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KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRasG12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRasG12C have shown promising efficacy against cancers harboring KRASG12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRasG12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRasG12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRasG12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Acinetobacter baumannii causes healthcare-associated infections worldwide. Capsular polysaccharide (CPS) is shown an important virulence factor of A. baumannii both in vitro and in vivo. Capsule locus 2 (KL2) for CPS is the most common KL type and is associated with carbapenem resistance. It is unclear whether KL2 is related to the clinical outcome of invasive A. baumannii infection. Here we had followed patients with A. baumannii bacteraemia prospectively between 2009 and 2014. One-third of the unduplicated blood isolates were randomly selected each year for microbiological and clinical studies. The KL2 gene cluster was identified using polymerase chain reaction. A total of 148 patients were enrolled randomly. Eighteen isolates (12.2%) carried KL2, and 130 isolates (87.8%) didn't. Compared with non-KL2 isolates, KL2 isolates had significantly higher resistance to imipenem, sulbactam, and tigecycline. Compared with the non-KL group, in the KL2 group, the hospital stay before development of bacteraemia was longer (P

Background: Epithelial splicing regulatory proteins (ESRPs) can regulate alternative splicing of RNA and play roles in tumorigenesis and development of various malignancies. In this study, bioinfor...

Graphical abstract, Highlights • PLA2G16 is up-regulated in CRC, and high expression of PLA2G16 is associated with the advanced stages. • PLA2G16 promotes the malignant progression of CRC through the Hippo signaling pathway. • GCK exerts its anti-CRC effects by inhibiting the protein expression of PLA2G16. • Provide a new insights towards the development of effective therapeutic strategies for CRC treatment by targeting PLA2G16., Introduction Colorectal cancer (CRC) is a common malignant tumor with a high global incidence, metastasis rate and low cure rate. Changes in lipid metabolism-related genes can affect the occurrence and development of CRC, and may be a potential therapeutic target for CRC. Therefore, starting from lipid metabolism-related genes to find natural medicines for tumor treatment may become a new direction in CRC research. Objectives This study aimed to investigate the effect of PLA2G16, a key gene involved in lipid metabolism, on the biological function of CRC, and whether the anti-CRC effect of GCK is related to PLA2G16. Methods To explore the role of PLA2G16 in CRC in vitro and in vivo, we performed cell proliferation, migration, invasion and nude mice tumorigenesis assays. As for the mechanism, we designed RNA-seq analysis and verified by western blotting and immunofluorescence experiments. Subsequently, we found the anti-CRC effect of GCK is related to PLA2G16 through western blotting and rescue experiments. Results We showed that PLA2G16 was significantly higher in CRC tissues than the adjacent normal appearing tissues, and high PLA2G16 expression correlates with unfavorable prognosis of CRC patients. Further, PLA2G16 promoted the malignant progression of CRC by inhibiting the Hippo signaling pathway determined by RNA-seq analysis, and GCK exerted anti-CRC effects by inhibiting the protein expression of PLA2G16 in vitro and in vivo. Conclusion Our results suggested that PLA2G16 promote the malignant progression of CRC by inhibiting the Hippo signaling pathway and the anti-CRC effect of GCK is through inhibiting the protein expression of PLA2G16.

Iron dyshomeostasis is associated with hepatocellular carcinoma (HCC) development. However, the role of iron in HCC metastasis is unknown. This study aimed to elucidate the underlying mechanisms of iron’s enhancement activity on HCC metastasis. In addition to the HCC cell lines and clinical samples in vitro, iron deficient (ID) mouse models were generated using iron-free diet and transferrin receptor protein knock out, followed by administration of HCC tumors through either orthotopic or ectopic route. Clinical metastatic HCC samples showed significant ID status, accompanied by overexpression of sphingosine-1-phosphate transporter spinster homologue 2 (SPNS2). Mechanistically, ID increased SPNS2 expression, leading to HCC metastasis in both cell cultures and mouse models. ID not only altered the anti-tumor immunity, which was indicated by phenotypes of lymphatic subsets in the liver and lung of tumor-bearing mice, but also promoted HCC metastasis in a cancer cell autonomous manner through the SPNS2. Since germline knockout of globe SPNS2 showed significantly reduced HCC metastasis, we further developed hepatic-targeting recombinant adeno-associated virus vectors to knockdown SPNS2 expression and to inhibit iron-regulated HCC metastasis. Our observation indicates the role of iron in HCC pulmonary metastasis and suggests SPNS2 as a potential therapeutic target for the prevention of HCC pulmonary metastasis.

BACKGROUND Hormone receptor-positive, human epidermal growth factor receptor II (HER2)-negative luminal B1 breast cancer is associated with a higher risk of disease relapse than luminal A breast cancer. Therefore, we assessed and compared the distant metastasis pattern and clinical outcomes associated with luminal B1 and luminal A breast cancer in an Asian population. METHODS In this observational study, we assessed patients with estrogen receptor-positive, HER2-negative breast cancer who underwent surgery from 2009 to 2016. Patients were classified into luminal A or luminal B1 subsets via immunohistochemical analysis. Disease-free survival, post-metastasis survival, and overall survival were estimated; time to disease relapse and patterns of distant metastasis were compared. Risk of relapse and mortality were assessed using Cox proportional hazards model. RESULTS Patients with luminal B1 breast cancer (n = 677) were significantly younger and had larger tumors and a higher degree of affected axillary lymph nodes, lymphovascular invasion, and tumor necrosis than those with luminal A breast cancer (n = 630). Higher rates of local recurrence and distant metastasis were observed for luminal B1 (both p < 0.05); however, no difference was observed in the specific distant metastatic sites. We observed a significant increase in disease relapse risk in luminal B1 patients compared with that in luminal A (hazard ratio: 2.157, 95% confidence interval: 1.340-3.473, p < 0.05). Patient age, tumor size, stage, lymphovascular invasion, and receiving chemotherapy and hormone therapy were independent risk factors for metastasis and recurrence. Only the luminal B1 subtype (hazard ratio: 5.653, 95% confidence interval: 1.166-27.409, p < 0.05) and stage (hazard ratio: 3.400, 95% confidence interval: 1.512-7.649, p < 0.05) were identified as independent risk factors for post metastatic mortality. CONCLUSION Luminal B1 breast cancer has aggressive tumor biology compared with luminal A breast cancer in the follow-up period. However, there was no significant difference in the disease relapse pattern between the groups.

