Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS: Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS: Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION: Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.

Rabies vaccination adherence and associated factors among rabies-exposed patients in Shenzhen, China: a hospital-based cross-sectional study.

Adherence to post-exposure prophylaxis and post-exposure vaccination (PEV) is an important measure to prevent rabies. The purpose of this study was to explore the adherence to the vaccination protocol and its influencing factors among rabies-exposed patients in Shenzhen, China. A cross-sectional survey was conducted in a tertiary hospital in Shenzhen, China, to obtain epidemiological characteristics of patients; knowledge, attitude, and practice scores of rabies prevention; and medical records. A total of 326 patients requiring full rabies PEV were included in this study, and only 62% (202) completed the full course of vaccination according to the norms of the vaccination guidelines. After multifactor logistic regression, the factors influencing adherence to vaccination were as follows: age 31 to 40 years, time spent to reach the nearest rabies prevention clinic was >60 min, the time of injury was at night to early morning, the place of injury was a school/laboratory, the animal causing injury was a cat, the health status of the animal causing injury could not be determined, and patients with higher practice scores (all p<0.05). Understanding the factors influencing rabies vaccination adherence among rabies-exposed patients in urban areas of China and promote changes in patients' practice toward rabies prevention is essential for rabies elimination by 2030.

Role of Trace Cadmium Exposure on the Development of Occlusal Traumatic Temporomandibular Arthritis.

OBJECTIVE: To investigate whether heavy metal cadmium acts as a risk factor for temporomandibular joint disorder disease and to study its pathogenic mechanism. METHODS: A total of 57 rats were allocated into 6 distinct groups, distinguished by 2 interventions: occlusal elevation and cadmium water gavage. These groups included a blank control group, occlusal elevation group, occlusal elevation + 0.42 mg/mL cadmium water gavage group, occlusal elevation + 4.2 mg/mL cadmium water gavage group, no occlusal elevation + 0.42 mg/mL cadmium water gavage group, and no occlusal elevation + 4.2 mg/mL cadmium water gavage group. The impact of cadmium exposure on cartilage oxidative stress was evaluated through the assessment of SOD, CAT, GST, and GSH-Px enzyme activities. In addition, the influence of cadmium exposure on alterations in the extracellular matrix and inflammatory mediators was examined by analyzing the expression levels of type II collagen, protein aggregation polysaccharide, glycosaminoglycan, IL1ß, IL-6, and TNF-α. Histologic examination of the condylar process cartilage of rats in the occlusal elevation + cadmium water gavage group was conducted to ascertain the occurrence of osteoarthritis. RESULTS: The variance in the expression levels of inflammatory factors did not demonstrate statistical significance between the occlusal elevation group and the blank control group; however, statistical significance was observed between the occlusal elevation + cadmium water gavage group and both the control and occlusal elevation groups. CONCLUSION: The severity of inflammation and condylar lesions correlates directly with the concentration of cadmium.

5G-Based Remote Virtual Bronchoscopic Navigation-Guided Transbronchial Lung Biopsy for Diagnosis of Lung Cancer: Description of 2 Cases.

INTRODUCTION: Bronchoscopic navigation combined with endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) is an important approach for the diagnosis of peripheral pulmonary lesions (PPL). The fifth-generation (5G) network, characterized by low latency and high stability, has shown promising possibilities in telemedicine for remote areas. METHODS: We present two cases of PPL in primary hospitals without navigation equipment. The EBUS-TBLB was performed with the guidance of remote augmented reality virtual bronchoscopic navigation (VBN) based on a 5G network. In practice, the 5G network could enable the matching of actual/virtual bronchoscopic images and navigation paths in real time, as well as high-speed transmission at long distances (>20 km), without any visual delay (<500 ms). CONCLUSION: Both patients were successfully diagnosed with lung cancer after accurate positioning and obtaining biopsies of target lesions. This 5G-based remote VBN-guided EBUS-TBLB appears to be safe with reliable connections in both cases and shows potential for cost-effectiveness. It would be an optimal resource for undeveloped regions and/or regions lacking endoscopists with extensive experience in navigation-related procedures.

The Novel Application of Robotic-Assisted Bronchoscopy Combined with Photodynamic Therapy for Adenoid Cystic Carcinoma of the Trachea.

