among hospitalized cancer patients admitted to a comprehensive hospital in China from January 2015 to December 2016. A total of 221 cases were confirmed to have VTE during hospitalization and 221 controls were selected randomly. The Caprini RAM and KS were implemented and the individual scores of each risk factor were summed to generate a cumulative risk score. Meanwhile, the sensitivity, specificity, areas under curve of the receiver operating characteristic curve and calibration of these 2 models were analysed. RESULTS Significant differences were observed in risk factors between VTE and non-VTE hospitalized cancer patients and the VTE risk increased significantly with an increase in the cumulative KS or Caprini RAM score. A classification of ‘high risk’ according to KS and Caprini RAM was associated with 2.272-fold and 3.825-fold increases in VTE risk, respectively. However, the Caprini RAM could identify 82.4% of the VTE cases that required preventive anticoagulant therapy according to American College of Chest Physicians guidelines, whereas the KS could only identify 35.3% of the VTE cases. In addition, the areas under curve of Caprini RAM were significantly higher than those of the KS (0.705 ± 0.024 vs 0.581 ± 0.025, P 0.05), but the risk of VTE events predicted by Caprini seemed closer to the observed risk of VTE events. CONCLUSIONS The Caprini RAM was found to be more effective than the KS in identifying hospitalized patients with cancer at risk of VTE.

Wide-angle optical systems play a vital role in imaging applications and have been researched for many years. In traditional lenses, attaining a wide field of view (FOV) by using a single optical component is difficult because these lenses have crucial aberrations. In this study, we developed a wide-angle metalens with a numerical aperture of 0.25 that provided a diffraction-limited FOV of over 170° for a wavelength of 532 nm without the need for image stitching or multiple lenses. The designed wide-angle metalens is free of aberration and polarization, and its full width of half maximum is close to the diffraction limit at all angles. Moreover, the metalens which is designed through a hexagonal arrangement exhibits higher focusing efficiency at all angles than most-seen square arrangement. The focusing efficiencies are as high as 82% at a normal incident and 45% at an incident of 85°. Compared with traditional optical components, the proposed metalens exhibits higher FOV and provides a more satisfactory image quality because of aberration correction. Because of the advantages of the proposed metalens, which are difficult to achieve for a traditional single lens, it has the potential to be applied in camera systems and virtual and augmented reality.

Background miR-100 is reported to be associated with cell proliferation and apoptosis. However, the function of miR-100 in mantle cell lymphoma (MCL) is unknown. The purpose of this study is to analyze the abnormal expression of miR-100 and mTOR in MCL together with their potential biological function and pathogenesis. Method Eighteen MCL tissue samples and 3 cell lines (Jeko-1, Mino, Granta-519) were investigated in this research study, while eighteen samples of proliferative lymphadenitis from patients and peripheral lymphocyte cells from healthy volunteers served as controls. The expression and alteration of miR-100 and mTOR mRNA were detected by RT-PCR. The expression and alteration of mTOR protein were explored by Western blot. LV-miR-100-up and LV-mTOR-RNAi were constructed and transfected by lentivirus transfection. Cell proliferation, cell apoptosis and the cell cycle were detected using CCK-8 and flow cytometry. Bioinformatics prediction software was used to predict the miR-100 target gene of mTOR. A double luciferase experiment was used to verify miR-100 targeting at the mTOR-3′-UTR. The interaction between miR-100 and mTOR was further studied using recovery experiments. GraphPad Prism 7 software (version 7.2) was used for statistical analysis, and a P value Results We found that the expression of miR-100 mRNA in MCL tissues and cell lines was lower, while that of the mTOR protein was higher. There was a negative correlation between miR-100 and mTOR in both MCL tissues and cell lines. Promoting miR-100 and inhibiting mTOR could inhibit cell proliferation, induce cell apoptosis and block the cell cycle in the G1 phase. A double luciferase reporter assay showed that mTOR was one of the target genes of miR-100. The recovery experiment demonstrated that PV-mTOR-up partially set off the effect of LV-miR-100-up on decreasing mTOR expression, inhibiting proliferation, inducing apoptosis and blocking the cell cycle in G1 phase in both Jeko-1 and Mino cells. Conclusions Abnormal expression of miR-100 and mTOR was found in MCL, which included downregulation of miR-100 and upregulation of mTOR. The expression of mTOR is negatively correlated with miR-100. It may play an important role in MCL pathogenesis. miR-100 up-regulation can inhibit cell proliferation, promote cell apoptosis, and inhibit cell cycle in G1 phase by targeting the mTOR gene. miR-100 may potentially be an anti-mantle cell lymphoma gene.