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.

Abstract: miRNA-129-5p belongs to the microRNA-129 (miRNA-129) family. miRNA-129-5p is expressed in many tissues and organs of the human body, and it regulates a wide range of biological functions. The abnormal expression of miRNA-129-5p is related to the occurrence and development of a variety of malignant tumors. miRNA-129-5p plays an important role in the tumorigenesis process and functions by promoting or inhibiting tumors. However, the role of miRNA-129-5p in cancer remains controversial. This article reviews the different biological functions of miRNA- 129-5p in cancer and provides ideas for research in this field to guide the development of targeted therapies and drugs for malignant tumors.

This study aimed to develop and assess the effectiveness of an encounter decision aid for Malaysian patients with MDD to support treatment decision-making during the consultation.The decision aid prototype was developed following a literature review and six focus groups. Alpha testing assessed its comprehensibility, acceptability, usability and desirability through user-centered cognitive interviews. Beta-testing evaluated preliminary evidence on its efficacy using the SDM Scale and PDMS. Feasibility was assessed by timing the consultation.The alpha testing demonstrated that the decision aid was patient-oriented, comprehensible, comprehensive, concise and objective with an appealing design. Beta-testing indicated that PtDA significantly increased patients satisfaction with SDM from patients' [83.32 (13.92) vs 85.76 (13.80); p 0.05] and physicians' [81.07 (10.09) vs 86.36 (10.10); p 0.05] perspectives and prepared the patients for decision making from the patients' [PDMS patients: 84.10 (12.69)] and physicians' [PDMS physicians: 83.78 (16.62)] perspectives as well. There was no change in the consultation time between the control and the intervention groups.We developed an antidepressant PtDA for Malaysian patients with MDD that increases patients' involvement in shared decision making and enhances their preparedness for decision making.Using the PtDA can support collaborative decision-making in routine clinical practice without extending the consultation time.

Purpose: The present study investigated the association between Systematic COronary Risk Evaluation (SCORE)-estimated cardiovascular risk and carotid stiffening in a middle-aged population using ultrafast pulse wave velocity (ufPWV).Methods: This study enrolled 683 participants without known cardiovascular disease or diabetes mellitus who underwent ufPWV measurements. Clinical interviews, physical examinations, laboratory findings, carotid intima-media thickness (cIMT), pulse wave velocity (PWV) at the beginning of systole (PWV-BS), and PWV at the end of systole (PWV-ES) were assessed. Each participant underwent an assessment of SCORE risk based on major cardiovascular risk factors (CVRFs), including age, sex, smoking, systolic blood pressure (SBP), and total cholesterol (TC). Crude and adjusted odds ratios (ORs) with 95% confidence intervals and ordinal logistic regression were used. Overall CVRFs were adjusted to assess ORs.Results: cIMT and carotid stiffening in PWV-BS and PWV-ES were significantly different between sex subgroups (all P0.05).Conclusion: Carotid stiffening quantified by ufPWV is linked to SCORE categories, and elevated PWV-ES may aid in cardiovascular risk stratification.

Acute porphyrias are rarely reported in Southeast Asia. They may be underdiagnosed due to their clinical mimicry and lack of awareness among physicians. There is a common cognitive bias to gravitate towards common conditions. In this case report, a 28-year-old woman, who presented with seizures, rhabdomyolysis hyponatraemia and altered mental state, was initially diagnosed as amphetamine overdose. She had presented 3 days prior with abdominal pain, treated for acute cystitis and discharged. On readmission for seizures a day later, she was extensively worked up for altered mental state. Despite normalisation of serum sodium concentration and control of her seizures, she remained unwell. Further investigations later confirmed a diagnosis of acute porphyria. The aim of this case report is to highlight the non-specific nature of presentation of acute porphyria and the importance of considering it as a differential diagnosis in cases of abdominal pain with neuropsychiatric features.

Background Recurrence of nasopharyngeal carcinoma (NPC) after chemoradiotherapy is common, but submucosal recurrence of NPC is rare. The final pathological results determine the optimal therapeutic schedule for treatment of NPC recurrence, but tissue retrieval from submucosal lesions is usually difficult. The present study aimed to assess the safety and efficacy of a novel approach of endonasopharyngeal ultrasound-guided transnasopharyngeal needle aspiration (ENUS-TNNA) for submucosal neoplasms in patients with suspected NPC recurrence. Methods Between March 2017 and June 2021, 11 post-chemoradiotherapy patients with suspected magnetic resonance imaging (MRI) findings of submucosal recurrence of NPC underwent ENUS-TNNA. The safety and effectiveness of using ENUS-TNNA to sample submucosal neoplasms were evaluated. Results Needle aspiration biopsies were performed without any incidences in all cases. Out of the 11 patients, nine were diagnosed with submucosal recurrence of NPC via histopathological or cytological evaluations. Of the two puncture-negative cases, one patient had atypical imaging findings and clinical manifestations and was therefore followed-up using MRI. After follow-up for 3 years, this patient was still considered to be cancer-free due to the shrinking diameters of the submucosal lesions. For the other puncture-negative patient, submucosal biopsy samples were obtained using a surgical method. Pathological examination of these biopsies revealed that an angiosarcoma had developed after radiotherapy. There were no severe complications that occurred during the ENUS-TNNA procedure. Conclusion ENUS-TNNA is a safe, effective, and minimally invasive approach to obtain tissue samples from the submucosal region of the nasopharynx for patients with suspected NPC recurrence.

Hepatocellular carcinoma (HCC) is a type of cancer that has high rates of recurrence and mortality. One of the most important factors that lead to treatment failure of HCC is the acquisition of multidrug resistance (MDR). Development of specific ligands for multidrug-resistant HCC will provide useful molecular tools for precise diagnosis and targeted theranostics. Herein, a multidrug-resistant HCC cell (HepG2/MDR)-specific aptamer was developed through Cell-SELEX (systematic evolution of ligands by exponential enrichment) technology. With dissociation constants lying in the nanomolar range, the molecularly designed PS-ZL-7c aptamer showed great selectivity to drug-resistant cancer cells. The in vivo imaging results illustrated that the PS-ZL-7c specifically accumulated in the drug-resistant tumors but not in drug-sensitive tumors and normal tissues, indicating that the PS-ZL-7c aptamer possessed excellent potential as a targeting ligand for precise diagnosis and target theranostics of multidrug-resistant HCC.