Robotic platforms have been widely used in the various fields of clinical diagnosis and therapy of diseases in the past decade. Robotic-assisted bronchoscopy (RAB) demonstrates its advantages of visibility, flexibility, and stability in comparison to conventional bronchoscopic techniques. Improving diagnostic yield and navigation yield for peripheral pulmonary lesions has been defined; however, RAB platform of treatment was not reported. In this article, we report a case of a 52-year-old woman who was diagnosed with the tracheal adenoid cystic carcinoma and recurred in the second postoperative year, leading to the involvement of the entire tracheal wall and lumen obstruction. Since the lesion was inoperable, we combined RAB and photodynamic therapy (PDT) for the patient. The potential advantages of using RAB for PDT delivery include precise light irradiation of target lesions and stable intra-operative control over the long term. This is a novel application of RAB combined with PDT for airway diseases. The case report may provide a new insight into the diagnosis and treatment of pulmonary diseases. In addition to improving the diagnostic rates, the RAB platform may also play an important role in the treatment of airway and lung disease in the future.

Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions.

RATIONALE: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2 ) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. METHODS: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2 . Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. RESULTS: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2 H3 O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. CONCLUSIONS: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.

Structure Elucidation and Mechanistic Study of a New Dimeric Degradant in Ropinirole Hydrochloride Extended-Release Tablets.

PURPOSE: The goal of the study was to elucidate the structure of a new degradant (1,3'-Dimer), generated in the stability testing of ropinirole extended-release tablets, and the formation mechanism of 1,3'-Dimer and its isomer (3,3'-Dimer). METHODS: The strategy of combining LC-PDA/UV-MSn (n = 1, 2) and NMR in conjunction with mechanism-based forced degradation study was employed to identify the structure of the unknown degradant and the formation mechanism of this dimeric degradant as well as its isomer, 3,3'-Dimer. The forced degradation was conducted by treating ropinirole API with formaldehyde under alkaline catalysis. A compatibility study between ropinirole and lactose was also performed. RESULTS: The degradant was isolated from the forced degradation sample and characterized by LC-PDA/UV-MSn as well as NMR measurement. The impurity was identified as a new dimeric degradant of ropinirole connected by a methylene bridge via the 1- and 3'-position of each ropinirole unit (i.e., 1,3'-Dimer of ropinirole), which is an isomer of a known dimeric degradant of ropinirole, namely 3,3'-Dimer. CONCLUSIONS: The newly occurred unknown degradant in ropinirole extended-release tablets was elucidated as the methylene-bridged 1,3'-Dimer of ropinirole. Based on the mechanistic study, 1,3'-Dimer and its isomer (3,3'-Dimer) were both formed by the reaction of ropinirole with residual formaldehyde present or formed in lactose, a main excipient of the formulation.

Identification of Cyt2Ba from a New Strain of Bacillus thuringiensis and Its Toxicity in Bradysia difformis.

Bradysia difformis is one of the most damaging pests in mushroom production in China. In this study, eight Bacillus thuringiensis strains were analyzed for insecticidal activity in B. difformis. The strain JW-1 showed the highest insecticidal activity against B. difformis larvae, but did not inhibit the mycelial growth of Pleurotus ostreatus and P. geesteranus. The 16S rRNA gene (1397 bp) and cyt2 gene (792 bp) were obtained from strain JW-1. The phylogenetic tree based on 16S rRNA gene and Cyt2 toxin showed that strain JW-1 was a member of B. thuringiensis and Cyt2 toxin belonged to Cyt2Ba toxin cluster. The Cyt2Ba toxin from strain JW-1 was overexpressed in E. coli as a fusion protein and the fusion protein (70 kDa) was purified by Ni-IDA affinity chromatography. The purified Cyt2Ba fusion protein was toxic to B. difformis larvae (LC50 was 2.25 ng/mL). The identification of Cyt2Ba from strain JW-1 and confirmation of the insecticidal activity of Cyt2Ba in B. difformis provided a new means of biological control of the important pest in mushroom production.

Os(II) phosphors with near-infrared emission induced by ligand-to-ligand charge transfer transition.

