CONSORT-Characteristics and metabolic phenotype of gut microbiota in NAFLD patients

Patients with nonalcoholic fatty liver disease (NAFLD) have symptoms of a gut microbiota disorder with abnormal amino acid and glycolipid metabolism. This study was designed to analyze the characteristics of gut microbiota in patients with NAFLD, predict the gut microbiota phenotype, explore its role in the diagnosis of NAFLD, and establish its significance in disease progression.The characteristics of the gut microbiota in NAFLD patients (n = 28, 45.8 ± 14.2 years, male/female = 18/10) and healthy subjects (n = 20, 49.6 ± 4.8 years, male/female = 14/6) during March–May 2020 were analyzed using 16S rRNA sequencing technology and the phenotypes with large differences were predicted using the Tax4Fun method. The metabolites in the fecal samples of the patients were analyzed using mass spectrometry, and their correlation with different microorganisms was examined. The accuracy of the gut microbiota in diagnosing NAFLD was investigated by receiver operating characteristic curve analysis.We found that the microbial diversity and Bacteroides/Firmicutes (BF) ratio changed significantly (P < .05) in the feces of NAFLD patients. Phenotypic prediction showed that there were significant differences in the phenotypes of amino acid, glucose, and lipid metabolism of gut microbiota in the NAFLD group (P < .05). receiver operating characteristic curve analysis revealed that combination of Bacteroides and the BF ratio resulted in 88% and 100% sensitivity and specificity, respectively, when used for NAFLD diagnosis. Metabolomics and bioinformatics analysis revealed changes in the metabolism of nicotinate, nicotinamide, and pyrimidine; signaling pathways of calcium and oxytocin; pancreatic secretion with metabolites such as uracil, xanthine, and biliverdin; and enzymes such as xanthine dehydrogenase and xanthine oxidase (P < .05).Therefore, the phenotypic changes may be a potential marker for NAFLD and we considered that a combined analysis of Bacteroides and BF ratio had good diagnostic accuracy for NAFLD.     

Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing: Case reports

Rationale:Congenital bile acid synthesis defect (BASD) is a rare disease caused by mutations in the aldo-keto reductase 1D1 gene, which encodes the primary Δ4-3-oxosteroid 5β-reductase enzyme. Early disease diagnosis is critical for early treatment with bile acid replacement therapy, with an excellent chance for recovery. In contrast, protracted diagnosis and treatment may lead to poor outcomes, including decompensated hepatic cirrhosis, liver transplant, and even death.Patient concerns:Three clinical congenital bile acid synthesis defect cases in the Vietnamese population are herein reported. These pediatric patients presented with symptoms of prolonged postpartum jaundice and abnormal loose stool (mucus, lipids, and white). The clinical examinations showed hepatosplenomegaly. Urinalysis showed a very low fraction of primary bile acids and atypical 3-oxo-Δ4- bile acids in all three patients.Diagnoses:The patients were diagnosed with primary Δ4-3-oxosteroid 5β-reductase deficiency. Next-generation gene sequencing revealed two homozygous mutations in the aldo-keto reductase family 1 member D1 gene. The first is a documented variant, c.797G>A (p.Arg266Gln), and the second is a novel mutation at c.155T>C (p.Ile52Thr).Interventions:Immediately after diagnosis, patients were treated with oral chenodeoxycholate 5 mg/kg/d.Outcomes:The patients’ symptoms, signs, and primary bile acids levels improved significantly.Lessons:Clinicians should consider genetic disorders related to cholestasis for effective and life-saving treatment. A prompt genetic analysis by next-generation gene sequencing enables patients to access bile acid replacement therapy earlier, significantly improving short- and long-term outcomes.     