PURPOSE To investigate the risk of poor delivery events (PDEs; premature delivery, abortion, and stillbirth) in female subjects with obstructive sleep apnea (OSA). METHODS The study identified 8346 female subjects with PDEs as cases between January 1, 2000 and December 31, 2015 from the Longitudinal Health Insurance Database 2005 in Taiwan. A total of 33,384 controls were also identified based on frequency matching for age and year of index date. Diagnoses of OSA and PDEs were determined according to the International Classification of Diseases, 9th Revision. The risk of PDEs in female subjects with OSA was estimated with conditional logistic regression analyses. FINDINGS The mean age of the 41,730 female subjects was 35.53 years. The overall incidence rate of PDEs was 506.22 per 100,000 person-years for subjects with OSA, which was significantly higher than that for the controls (501.95 per 100,000 person-years). The risk of PDEs was higher in subjects with OSA than in controls (adjusted odds ratio [AOR] = 1.19; 95% confidence interval [CI] [95% CI]: 1.08-1.43), including for premature delivery (AOR = 1.20; 95% CI: 1.16-1.50), and abortion (AOR = 1.19; 95% CI: 1.09-1.47). OSA showed no relation to stillbirth (AOR = 1.04; 95% CI: 0.99-1.31). The findings indicate that the longer a subject has been experiencing OSA, the higher the probability of PDEs. CONCLUSIONS The risk of PDEs associated with OSA was found in this study. In particular, the longer a subject has OSA, the higher the likelihood of PDEs, exhibiting a dose-response effect. CLINICAL RELEVANCE To effectively promote maternal health in clinical practice, health providers need to recognize OSA as a risk factor associated with negative pregnancy outcomes. Furthermore, OSA symptoms should be assessed and managed in all pregnant women to enable more comprehensive maternal care.

Background Metabolic syndrome (MetS) was a risk factor for papillary thyroid cancer (PTC). Whether MetS impacts the aggressiveness of PTC is still unclear. We carried out this study to clarify this issue. Methods We evaluated 745 consecutive PTC patients treated with surgery. Patients were divided into three groups based on their number of MetS components: patients without any MetS components, patients with 1–2 MetS components, and patients with 3–5 MetS components. The clinical features and histological aggressiveness of PTC at the time of diagnosis were evaluated. Results A total of 745 patients were included in this study. And, 145 patients had three or more metabolic components and were diagnosed as MetS. MetS was a risk factor for larger tumors (OR = 2.29, 95% CI: 1.31–4.03), more lymph node metastasis (OR = 1.97, 95% CI: 1.11–3.51), and later clinical stage (OR = 7.92, 95% CI: 1.59–39.34) after correction for age, sex, and thyroid-stimulating hormone (TSH) level and body mass index (BMI). Conclusion In our hospital-based cohort study MetS was associated with the aggressiveness of PTC. This association was still significant after adjusting for age, sex, TSH, and BMI.

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.

The population is rapidly aging worldwide, and there is an age-related decline in muscle mass. Therefore, it is important to examine the prevalence and associated factors of low appendicular skeletal muscle mass index (ASMI) in older adults. The objectives of this cross-sectional study were (i) to determine the prevalence of low ASMI (ASM/height2) and (ii) to identify factors associated with low ASMI. This study included 1211 community-dwelling adults aged ≥ 65 years. Low ASMI was defined as 2 in males and 2 in females (bioelectrical impedance analysis). Gender-specific cut-off values of calf circumference for low ASMI were determined. The prevalence of low ASMI in the overall cohort was 59.9%, i.e., 57.0% among males and 61.8% among females, with no significant difference between genders (P = 0.1068). The prevalence of low ASMI was 81.3% in individuals at risk of malnutrition compared to 20.6% in their counterparts with normal nutritional status (P P P ≤ 0.0328). Cut-off values of calf circumference for low ASMI for males was 33.4 cm and for females was 32.2 cm. In conclusion, we found that low ASMI was highly prevalent among community-dwelling older adults at risk of malnutrition. Other significant factors associated with low ASMI were age, smoking, drinking, calf circumference, and bone mass. Screening community-dwelling older adults for risk of malnutrition can prevent or delay onset of low ASMI.