Heating of Os3(CO)12 with 6 equiv of 2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) pyridine (fptzH) in refluxing diethylene glycol monomethyl ether, followed by sequential treatment with stoichiometric Me3NO and addition of PPhMe2, afforded two isomeric mixtures of red-emitting [Os(fptz)2(PPhMe2)2] (1T and 1C), for which the notations T and C stand for the trans and cis-oriented fptz chelates, respectively. Alternatively, preparation of Os(II) complex using a 1:1 mixture of 5,5'-di(trifluoromethyl)-3,3'-di-1,2,4-triazole (dttzH2) and 2,2'-bipyridine (bpy), instead of fptzH, gave isolation of a mononuclear Os(II) complex [Os(bpy)(dttz)(CO)2] (2) in moderate yield. Replacement of CO with PPhMe2 on 2 afforded near-infrared (NIR)-emitting Os(II) complex [Os(bpy)(dttz)(PPhMe2)2] (3). The single-crystal X-ray structural analyses were executed on 1C, 2, and 3 to reveal the structural influence imposed by the various chelates. The photophysical and electrochemical properties were measured and discussed using the results of density functional theory (DFT) and time-dependent DFT calculations. Complex 3 is selected as the dopant to probe its electroluminescent properties by fabrication of the NIR emitting organic light-emitting diodes.

Effects of 60Coγ-irradiation combined with sodium dehydrogenate on post-harvest preservation and physiological indices of Volvariella volvacea.

Volvariella volvacea is a mushroom known for its high palatability and nutritional value. However, it is susceptible to spoilage thus making it challenging to preserve and keep fresh after harvest, resulting in constraints in long-distance transportation and long-term storage. This study aimed to investigate the feasibility of using irradiation and sodium dehydrogenate (SD) as a preservative in the preservation process of V. volvacea. The effects of three treatments of 0.8 kGy 60Coγ irradiation (B), 0.04% SD (C), combined with 0.04% SD and 0.8 kGy 60Coγ irradiation (A) on the postharvest freshness of V. volvacea were investigated. The assessment indices for V. volvacea, including appearance, browning rate, weight loss, respiration rate, MDA content, antioxidant enzyme activities, vitamin C (Vc), and soluble protein content, were measured and compared. The three treatments were compared to determine the changes in storage time over 7 days post-harvest. The results demonstrated that the hardness of the fruiting body exhibited a significant increase of 81.19%, 97.96% and 168.81% in comparison to the control, B and C, respectively, following the application of the treatment A. Compared to the control group, the soluble protein content was significantly increased by 20.28%. Respiration intensity and browning rate were significantly lower in the control treatment, decreasing by 35.07% and 45.49% respectively. On the 6th day of storage, the activities of SOD and POD increased by 81.06% and 73.71%, respectively, compared to the control, which significantly delayed the senescence of the fruiting bodies. The Vc content was significantly increased by 50.27%, 133.90%, and 101.39% in treatment B, which received 0.8 kGy 60Coγ irradiation alone, compared to the control, treatment A, and treatment C, respectively. The treatment C alone significantly reduced respiratory intensity and MDA variables by 39.55% and 31.01%, respectively, compared to the control. The findings can provide theoretical references and technical support for extending the preservation period of V. volvacea after harvesting by using irradiation and sodium dehydrogenate as a preservative.

Imaging features and deep learning for prediction of pulmonary epithelioid hemangioendothelioma in CT images.

Background: Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumour, and its early diagnosis remains challenging. This study aims to comprehensively analyse the imaging features of PEH and develop a model for predicting PEH. Methods: Retrospective and pooled analyses of imaging findings were performed in PEH patients at our center (n=25) and in published cases (n=71), respectively. Relevant computed tomography (CT) images were extracted and used to build a deep learning model for PEH identification and differentiation from other diseases. Results: In this study, bilateral multiple nodules/masses (n=19) appeared to be more common with most nodules less than 2 cm. In addition to the common types and features, the pattern of mixed type (n=4) and isolated nodules (n=4), punctate calcifications (5/25) and lymph node enlargement were also observed (10/25). The presence of pleural effusion is associated with a poor prognosis in PEH. The deep learning model, with an area under the receiver operating characteristic curve (AUC) of 0.71 [95% confidence interval (CI): 0.69-0.72], has a differentiation accuracy of 100% and 74% for the training and test sets respectively. Conclusions: This study confirmed the heterogeneity of the imaging findings in PEH and showed several previously undescribed types and features. The current deep learning model based on CT has potential for clinical application and needs to be further explored in the future.

Treatment of progressive ischemic stroke with low­dose eptifibatide: A retrospective case­control study.