Associations of blood pressure components with risks of cardiovascular events and all‐cause death in a Chinese population: A Prospective Study

The associations of blood pressure components with cardiovascular risks and death remain unclear, and the definition of wide pulse pressure (PP) is still controversial. Using data from 1257 participants without a history of cardiovascular disease, who were followed for 4.84 years, we performed multivariable Cox regression analyses to assess how systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP contribute to risks of cardiovascular events and all‐cause death. Among all participants, SBP and PP were significantly associated with the risks of cardiovascular events and all‐cause death (all p < .05). DBP was not significantly associated with the risk of all‐cause death; rather, it was only associated with a marginally significant 1% increased risk for cardiovascular events (p = 0.051). In participants aged < 65 years, DBP was significantly associated with a 3% increased risk for cardiovascular events (hazard ratio [HR]: 1.03, 95% confidence interval [95% CI]: 1.01–1.06). The association between PP and cardiovascular events appeared to be J‐shaped in comparison to participants with the lowest‐risk PP (50–60 mmHg), with adjusted HRs of 1.71 (95% CI: 1.03–2.85), 1.63 (95% CI: 1.00–2.68), and 2.13 (95% CI: 1.32–3.43) in the <50, 60.0–72.5, and ≥72.5 mmHg subgroups, respectively. The optimal cutoff points of a wide PP for predicting the risks of cardiovascular events and all‐cause death were 70.25 and 76.25 mmHg, respectively. SBP and PP had a greater effect on cardiovascular risk, whereas DBP independently influenced cardiovascular events in middle‐aged participants. Considerable PP alterations should be avoided in antihypertensive treatment.     

Development and evaluation of time‐resolved fluorescent immunochromatographic assay for quantitative detection of SARS‐CoV‐2 spike antigen

BackgroundThe spread of COVID‐19 worldwide caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has necessitated efficient, sensitive diagnostic methods to identify infected people. We report on the development of a rapid 15‐minute time‐resolved fluorescent (TRF) lateral flow immunochromatographic assay for the quantitative detection of the SARS‐CoV‐2 spike protein receptor‐binding domain (S1‐RBD).ObjectivesOur objective was to develop an efficient method of detecting SARS‐CoV‐2 within 15 min of sample collection.MethodsWe constructed and evaluated a portable, disposable lateral flow device, which detected the S1‐RBD protein directly in nasopharyngeal swab samples. The device emits a fluorescent signal in the presence of S1‐RBD, which can be captured by an automated TRF instrument.ResultsThe TRF lateral flow assay signal was linear from 0 to 20 ng/ml and demonstrated high accuracy and reproducibility. When evaluated with clinical nasopharyngeal swabs, the assay was performed at >80% sensitivity, >84% specificity, and > 82% accuracy for detection of the S1‐RBD antigen.ConclusionThe new S1‐RBD antigen test is a rapid (15 min), sensitive, and specific assay that requires minimal sample preparation. Critically, the assay correlated closely with PCR‐based methodology in nasopharyngeal swab samples, showing that the detected S1‐RBD antigen levels correlate with SARS‐CoV‐2 virus load. Therefore, the new TRF lateral flow test for S1‐RBD has potential application in point‐of‐care settings.     

Network pharmacology-based pharmacological mechanism prediction on Eucommia ulmoides against rheumatoid arthritis

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Eucommia ulmoides (EU) is a kidney-tonifying Chinese medicine that has been applied to treat RA for decides. The present study aims to explore pharmacological mechanisms of EU against RA using network pharmacology approach. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of EU, and their relative targets were fished from UniProt database. RA-related targets were screened from GeneCards database and DisGeNET database. The overlapping genes between EU and RA were identified by Venn diagram, and further analyzed for protein-protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Fifty active ingredients were identified in EU, and corresponded to 207 targets. Meanwhile, 499 targets were closely associated with RA development. A total of 50 overlapping genes between EU and RA were identified, which were regarded as therapeutically relevant. GO enrichment analysis indicated that EU exerted antiRA effects depending on regulating multiple biological processes including inflammatory response, oxidative stress, cell apoptosis and matrix catabolism. Several key pathways such as TNF pathway, IL-17 pathway, T cell receptor pathway, NOD-like receptor pathway and Toll-like receptor pathway, were involved in the above biological processes. Network pharmacology revealed that EU exerts therapeutic effects on RA through multi-ingredients, multi-targets and multi-pathways, which provides basis for its clinical application and promising directions for subsequent research.     