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

To address the diagnostic delay in axial spondyloarthritis (axSpA), we have cross-culturally adapted the Hamilton axSpA questionnaire, a self-administered screening questionnaire, in the Singapore population. In this study, we compared the performance of various scoring methods for this questionnaire in detecting axSpA. The questionnaire was self-administered by eligible subjects. Scoring methods included method A, the original questionnaire scoring, and methods B–E, scoring developed based on the Assessment of SpondyloArthritis International Society (ASAS) criteria for inflammatory back pain (IBP) and the referral, classification and both referral and classification of axSpA, respectively. The reference standard was diagnosis by a rheumatologist. Since the ASAS criteria-based scoring methods were mainly based on clinical axSpA features, self-report and rheumatologist-assessment of clinical axSpA features were also compared in subjects with axSpA. Of 1418 subjects (age: 54 ± 14 years, female: 73%) recruited, 46 were diagnosed with axSpA by a rheumatologist. Sensitivities of methods A–E were 35%, 61%, 63%, 48% and 83%, respectively. Self-report of clinical axSpA features exceeded rheumatologist-assessment for arthritis (83 vs 26%), good response to NSAIDs (37 vs 30%), enthesitis (35 vs 30%), dactylitis (20 vs 2%) and family history for axSpA (13 vs 4%). The reverse was true for IBP (41 vs 63%) and uveitis (4 vs 15%). A self-administered questionnaire using the ASAS referral and classification criteria-based scoring yielded relatively high sensitivity in detecting axSpA in subjects newly referred to rheumatology clinics. This supports its evaluation as a screening and referral tool in the general population in future studies.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Hanqing Liu,1,&ast; Ling Zhan,1,&ast; Liantao Guo,1 Xizi Yu,1 Lingrui Li,1 Hongfang Feng,2 Dan Yang,3 Zhiliang Xu,1 Yi Tu,1 Chuang Chen,1 Shengrong Sun1 1Department of Thyroid and Breast Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Huangshi Central Hospital of Edong Healthcare Group, Hubei Polytechnic University, Huangshi, 435000, Hubei, People’s Republic of China; 3Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shengrong Sun; Chuang ChenDepartment of Thyroid and Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University at Jiefang Road 238, Wuhan, 430060, People’s Republic of ChinaTel/Fax +86 27 88041911Email sun137@sina.com; chenc2469@163.comPurpose: Many thyroid cancer patients have suffered from treatment delays caused by the coronavirus disease 2019 pandemic. Although there have been many reviews, recommendations, or clinical experiences, clinical evidence that evaluates patient disease status is lacking. The aim of our research was to evaluate thyroid cancer behaviour in the post-COVID-19 era.Patients and Methods: A retrospective study was conducted and thyroid cancer patient data from February 1, 2017 to September 15, 2020 were pooled for analysis. The demographic, ultrasound and pathological data of the pre- and post-COVID-19 groups were compared. Lymph node metastases, tumour size, extrathyroidal extension, and multifocality were compared year-by-year to evaluate annual changes in patient characteristics. Regression analyses were adopted to reveal cancer behaviour along with the admission date interval and to reveal risk factors for lymph node metastasis. Patient ultrasound data were compared before and after the lockdown to assess tumour progression. The outcomes of delays in treatment ≤ 180 days were then studied.Results: The post-lockdown patients were more likely to have multiple lesions (31.2% vs 36.5%, p = 0.040), extrathyroidal extension (65.5% vs 72.2%, p = 0.011) and lymph node metastases (37.7% vs 45.0%, p = 0.007), while tumour size remained stable (1.01cm vs.1.02cm, p = 0.758). The lymph node metastasis rate increased by year (p < 0.001). The tumour size correlated negatively with the post-lockdown admission date (p = 0.002). No significant difference in tumour size, multifocality or lymph node metastasis on ultrasound was revealed between the pre- and post-lockdown group. No significant difference in tumour size, multifocality, extrathyroidal extension or lymph node metastasis was revealed among patients with a delayed treatment time ≤ 180 days.Conclusion: Patients with a COVID-19-induced treatment delay had more aggressive cancer behaviour. Rebound medical visits and annually increasing aggressiveness may be potential reasons for this observation, as individual patient tumour did not progress during the delay.Keywords: treatment delay, lockdown, rebound medical visit, tumor behavior

Patients with cancer are at increased risk of myocardial infarction (MI) and stroke. Guidelines do not address lipid profile targets for these patients. Within the lipid profiles, we hypothesized that patients with cancer develop MI or stroke at lower low density lipoprotein cholesterol (LDL-C) concentrations than patients without cancer and suffer worse outcomes. We linked nationwide longitudinal MI, stroke and cancer registries from years 2007–2017. We identified 42,148 eligible patients with MI (2421 prior cancer; 39,727 no cancer) and 43,888 eligible patients with stroke (3152 prior cancer; 40,738 no cancer). Median LDL-C concentration was lower in the prior cancer group than the no cancer group at incident MI [2.43 versus 3.10 mmol/L, adjusted ratio 0.87 (95% CI 0.85–0.89)] and stroke [2.81 versus 3.22 mmol/L, adjusted ratio 0.93, 95% CI 0.91–0.95)]. Similarly, median triglyceride and total cholesterol concentrations were lower in the prior cancer group, with no difference in high density lipoprotein cholesterol. Prior cancer was associated with higher post-MI mortality [adjusted hazard ratio (HR) 1.48, 95% CI 1.37–1.59] and post-stroke mortality (adjusted HR 1.95, 95% CI 1.52–2.52). Despite lower LDL-C concentrations, patients with prior cancer had worse post-MI and stroke mortality than patients without cancer.

BACKGROUND: Numerous studies have shown pulmonary artery enlargement when measured by chest computed tomography (CT) could predict a worse outcome in chronic obstructive pulmonary disease (COPD) patients. Herein, we studied the prognostic implication of main pulmonary artery diameter (MPAD) in Chinese COPD patients. METHODS: This is an observational case-control study. Patients with 90-day readmissions are case group and those without 90-day readmission are control group. The study comprised of 417 COPD patients who underwent chest CT in their initial admission due to acute exacerbation of COPD (AECOPD). We analyzed their clinical characteristics such as MPAD, arterial blood gas (ABG) results, other chest CT findings and comorbidities to identify the cause of readmission within 90 days. RESULTS: Median age of our study population is 75 years old, and 79.6% of them are male. The median MPAD is 2.8 cm and 80.6% were also diagnosed with community acquired pneumonia (CAP) in their first admission. The median MPAD in patients with 90-day readmission was 3.1 cm while patients without 90-day readmission had median MPAD of 2.8 cm. Through multivariate logistic regression analysis CAP (P=0.019, OR: 3.105, 95% CI: 1.203–8.019) and MPAD (P2.9 cm are at increased risk of 90-day readmission.

Background Although previous studies have made significant contributions to establishing animal traumatic brain injury (TBI) models for simulation of human TBI, the accuracy, controllability, and modeling efficiency of animal TBI models need to be further improved. This study established a novel high-efficiency graded mouse TBI model induced by shock wave. Methods A total of 125 mice were randomly divided into sham, 0.7 mm, 0.6 mm, and 0.5 mm groups according to the depth of the cross groove of the aluminum sheets. The stability and repeatability of apparatus were evaluated, and the integrity of the blood-brain barrier, cerebral edema, neuropathologic immunohistochemistry, apoptosis-related protein, and behavioral tests of neurologic function were used to validate this new model. Results The results showed that 4 mice were injured simultaneously in 1 experiment. They received the same intensity of shock waves. Moreover, the mortality rates caused by 3 different aluminum sheets were consistent with the mortality rates of mild TBI, moderate TBI, and severe TBI. Compared with the sham group, mice in different injured groups significantly increased brain water content, blood-brain barrier permeability, and neuronal apoptosis. And the mice in all injured groups showed poor motor ability, balancing, spatial learning, and memory abilities. Conclusions The novel TBI apparatus has advantages in its small size, simple operation, high repeatability, high efficiency, and graded severity. Our TBI apparatus provides a novel tool to investigate the neuropathologic changes and underlying mechanisms of TBI with various levels of severities.