Progressive ischemic stroke (PIS) is a therapeutic challenge in clinical practice. The present retrospective study aimed to investigate the safety and effectiveness of eptifibatide in the treatment of PIS. The present study enrolled patients with PIS admitted to Xiangtan Central Hospital (Xiangtan, China) between March 2020 and March 2021 with National Institutes of Health Stroke Scale (NIHSS) progression scores of ≥2 points during the initial 72 h. Patients were then divided into two groups according to their different anti-platelet treatment regimens. The control group was administered anti-platelet aggregation with aspirin 100 mg/day, or aspirin 100 mg/day in combination with clopidogrel 75 mg/day, whilst eptifibatide was administered in the eptifibatide group in addition to the treatment regimen used in the control group. Changes in NIHSS scores at the time of progression and 7 days after treatment (∆NIHSS) were used to assess early neurological recovery, and there were no significant differences in ∆NIHSS and adverse reactions between the groups (P>0.05). Subgroup analysis was subsequently performed according to the type of blood vessel that was involved [large artery atherosclerosis (LAA) or small artery occlusion (SAO)]. For the SAO subgroup, the ∆NIHSS in the eptifibatide group was significantly superior to that of the control group (P=0.008), while for the LAA subgroup, there were no significant differences in ∆NIHSS between groups (P=0.334). The present retrospective study found that patients with PIS tolerated eptifibatide treatment well. Eptifibatide exerted different effects on patients with acute PIS involving different types of blood vessels compared with oral antiplatelet drugs. In addition, application of eptifibatide may lead to faster and earlier recovery in patients with SAO, but not in those with LAA. Low-dose eptifibatide is a safe and effective treatment option for patients with PIS caused by SAO.

Forced degradation studies of elagolix sodium with the implementation of high resolution LC-UV-PDA-MSn (n = 1,2,3 ) and NMR structural elucidation.

Elagolix sodium (ELS) is a marketed product using to release moderate to severe endometriosis-associated pain. It contains functional groups such as carboxyl group, secondary amino group, 2,4-dioxo pyrimidinyl and several benzyl or benzyl-like position hydrogen atom that are susceptive to occur stress degradation. Forced degradation studies of ELS reveal different degradation profiles of the drug substance which are conducted under photo, thermal, acidic, neutral, alkaline and hydrogen peroxide oxidative conditions in the direction of the ICH guidances. With structural elucidation of LC-PDA/UV-MSn and NMR, the degradants were identified, and seven new degradants are reported in this study. It is confirmed that most of the degradation behaviors of ELS are related to the carboxyl group and secondary amino group in the 3-carboxyl propylamine side chain. Under the oxidative condition using hydrogen peroxide as the oxidant, the secondary amine was oxidized to form an N-hydrogen amine degradant and two further degradants of amine and carbonyl analogs were generated. Under the alkaline degradation condition, the ELS is proven to be stable and no obvious degradants are produced. On the other hand, under the acidic and neutral degradation condition, the 2,4-dioxo pyrimidinyl core of elagolix sodium is stable but the carboxyl group and secondary amine will occur ring cyclization to form the δ-lactam analogs of elagolix sodium. The plausible mechanisms for the degradation of acidic, thermal, photo-degradative and hydrogen peroxide mediated oxidative of elagolix sodium are proposed. It is worth to note that DP-3-4 are the potential degradants which are only found in the solution degradation and are not the real impurities of elagolix sodium.

Investigation of nirmatrelvir epimerization occurred in analytical sample solution by using high resolution LC-MSn, NMR, and hydrogen/deuterium exchange study.

During the related substances testing of nirmatrelvir, an unknown peak was observed and the level of the peak increased over time during the storage of the sample solution. By using a strategy including LC-PDA/UV-MSn analysis, the degradant was rapidly identified as an epimer of nirmatrelvir, a solution degradation product that is caused by the trace amount of alkaline impurities leaching from the glass HPLC vials. In addition, by using hydrogen/deuterium exchange NMR spectroscopy analysis, the epimerization position was determined to be the carbon α to the adjacent cyano group. Further investigation indicated that the occurrence of the solution degradation can be suppressed when the glass HPLC vials were replaced by plastic HPLC or mass spectrometric grade vials.