Catalytic N-methyl amidation of carboxylic acids under cooperative conditions

Amide is a fundamental group that is present in molecular structures of all domains of organic chemistry and the construction of this motif with high atom economy is the focus of the current research. Specifically, N-methyl amides are valuable building blocks in natural products and pharmaceutical science. Due to the volatile nature of methyl amine, the generation of N-methyl amides using simple acids with high atom economy is rare. Herein, we disclose an atom economic protocol to prepare this valuable motif under DABCO/Fe₃O₄ cooperative catalysis. This protocol is operationally simple and compatible with a range of aliphatic and (hetero)aromatic acids with very good yields (60–99%). Moreover, the Fe₃O₄ can be easily recovered and high efficiency is maintained for up to ten cycles.

The generation of N-methyl amides using simple acids with high atom economy is rare owning to the volatile nature of methyl amine. Herein, an atom economic protocol was disclosed to prepare this valuable motif under DABCO/Fe₃O₄ cooperative catalysis.

Amide is a fundamental group that is present in molecular structures of all domains of organic chemistry.¹ It is widely distributed in natural products, synthetic drugs and functional polymers, and is also the key chemical connection in proteins.² It has been shown that amide bond formation alone accounts for 65% of all preliminary screening reactions in the pharmaceutical industry.³ This means the generation of amide bonds with high atom efficiency is of high practical importance. And not surprisingly, ‘amide formation avoiding poor atom economy reagents’ was voted as the top challenge for organic chemistry by the ACS Green Chemistry Institute in 2007.³From synthetic point of view, the ideal way to produce amide bonds would be the direct coupling of readily available carboxylic acids and amines, but this process is thermodynamically unfavourable due to the formation of the corresponding carboxylate-ammonium salt,⁴ therefore, stoichiometric amount of coupling reagents, such as DCC, DIC, EDCI, HATU, HBTU, HCTU, SOCl₂, BOP, acid chloride etc, are generally required to sidestep thermal conditions for amide bond formation.⁵ These reagents are highly successful, but the process generally suffers from poor atom economy and side products removal issue especially in the large-scale applications.⁵ To overcome these drawbacks, “nonclassical” amide bonds formation routes were investigated.⁶ In these processes, the catalyst takes the role of a coupling reagent in generating an active ester suitable for amidation in a waste-free manner. However, these processes have not been applied in the preparation of N-methyl amides, probably because the methyl amine was delivered in its hydrochloride salt, alcoholic or aqueous form due to its volatile nature.On a different note, N-methyl amides are extensively presented in numerous natural products and pharmaceutical molecules, as shown in Fig. 1,⁷ and the methylation of amides is a promising way to improve the pharmacological property of molecules.⁸ However, the synthesis of N-methyl amides compounds relies heavily on non-catalytic approaches.^5,9 Catalytic approaches were also investigated by Hisaeda,¹⁰ Kundu,¹¹ Li,¹² Guo,¹³ Yu,¹⁴ Maruoka,¹⁵ Wang,¹⁶ Chen,¹⁷ Lamaty¹⁸ and their co-workers starting from nitriles, primiary amides, aldoximes, aldehydes, lignin, carbamoylsilane and alcohols. Until recently, Thakur,¹⁹ Marce,²⁰ Sadeghzadeh²¹ and their co-workers developed elegant N-methyl amidation approach starting from carboxylic acids under nano-MgO, diatomite Earth@IL/ZrCl₄ and Mg(NO₃)₂·6H₂O catalysis respectively, while limitations like poor substrate scope or sophisticated tailored catalyst still persist. Mindful of all the above issues, developing an N-methyl amidation process of simple carboxylic acids, which is still of great challenge in synthesis, and establishing a broad (hetero)aryl scope with high atom economy from commercial available reagents and catalysts were critical considerations in this study. Moreover, the significance of N-methyl amides combined with our interests in the development of green synthetic approaches motivated us to explore the direct coupling of the carboxylic acids and isothiocyanates. To the best of our knowledge, this is the first successful work using isothiocyanatomethane to prepare N-methyl amides.Open in a separate windowFig. 1Marketed drugs bearing N-methyl amide group.Our initial investigation begins with phenylacetic acid and isothiocyanatomethane as model substrate for condition optimization. Using acetonitrile as solvent, only trace amount of product was detected under catalyst free or p-toluenesulfonic acid (PTSA) catalysis conditions (