The purpose of this study was to clarify the differences in the diagnosis and treatment outcomes between radioactive iodine-induced sialadenitis (RAIS) and chronic obstructive parotitis (COP). The study cohort comprised 47 consecutive patients diagnosed with RAIS and 50 patients with COP. All patients were treated by interventional endoscopy. Clinical, sialography, and endoscopy characteristics and treatment outcomes were compared between the two groups. Compared with the COP group, the RAIS group included more females (male:female ratio 1:8.4 vs 1:2.1; P = 0.011) and had a younger onset age (42 vs 50 years; P = 0.001) and shorter disease duration prior to hospital visit (5.4 vs 34.8 months; P0.001). In the RAIS group, sialography revealed obliteration of the main duct (20.4% vs 0%; P0.001), non-visualization of the main gland (23.7% vs 0%; P0.001), and incomplete contrast filling of the main gland (19.4% vs 6.4%; P = 0.008), which were scarcely observed in the COP group. Endoscopy revealed a higher percentage of duct atresia in RAIS compared to COP (20.4% vs 0%; P0.001). During follow-up, a higher percentage of RAIS patients had duct atresia and gland atrophy (49.5% vs 1.1%, P0.001). Compared with COP, RAIS more commonly involves younger females and has a shorter disease duration. Atresia of the main duct and atrophy of the gland parenchyma occur more often despite the use of interventional endoscopy.

Background Follow-up of subjects with putative pre-psychotic states is essential to clarify the transition process to psychosis, while "non-converters" also deserve clinical attention as many may evolve into other psychiatric disorders with diverse outcomes. This study aimed to examine help-seeking individuals who have been labelled at clinical high-risk state but not converting to full-blown psychosis during first two years of follow-up. Methods A retrospective observational cohort study of help-seeking subjects was conducted by reviewing medical records of participants in a previous early psychosis study at the study hospital between 2006 and 2020. We portrayed those who developed first episode psychosis after first 2-year follow-up in detail, and provided sketches of clinical macrophenotypes other than psychosis emerging from subjects among different risk groups. Results Among 132 eligible subjects, data of 98 (74.2%) were available for detailed evaluation. Of these, 15 transitioned to first-episode psychosis (11.4%) with time to psychosis from 2 to 11 years, 11 had anxiety spectrum (8.3%), 11 had depressive spectrum (8.3%), 10 had obsessive compulsive (7.6%), 5 had bipolar spectrum disorders (3.8%), 13 had predominantly schizotypal (9.8%) and 4 had other personality traits (3%), and 13 had problems attributable to adjustment or developmental issues (9.8%). Conclusions Various diagnoses, either full- or sub-threshold, appropriately describe the diverse clinical phenomenology of a cohort presenting with non-specific and/or subthreshold psychotic symptoms. The clinical high-at-risk mental state (CHARMS) paradigm provides a reasonable transdiagnostic approach for orienting clinicians' attention toward young subjects seeking mental health help at an early stage of illness to potentially pluripotent trajectories.

BACKGROUND Atherosclerosis and vascular inflammatory response have been considered as risk factors for non-typhoidal Salmonella (NTS) vascular infection. The study aims to assess the risk of vascular infection by measuring atherosclerosis severity, NTS vascular infection (NTSVI) score, and serum levels of inflammatory markers in people with NTS bacteremia. METHODS A prospective observational study was conducted in two medical centers and two regional hospitals. Adults aged ≥50 years with NTS bacteremia who underwent computed tomography (CT) scan for revealing vascular infections were enrolled. The degree of atherosclerosis was scaled by a calcium score determined by a CT scan. Serum concentrations of inflammatory biomarkers were determined in the patients enrolled in a medical center. RESULTS Fourteen (20.3%) of 69 patients with NTS bacteremia had vascular infections. Calcium scores over the thoracic (12,540 vs. 3,261, P = 0.0005) and abdominal (9755 vs. 3,461, P = 0.0006) aorta of those with vascular infections were higher than those without vascular infection. All vascular infections were present in the high-risk group (NTSVI score ≥1), yielding a sensitivity of 100% and specificity of 30.9%. Among 17 low-risk patients (NTSVI score

Introduction The transplantation of mesenchymal stem cells (MSCs) in patients with premature ovarian failure (POF) could lead to clinical improvement. The transplantation to the ovaries among other transplantation methods have been reported in various animal models, however, there is little evidence regarding the optimal method, including the clinical safety and the efficiency for the treatment of age associated ovarian hypofunction. Objectives To establish the most effective transplantation route of MSCs, explore the resistance to therapy, its safety and role in the natural aging process of the ovaries. Methods Highly purified MSCs were injected intraperitoneally, directly into the ovaries or tail-intravenously in mice animal model. The ovarian function, quantity and quality of oocytes, cell viability/apoptosis, were evaluated, applying chemiluminescence analysis (CLIA), western blotting, immunofluorescence staining, transmission electron microscope (TEM), TdT mediated dUTP Nick End Labeling (TUNEL) assay and other techniques. The organ tumorigenicity was also evaluated by long-term observation and histopathological examination. The efficiency of MSCs was further verified in non-human primates by the most effective transplantation route. Results The 32nd week was ultimately determined as the time point of MSCs transplantation. Our results showed that the intra-ovarian injection was the best transplantation method with a more conspicuous effect. With deeper investigations, we found that the transplanted MSCs showed an effective influence on the follicular number, promoted follicle maturation and inhibited cell apoptosis, which was further verified in non-human primates. In addition, the long-term observation and the histopathological examinations ruled out neoplasms or obvious prosoplasia after MSCs transplantation. Conclusion MSCs transplantation by intra-ovarian injection could within a month exert the most conspicuous anti-age-associated ovarian hypofunction effects, which may improve the quantity and quality of oocytes by changing the mitochondrial structure, regulating mitochondrial function and attenuating cell apoptosis to increase the storage of the follicle pool without a remarkable potential of tumorigenicity.

Takotsubo syndrome (TTS) is characterized by acute and transient dysfunction of the apical segment of the left ventricle. In recent years, there have been increasing numbers of case reports about TTS; however, it is still being neglected and misdiagnosed in many primary hospitals in China. We present a case of a 68-year-old female who presented to our hospital with one month of paroxysmal cough. Here severe cough would sometimes induce headache, chest pain, nausea, and vomiting. She had an unexplained cardiogenic shock approximately 4 months prior and gradually developed orthopnea. Cardiac biomarkers were mildly elevated, and electrocardiogram (ECG) displayed diffuse and deep T-waves inversion in leads I, II, AVL, and V2-V9, like acute myocardial infarction. However, coronary angiography was performed and showed the absence of obstructed coronary atherosclerosis or acute plaque rupture. The patient was successively treated in four hospitals and was eventually diagnosed with TTS in our hospital (the fourth hospital) due to noncardiogenic discomfort. Physicians at some primary hospitals require additional clinical experience to deeply understand TTS. Many doctors could learn about TTS from a medical textbook but remain unfamiliar with the disease. We hope that through analysis of this case, primary doctors will have a deeper understanding of TTS, avoid misdiagnosing the typical cases that occur in their patients.