Risk factors and prognosis of airway complications in lung transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Airway complications (AC) are one of leading causes of morbidity and mortality after lung transplant (LTx), but their predictors and outcomes remain controversial. This study aimed to identify potential risk factors and prognosis of AC. METHODS: A systematic review was performed by searching PubMed, Embase, and Cochrane Library. All observational studies reporting outcome and potential factors of AC after LTx were included. The incidence, mortality, and estimated effect of each factor for AC were pooled by using the fixed-effects model or random-effects model. RESULTS: Thirty-eight eligible studies with 52,116 patients undergoing LTx were included for meta-analysis. The pooled incidence of AC was 12.4% (95% confidence interval [CI] 9.5-15.8) and the mean time of occurrence was 95.6 days. AC-related mortality rates at 30-days, 90-days, 6 months, 1 year, and 5 years were 6.7%, 17.9%, 18.2%, 23.6%, and 66.0%, respectively. Airway dehiscence was the most severe type with a high mortality at 30 days (60.9%, 95% CI 20.6-95.2). We found that AC was associated with a higher risk of mortality in LTx recipients (hazard ratio [HR] 1.71, 95% CI 1.04-2.81). Eleven significant predictors for AC were also identified, including male donor, male recipient, diagnosis of COPD, hospitalization, early rejection, postoperative infection, extracorporeal membrane oxygenation, mechanical ventilation, telescopic anastomosis, and bilateral and right-sided LTx. CONCLUSION: AC was significantly associated with higher mortality after LTx, especially for dehiscence. Targeted prophylaxis for modifiable factors and enhanced early bronchoscopy surveillance after LTx may improve the disease burden of AC.

Imaging features and clinical value of 18F-FDG PET/CT for predicting airway involvement in patients with relapsing polychondritis.

BACKGROUND: The clinical value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in assessing relapsing polychondritis (RP) with airway involvement remains controversial. This study aimed to investigate PET/CT features of RP with airway involvement and explore its clinical value in predicting disease pattern, severity and prognosis. METHODS: RP patients with airway involvement who underwent PET/CT from January 2010 to July 2022 were retrospectively reviewed. PET/CT features were analyzed both visually and semiquantitatively with the maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG). Patterns of airway involvement on PET were summarized. Correlations of SUVmax and TLG of the airway were made with spirometric indicators and serological inflammatory markers (CRP and ESR). In addition, long-term follow-up was conducted through questionnaires in regard to symptom control, subjective feeling, pulmonary function, and quality of life. RESULTS: Fifty-two cases were finally included. 18F-FDG PET showed FDG-avid lesions with increased FDG uptake in the airway among 94.2% of the patients. Three patterns (focal, multifocal and diffuse patterns) were identified. TLG of the whole airway was lower in patients with previous therapy (p = 0.046). Bronchoscopy was more sensitive in detecting tracheal abnormalities (90.7% vs.53.5%, p = 0.039) but less sensitive for peripheral airway lesions (65.1% vs. 79.1%, p = 0.046) compared with PET. SUVmax and TLG of the airway positively correlated with spirometry indicators (FEV1%pred, FEV1/FVC, MEF 50%pred, etc.) and serological inflammatory markers. Five patients died during the follow-up, with two deaths related to airway problems. Higher FDG uptake predicted worse subjective feeling, but not with symptom control or pulmonary function. CONCLUSION: PET/CT is a valuable tool for RP with airway involvement, particularly in assessing peripheral airway lesions, and PET/CT related parameters are significantly associated with disease patterns, severity, and long-term outcomes.

Age and Sex Affect Essential Tremor (ET) Plus: Clinical Heterogeneity in ET Based on the National Survey in China.

The new term essential tremor (ET) plus was proposed in the 2018 tremor consensus criteria. The National Survey of Essential Tremor Plus in China, a large multicenter registry study, aimed to evaluate the clinical features of pure ET and ET plus and explore possible factors related to ET plus. All patients with ET underwent neurological examination and neuropsychological assessment at 17 clinical sites. The diagnosis was made according to the 2018 consensus criteria. Clinicodemographic characteristics were analyzed. A total of 1160 patients were included, including 546 patients with pure ET and 614 patients with ET plus. The proportion of females was significantly higher in the ET plus than that in the pure ET (P = 0.001). The age at onset (AAO) of pure ET showed a bimodal distribution, with peaks in the 2nd and 5th decades. However, the AAO of the ET plus group demonstrated a skewed distribution, with a single peak in the 6th decade. Female sex (OR=1.645, P<0.001), older age (OR=1.023, P<0.001), lower educational level (OR=0.934, P<0.001), head tremor (OR=1.457, P<0.001), and higher the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-II scores (OR=1.134, P<0.001) were significantly associated with ET plus. Old age and female sex may contribute to ET plus development. Pure ET showed a bimodal distribution for AAO, whereas ET plus showed a unimodal distribution. It remains unclear whether pure ET and ET plus are merely different stages of a single disease or represent distinct disease entities.

Myocardial infarction and stroke risks in multiple sclerosis patients: A two-sample Mendelian randomization study.