多学科康复小组及分级运动对ICU机械通气患者术后康复的影响

目的 探讨多学科康复小组及分级运动对重症监护病房（ICU）机械通气患者术后康复的影响。方法 前瞻性选取2020年6月～2021年5月首都医科大学附属北京朝阳医院收治的174例患者,按随机数表法分为观察组与对照组,各87例。对照组患者给予常规治疗,在病情稳定后进行常规康复训练;观察组患者在对照组基础上组建多学科康复小组并对患者采取分级运动方式进行康复训练。结果 观察组机械通气时间、ICU住院时间、总住院时间显著少于对照组,差异有统计学意义（P <0.05）;两组干预后MRC评分、FIM评分、MBI评分显著高于干预前,且观察组显著高于对照组,差异有统计学意义（P <0.05）;两组干预后CD4+、CD4+/CD8+显著高于干预前,CD8+显著低于干预前,且观察组干预后CD4+、CD4+/CD8+显著高于对照组,CD8+显著低于对照组,差异有统计学意义（P <0.05）;观察组ICU获得性肌无力发生率及总发生率显著低于对照组,差异有统计学意义（P <0.05）。结论 多学科康复小组及分级运动可降低ICU机械通气患者发生获得性肌无力的风险。     

理气通便方对功能性便秘气滞证大鼠脑肠肽的影响

目的 探讨理气通便方治疗功能性便秘的机制.方法 采用复方地芬诺酯灌胃及夹尾激怒法构建功能性便秘气滞证大鼠模型.按照随机数字表法将48只雌雄各半大鼠分为空白组、模型组、莫沙必利组(2 mg/kg)、理气通便方低剂量组(5.15 g/kg)、理气通便方中剂量组(10.3 g/kg)、理气通便方高剂量组(20.6 g/kg)...     

维生素D对妊娠糖尿病患者血清25(OH)D3、脂肪因子及C反应蛋白水平的影响

目的 分析维生素D对妊娠糖尿病(GDM)患者血清25-羟基维生素D3[25(O H)D3]、脂联素、内脂素和瘦素3种脂肪因子及C反应蛋白(CRP)水平的影响.方法 选取2017年6月至2019年6月南京市中西医结合医院收治的90例GDM患者为研究对象,按照随机数字表法分为试验组和对照组,每组45例.对照组皮下注射门冬胰...     

A Novel Model of Ultrasonic Fatigue Test in Pure Bending

The very high cycle fatigue (VHCF) failure of in-service components is mainly caused by the vibration of thin-wall elements at a high frequency. In this work, a novel model of ultrasonic fatigue test was developed to test thin-wall material in bending up to VHCF with an accelerated frequency. The theoretical principle and finite element analysis were introduced for designing a sample that resonated at the frequency of 20 kHz in flexural vibration. In the advantage of the second-order flexural vibration, the gauge section of the sample was in the pure bending condition which prevented the intricate stress condition for thin-wall material as in the root of cantilever or the contact point of three points bending. Moreover, combining the constraint and the loading contact in one small section significantly reduced heating that originated from the friction at an ultrasonic frequency. Both strain gauge and deflection angle methods were applied to verify the controlling of stress amplitude. The fractography observation on Ti6Al4V samples indicated that the characterized fracture obtained from the novel model was the same as that from the conventional bending test.