Background Cystic fibrosis (CF) is a recessive condition caused by variants in each CF transmembrane conductance regulator (CFTR) allele. Clinically affected individuals without two identified causal variants typically have no further interrogation of CFTR beyond examination of coding regions, but the development of variant-specific CFTR-targeted treatments necessitates complete understanding of CFTR genotype. Methods Whole genome sequences were analyzed on 5,058 individuals with CF. We focused on the full CFTR gene sequence and identified disease-causing variants in three phases: screening for known and structural variants; discovery of novel loss-of-function variants; and investigation of remaining variants. Results All variants identified in the first two phases and coding region variants found in the third phase were interpreted according to CFTR2 or ACMG criteria (n = 371; 16 [4.3%] previously unreported). Full gene sequencing enabled delineation of 18 structural variants (large insertions or deletions), of which two were novel. Additional CFTR variants of uncertain effect were found in 76 F508del homozygotes and in 21 individuals with other combinations of CF-causing variants. Both causative variants were identified in 98.1% (n = 4,960) of subjects, an increase of 2.3 percentage points from the 95.8% (n = 4,847) who had a registry- or chart-reported disease-causing CFTR genotype. Of the remaining 98 individuals, 78 carried one variant that has been associated with CF (CF-causing [n = 70] or resulting in varying clinical consequences n = 8]). Conclusions Complete CFTR gene sequencing in 5,058 individuals with CF identified at least one DNA variant in 99.6% of the cohort that is targetable by current molecular or emerging gene-based therapeutic technologies.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

To study the prognostic features of Creutzfeldt-Jakob disease (CJD) and shed light on its future therapy.Retrospective cohort study of a longitudinal national cohort of the Taiwan Centers for Disease Control.All patients with suspected CJD are reported to the CJD surveillance unit of the Taiwan Centers for Disease Control. An expert committee discussed the reported cases and designated a consensus-based diagnosis. From 1996 to 2020, a total of 809 cases were referred to the CJD surveillance unit for confirmation; of these, 441 cases (women, n = 230) were determined to be sporadic CJD.We investigated the clinical manifestations and laboratory findings for 400 patients diagnosed with definite or probable sporadic CJD. We used Kaplan-Meier analyses and Cox proportional hazards model to identify prognostic factors.The mean age of onset was 67 ± 9.9 years. The mean survival duration was 13.3 ± 14.2 (median 10) months. The leading clinical symptoms were myoclonus (73%) and akinetic mutism (54%). For PRNP polymorphism, 99% of patients (195/197) showed a methionine homozygous genotype at codon 129 (M129M). The sensitivity of periodic sharp wave complexes (PSWCs) on electroencephalograms (EEGs) was 59.7%. The sensitivity of cerebrospinal fluid 14-3-3 protein and total tau protein (1200 pg/mL) were 69.7% and 75.6%, respectively. Younger patients lived longer than those aged ≥65 years [hazard ratio (HR) 0.466, P.001]. Women had a better survival probability in the first 3 years than their male counterparts (HR 0.712, P = .005). PSWCs had a persistent negative effect on survival (HR 0.788, P.05). Although uncommon, epileptic seizures were the only clinical prognostic factor for survival time (HR 0.768, P.05). PSWCs can be used as an EEG biomarker for prognosis. Epileptic seizures, though not common, are the only clinical prognostic factor for a short survival.We found that a lower age of onset and female gender favor the survival of patients with sCJD. PSWCs are EEG biomarkers unfavorable for survival, and so are epileptic seizures.

Cronobacter species are a group of Gram-negative opportunistic pathogens, which cause meningitis, septicemia, and necrotizing enterocolitis in neonates and infants, with neurological sequelae in severe cases. Interest in Cronobacter has increased significantly in recent years due to its high virulence in children. In this review, we summarize the current understanding of the prevalence of Cronobacter species in several important food types. We discuss the response mechanisms enabling persistence in adverse growth conditions, as well as its pathogenicity. We emphasize the food safety concerns caused by Cronobacter and subsequent control methods, and clinical treatments.

Gastric cancer is a global cancer with a high mortality rate. A growing number of studies have found the abnormal expression of lncRNA (long noncoding RNA) in many tumors, which plays a role in promoting or inhibiting cancer. Similarly, lncRNA abnormal expression plays an essential biological function in gastric cancer. This article focuses on lncRNA involvement in the development of gastric cancer in terms of cell cycle disorder, apoptosis inhibition, metabolic remodeling, promotion of tumor inflammation, immune escape, induction of angiogenesis, and Epithelial Mesenchymal Transition (EMT). The involvement of lncRNA in the development of gastric cancer is related to drug resistance, such as cisplatin and multi-drug resistance. It can also be used as a potential marker for the diagnosis and prognosis of gastric cancer and a target for the treatment. With an in-depth understanding of the mechanism of lncRNA in gastric cancer, new ideas for personalized treatment of gastric cancer are expected.