Observational studies indicated multiple sclerosis (MS) patients may have a higher risk of myocardial infarction (MI) and stroke than the general population, whereas the previously reported findings were inconsistent. Using two-sample Mendelian randomization (MR) analysis with genetic data from large-scale genome-wide association studies (International Multiple Sclerosis Genetics Consortium containing 14,498 MS cases, Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics consortium containing 43,676 MI cases and 40,585 stroke cases), we found that MS was causally associated with an increased risk of MI (OR = 1.03; 95%CI 1.00-1.06; P = 0.0243), directionally consistent in the weighted median, MR-Egger, and the MR-PRESSO methods. No causal association between MS and stroke was observed (OR = 1.01; 95%CI 0.99-1.04; P = 0.2974). Therefore, timelier and more effective measures should be conducted among MS patients to decrease the burden of both diseases.

Investigation of an artificial solution degradant of linagliptin: An undesired linagliptin urea derivative generates in sample preparation of linagliptin tablet treated by sonication in acetonitrile containing diluent.

During the related substances testing method development for linagliptin tablet, an unknown peak was observed in HPLC chromatograms with a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as linagliptin urea, a solution degradant that is caused by the reaction between the API and hydrocyanic acid with sonication treatment to accelerate dissolution of the drug substance in sample preparation of linagliptin tablets, and hydrocyanic acid is a known impurity in HPLC grade acetonitrile and acetonitrile is used as part of diluent. The mechanism of the solution degradation chemistry was verified by stressing linagliptin API with trimethylsilyl cyanide (TMSCN, which can give off HCN slowly in the presence of water) treated with sonication in the sample preparation. Further investigation found that when the sonication treatment was replaced by vortex vibration in the process of the sample preparation, the RRT 1.28 species was decreased to below the level of the detection limit (0.02%). The structure of this impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the presence of trace amount of HCN in HPLC grade acetonitrile, these types of solution degradation would likely occur in analysis of pharmaceutical finished products containing APIs with primary and secondary amine moieties drug product during sample preparations, particularly when sonication treatment is used to accelerate dissolution of drug substance from the finished drug product. In the GMP quality control laboratories, such events may trigger undesirable out-of-specification (OOS) events. Hence, the results of this paper can help to prevent these events from happening in the first place or resolve these OOS events in GMP laboratories.

Activation of mycelial defense mechanisms in the oyster mushroom Pleurotus ostreatus induced by Tyrophagus putrescentiae.

Fungal chemicals are vital in processes recognizing damage- and microbe-associated molecules (DAMPs/MAMPs) that trigger defense responses in fungi. Pleurotus ostreatus is a widely cultivated edible fungus that is prone to attack from fungivorous insects and mites. Yet P. ostreatus has evolved an elegant defense system against fungivore attacks. In this study, we investigated how the oyster mushroom responds to the fungivory and mechanical wounding by conducting transcriptome, proteome, and secondary metabolic analyses. The profiling analysis revealed a total of 11,495 transcripts and 866 proteins, 4416 differentially expressed genes (DEGs), and 62 differentially expressed proteins (DEPs) were identified in response to the mite Tyrophagus putrescentiae feeding and mechanical wounding. In comparing the responses induced by mechanical wounding, some genes, proteins, and metabolites were uniquely induced or repressed by the mite. At the transcript level, nine pathways were activated by the mite feeding, including those of "MAPK signaling pathway-yeast", "Phenylalanine metabolism", and "Biotin metabolism", among others, while both enrichment of "Ribosome", "Ribosome biogenesis in eukaryotes", and "Regulation of Mitophagy in Yeast" demonstrated the common effects upon fungal secretory protein synthesis and processing induced by fungivory and mechanical wounding. Fungivory also stimulated the synthesis of C8-aryl compounds and sesquiterpenes (especially1-octen-3-ol and α-/ß-bisabolene), and these compounds repellent to T. putrescentiae. Both jasmonic acid (JA) and jasmonic acid methyl ester (MeJA) were specifically regulated by mite feeding and mechanical wounding. The terpene synthase gene transcription was significantly increased induced by the exogenous addition of MeJA, resulting in defensive sesquiterpene production against the mite. These findings are the first to demonstrate that the reactive oxygen species (ROS)/MAPK signaling pathway, JA regulation, specific gene expression, and protein synthesis, and anti-mite substance metabolism are all involved in coordinated inducible chemical-based defense responses in P. ostreatus, which could be especially effective the mite T. putrescentiae.