Chylothorax is an infrequent pleural effusion often caused by traumatic or nontraumatic injury to the thoracic duct. Nontraumatic chylothorax caused by chronic lymphocytic leukemia (CLL) is rarely reported. Previous experience has implied that the main factor affecting the treatment of chylothorax is whether the anti-cancer treatment is effective. The patient diagnosed with chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) before the hospital admission, and not received any treatment. After four months, he had progressive dyspnea. Chest computed tomography (CT) scan showed bilateral pleural effusion with progressive lymphadenopathy, and massive chylous pleural effusion was drained by closed thoracic drainage. After a course of chemotherapy including fludarabine, cyclophosphamide and rituximab (FCR), the patient developed agranulocytosis and his pleural effusion was still abundant. After careful consideration, the patient refused to receive following chemotherapy and chose to take ibrutinib orally. Two months after oral ibrutinib, ultrasound examination showed that pleural effusion completely disappeared. In the next one year, the patient had a routine follow-up and was in good condition. To our knowledge, this is the first report of ibrutinib in the treatment of chylothorax associated with CLL. Ibrutinib provides a more palliative treatment for elderly CLL patients with chylothorax.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

In this article, a three-dimensional detection framework for detecting non-small cell lung cancer (NSCLC) in 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) images and guided by a multi-modality attention fusion is proposed. A total of 250 18F-FDG PET/CT scans between January 1, 2015 and December 31, 2019 of patients who had histopathologically proven NSCLC were acquired. A customized dual-path 3D CenterNet is used for NSCLC detection. Moreover, we propose a multi-modality attention module that adaptively refines the multi-modality feature map fusion. Since the 3D convolutional neural network (CNN) requires many graphic memories and sliding windows, a 384×384×32 patch size is designed and used for training and testing. Five-fold cross-validation is applied for this study. The sensitivity and false positive per scan (FPPS) obtained by our proposed method are 0.96 and 1.04, respectively. Our method significantly outperforms 3D CenterNet in terms of sensitivity (P =.031). This module demonstrates the potential to be implemented in other multi-modality applications. Our result performs competitively against other lung cancer detections. Furthermore, case studies show that the proposed method can detect difficult-to-diagnose NSCLCs. Our result shows the proposed method can help radiologists and medical physicists diagnose NSCLC.

Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, cholesPt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of CholesPt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, CholesPt(IV)-Liposomes showed a small particle size (105.6 nm), the rapid release of platinum (Pt) ions, and notable apoptosis of cancer cells. In addition, according to the fluidity and safety results of animal experiments in mice, CholesPt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patient-derived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.

This regional 2-center study was designed 1) to analyze the clinical features of all patients with odontogenic orofacial infection as per type of visit, 2) to analyze the clinical features of diabetic patients compared with nondiabetic patients, and 3) to identify potential variables that may associate with long length of stay (LOS) of patients admitted for orofacial odontogenic infection in Northern Peninsular Malaysia.All adult patients with orofacial odontogenic infections who attended the Oral and Maxillofacial Department of Hospital Raja Permaisuri Bainun and Hospital Sultan Abdul Halim from March 2015 to February 2019 were included. Data on patients' demography, medical history, smoking status, clinical presentation, and LOS were collected. Multivariate logistic regression analysis was performed using the dichotomous dependent variable, namely, short LOS (LOS5 days) and long LOS (LOS ≥5 days).A total of 355 patients were reported with the mean age of 39.93 ± 15.95 years old. Multivariate analysis revealed that diabetes (adjusted odds ratio = 4.387, 95% confidence interval = 1.453 to 13.241, P value = .009) and multiple space involvement (adjusted odds ratio = 4.859, 95% confidence interval = 1.280, 18.454, P value = .020) were responsible for long LOS.Judicious treatment is recommended when treating patients of such infection that involves multiple spaces with underlying diabetes mellitus.

Abstract: Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.

Post-Refractive Surgery Ectasia is a serious, sight-threatening, and highly - avoided complication seen after the following procedures: Laser in situ Keratomileusis, Photorefractive Keratectomy, Small Incision Lenticule Extraction, Radial and/or Arcuate Keratotomy. Specific risk factors may include age, corneal thickness, degree of refractive error, corneal topographic changes including irregular astigmatism, percent tissue ablation, and residual stromal bed. Biomarkers may be a new option to help indicate who is at greatest risk for ectasia. Visual aids including glasses or contacts lenses are often required to achieve optimal vision. Collagen crosslinking is the only treatment thought to stop progression of ectasia and prevent keratoplasty. Other surgical options may include topography-guided phototherapeutic keratectomy and intrastromal corneal ring segments. Ultimately an "ounce of prevention is a pound of cure" so careful preoperative screening and ultimately offering the safest and most effective treatments for patients is arguably the most important job of the refractive surgeon.

Oral potentially malignant disorders (OPMD) are lesions that may precede the onset of cancers in the oral cavity, and oral submucosal fibrosis (OSF) is one of the OPMD that is usually found in the buccal mucosa. Considerable effort has been made to elucidate the pathogenesis of OSF, and emerging evidence has suggested that microRNAs may play significant roles in the development of OSF. Several studies demonstrated that aberrant expression of miRNAs is also observed in the fibrotic BMFs (fBMFs) derived from OSF tissues. For instance, it has been shown that miR-10b, miR-21, and miR-1246 are significantly elevated, and miR-29b, miR-200b, and miR-200c are reduced in fBMFs. This review systematically summarizes the current knowledge regarding the aberrant expression of microRNAs, molecular mechanisms underlying oral fibrogenesis by the dysregulated microRNAs, and how the interaction between microRNAs and long non-coding RNAs contributes to the progression of OSF. An overview of the modes of action by these microRNAs will provide a fundamental basis for clinical application.

To study the mechanism of Chinese herbal medicine Fuzheng Kang’ai Formula (扶正抗癌方, FZKA) on tumor microenvironment (TME). CIBERSORTx was used for analysis of TME. Traditional Chinese Medicine Systems Pharmacology and Analysis Platform was applied to identify compounds-targets network and the Cancer Genome Atlas (TCGA) was employed to identify the differential expression genes (DEGs) between tumor and paracancerous tissues in lung adenocarcinoma (LUAD) from TCGA-LUAD. Additionally, DEGs with prognosis in LUAD was calculated by univariable and multivariate Cox regression. The core targets of FZKA were analyzed in lung adenocarcinoma TME. Protein-protein interaction database was employed to predict down-stream of target. Quantitative reverse transcription polymerase chain reaction was employed for biological experiment in A549, H1299 and PC9 cell lines. The active and resting mast cells were significantly associated with prognosis of LUAD (P

This paper reports two new Cd(II)-based coordination polymers which are formulated as {[(CH3)2NH2][Cd(btc)]}n·n(DMF) (1) as well as [Cd3(btc)2(2-bpmh)(H2O)6]}n·3n(H2O) (2) (H3btc = 1,3,5-benzenetricarboxylic acid, 2-bpmh = N,N-bis-pyridin-2-ylmethylene-hydrazine) under the solvothermal reaction conditions, compounds 1–2 exhibit intense luminescence emission and excellent photocatalytic property for MB decomposition under the light irradiation of UV. For the children lobar pneumonia treatment, we use ELISA detection kits to determine the TNF-α and IL-1β levels released by the lung epithelial cells. In addition to this, we can also determine the NF-κB’s activation levels by real-time RT-PCR.

STUDY QUESTION Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION A total of 652 women of Chinese, Malay or Indian ethnicity 18–45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant’s pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51–0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55–0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56–1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S) This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov, NCT03531658.

This prospective non-randomized, multicenter clinical trial was performed to investigate efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 months in the TACE+131I-metuximab group (n = 160) and 3 months in the TACE group (n = 160) (hazard ratio, 0.55; 95% confidence interval, 0.43 to 0.70; P < 0.001). The median overall survival was 28 months in the TACE+131I-metuximab group and 19 months in the TACE group (hazard ratio, 0.62; 95% confidence interval, 0.47 to 0.82; P = 0.001). Conclusion: TACE+131I-metuximab showed a greater anti-recurrence benefit, significantly improved the 5-year survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

Background Cyclooxygenase-2 (COX-2) inhibitors are prescribed for the management of osteoarthritis (OA)-associated pain and inflammation. However, the role of COX-2 in normal and osteoarthritic articular chondrocytes has not been well investigated. We hypothesize that COX-2 plays a role in articular chondrocytes under normal conditions and during OA progression. Methods In vivo COX-2 levels in articular cartilage of normal and papain-induced osteoarthritic rats were compared. The role of COX-2 in human articular chondrocytes (HACs) was tested in vitro by COX-2 overexpression or activity inhibition. The levels of COX-2 and marker gene for normal function or articular cartilage degeneration were evaluated: mRNA by qRT-PCR; proteins by western blotting or immunohistochemistry; and glycosaminoglycan (GAG) by Safranin O–fast green staining. Parathyroid hormone-related protein (PTHrP) promoter activity was detected with luciferase reporter assays. Results In the OA rat study, COX-2 and PTHrP were simultaneously increased in osteoarthritic rat chondrocytes, while increased PTHrP levels were reduced by celecoxib, a COX-2 selective inhibitor. The levels of normal cartilage matrices, GAG and type II collagen decreased, while markers of degeneration, collagen type X and MMP13 were elevated in osteoarthritic articular chondrocytes. Celecoxib rescued the loss of GAG and the increased collagen type X and MMP13 levels. In vitro, COX-2 overexpression in HACs significantly increased Col2a1, Col10a1, PTHrP and MMP13 mRNA expression, which was decreased when COX-2 activity was suppressed. More importantly, COX-2 overexpression upregulated the PTHrP transcription, mRNA expression and protein levels. Conclusion COX-2 plays a pathophysiological role by preventing terminal differentiation of articular chondrocytes by upregulating PTHrP expression at the early stage of OA progression. The Translational potential of this article COX2 up-regulates PTHrP expression in normal and OA articular chondrocytes.

BackgroundInfertility is a widespread global challenge. Currently, the most effective treatment strategy for infertility is in vitro fertilization (IVF), which is an assisted reproductive technique (ART). The use of IVF for assisted pregnancy dates back to the last 41 years when the first IVF baby was born. During IVF, many oocytes are obtained in an IVF cycle, and more than one embryo is formed. Subsequently, frozen-thawed embryo transfer (FET) is increasingly being used in IVF cycles for women in whom a fresh embryo transfer fails to result in a pregnancy, or in those who return for a second baby. However, the pregnancy success rates following FET treatment cycles are reportedly lower than in fresh embryo transfers. Therefore, recent related studies are increasing determining mechanisms of improving the sustained pregnancy rate of FET and reducing the rate of early abortion.The Gushen’antai pill (GSATP), which contains a mixture of 10 herbs, has been widely used in traditional Chinese medicine (TCM) as a pharmacological option to prevent miscarriage. However, randomized controlled trials (RCT) have never been conducted to provide high-level clinical evidence on the clinical efficacy of GSATP. The objective of this study is to investigate the effect of GSATP of hormone therapy (HT) FET cycles on pregnancy rate.MethodsA total of 300 subjects aged between 18 and 40 years which prepared for HT cycle FET will be enrolled in the study. The patients were from five different hospitals, with 60 patients from each hospital. Patients were randomly divided into two groups, and medication was started on the day of endometrial transformation. After FET 28 days, B-ultrasound was done to determine whether to continue the medication. Baseline assessments were carried out before the trial and outcomes were collected 4, 6, 8, 10, and 12 weeks of each gestational cycle.DiscussionDifferences in ongoing pregnancy rate, clinical pregnancy rate, implantation rate, and threatened abortion rate between the two groups will be statistically analyzed. We can finally have an objective evaluation of the efficacy of the traditional Chinese medicine Gushen’antai pills.Trial registrationChiCTR1900026737. Registered October 20, 2019.

Elevated blood urea nitrogen to serum albumin (BUN/ALB) ratio had been identified as an independent risk factor related to mortality in community-acquired and hospital-acquired pneumonia. This study aimed to investigate whether this clinical index can predict the clinical outcomes of E. coli bacteraemia.Clinical data were collected from patients with E. coli bacteraemia attended at our hospital between January 2012 and December 2018. The endpoints were mortality within 30 days after the diagnosis of E. coli bacteraemia and intensive care (IC) requirement. Cox regression analysis was performed to evaluate the risk factors.A total of 398 patients with E. coli bacteraemia were enrolled in this study and 56 patients died within 30 days after bacteraemia onset. Multivariate Cox regression analysis showed that age greater than 65 years, lymphocyte count.8×10e9/L, elevated BUN/ALB ratio, increased SOFA score, carbapenem resistance, central venous catheterization before onset of bacteraemia, and infection originating from abdominal cavity were independent risk factors for 30-day mortality (P.05). The risk factors associated with IC requirement were similar to those for 30-day mortality except central venous catheterization before onset of bacteraemia. The area under the receiver-operating characteristic curve for BUN/ALB ratio predicting 30-day mortality and IC requirement was similar to that for SOFA score, but higher than that for lymphocyte count. The cut-off points of BUN/ALB ratio to predict 30-day mortality and IC requirement were both .3.BUN/ALB ratio is a simple but independent predictor of 30-day mortality and severity in E. coli bacteraemia. A higher BUN/ALB ratio at the onset of bacteraemia predicts a higher mortality rate and IC requirement.