Flexible molecular crystals for optoelectronic applications.

The cornerstones of the advancement of flexible optoelectronics are the design, preparation, and utilization of novel materials with favorable mechanical and advanced optoelectronic properties. Molecular crystalline materials have emerged as a class of underexplored yet promising materials due to the reduced grain boundaries and defects anticipated to provide enhanced photoelectric characteristics. An inherent drawback that has precluded wider implementation of molecular crystals thus far, however, has been their brittleness, which renders them incapable of ensuring mechanical compliance required for even simple elastic or plastic deformation of the device. It is perplexing that despite a plethora of reports that have in the meantime become available underpinning the flexibility of molecular crystals, the "discovery" of elastically or plastically deformable crystals remains limited to cases of serendipitous and laborious trial-and-error approaches, a situation that calls for a systematic and thorough assessment of these properties and their correlation with the structure. This review provides a comprehensive and concise overview of the current understanding of the origins of crystal flexibility, the working mechanisms of deformations such as plastic and elastic bending behaviors, and insights into the examples of flexible molecular crystals, specifically concerning photoelectronic changes that occur in deformed crystals. We hope this summary will provide a reference for future experimental and computational efforts with flexible molecular crystals aimed towards improving their mechanical behavior and optoelectronic properties, ultimately intending to advance the flexible optoelectronic technology.

Dion-Jacobson Type Lead-Free Double Perovskite with Ultra-Narrow Aromatic Interlayer Spacing for Highly Sensitive and Stable X-ray Detection.

The low-toxic and environmentally friendly 2D lead-free perovskite has made significant progress in the exploration of "green" X-ray detectors. However, the gap in detection performance between them and their lead-based analogues remains a matter of concern that cannot be ignored. To reduce this gap, shortening the interlayer spacing to accelerate the migration and collection of X-ray carriers is a promising strategy. Herein, a Dion-Jacobson (DJ) lead-free double perovskite (4-AP)2 AgBiBr8 (1, 4-AP = 4-amidinopyridine) with an ultra-narrow interlayer spacing of 3.0 Å, is constructed by utilizing π-conjugated aromatic spacers. Strikingly, the subsequent enhanced carrier transport and increased crystal density lead to X-ray detectors based on bulk single crystals of 1 with a high sensitivity of 1117.3 µC Gy-1  cm-2 , superior to the vast majority of similar double perovskites. In particular, the tight connection of the inorganic layers by the divalent cations enhances structural rigidity and stability, further endowing 1 detector with ultralow dark current drift (3.06 × 10-8  nA cm-1  s-1  V-1 , 80 V), excellent multiple cycles switching X-ray irradiation stability, as well as long-term environmental stability (maintains over 94% photoresponse after 90 days). This work brings lead-free double perovskites one step closer to realizing efficient practical green applications.

Association of CTACK, IL-2, and IL-13 with increased risk of lung cancer: A Mendelian randomization study.

BACKGROUND: In recent years, relevant studies have reported that inflammatory cytokines are related to the occurrence of cancer. However, the correlation with lung cancer is not clear. This study used the Mendelian random grouping method to investigate the correlation between inflammatory factors and lung cancer in different populations. METHODS: We obtained the single nucleotide polymorphisms (SNPs) of inflammatory cytokines through the open database and the SNPs of lung cancer (European and East Asian) through the IEU OpenGWAS project. Inverse variance-weighted (IVW) MR analyses were used to determine the causalities of exposures and outcomes. Supplementary analyses were also performed using weighted median and MR-Egger regressions. Afterward, sensitivity analyses were performed to test the robustness. Search the ChEMBL database for target drugs and indications for CTACK, IL-2, and IL-13. RESULTS: By IVW method, we found that CTACK, IL-2, and IL-13 were associated with an increased risk of lung cancer in the European population (CTACK, OR = 1.098, 95 % CI 1.001-1.204, P = 0.047; IL-2, OR = 1.112, 95 % CI 1.009-1.225, P = 0.032; IL-13, OR = 1.068, 95 % CI 1.007-1.132, P = 0.029), while only IL-13 was associated with an increased risk of lung cancer in the East Asian population (IL-13, OR = 1.110, 95 % CI 1.010-1.220, P = 0.030). The weighted median and MR-Egger regression methods were in the same direction as the IVW effect sizes. Furthermore, no evidence of multidirectionality was detected using the MR-Egger intercept as a sensitivity analysis. Currently, there are no approved or phase III studied indications for CTACK, IL-2, and IL-13 targets in lung cancer. CONCLUSION: The study outcomes supported that the inflammatory cytokines CTACK, IL-2, and IL-13 increase the risk of lung cancer. There is a lack of indications for drugs in these three targets. We explored the causal relationship between inflammatory cytokines and lung cancer, providing a basis for future cancer prediction models and targets for anti-tumor therapy.

Blood transcriptome analysis uncovered COVID-19-myocarditis crosstalk.

BACKGROUND: The condition of COVID-19-related myocarditis has emerged as a prominent contributor to COVID-19 mortality. As the epidemic persists, its incidence continues to rise. Despite ongoing efforts, the elucidation of COVID-19-related myocarditis underlying molecular mechanisms still requires further investigation. METHODS: Hub genes for COVID-19-related myocarditis were screened by integrating gene expression profile analysis via differential expression in COVID-19 (GSE196822) and myocarditis (GSE148153 and GSE147517). After verification with independent datasets (GSE211979, GSE167028, GSE178491 and GSE215865), the hub genes were studied using a range of systems-biology approaches, such as ceRNA, TF-mRNA networks and PPI networks, as well as gene ontology, pathway enrichment, immune infiltration analysis and drug target identification. RESULTS: TBKBP1 and ERGIC1 were identified as COVID-19-related myocarditis hub genes via integrated bioinformatics analysis. In addition, receiver operating characteristic curves constructed based on the expression levels of TBKBP1 and ERGIC1 could effectively distinguish healthy control individuals from patients with COVID-19. Functional enrichment analysis suggested several enriched biological pathways related to inflammation and immune response. Immune cell changes correlated with TBKBP1 and ERGIC1 levels in patients with COVID-19 or patients with COVID-19 and myocarditis. Tamibarotene, methotrexate and theophylline were identified as a potential drug targeting TBKBP1 and ERGIC1. CONCLUSION: TBKBP1 and ERGIC1 were identified as crucial genes in the development of COVID-19-related myocarditis and have demonstrated a strong association with innate antiviral immunity. The present work may be helpful for further investigation of the molecular mechanisms and new therapeutic drug targets correlated with myocarditis in COVID-19.

Faecalibacterium prausnitzii as a potential Antiatherosclerotic microbe.

BACKGROUND: The gut microbiota plays a crucial role in coronary artery disease (CAD) development, but limited attention has been given to the role of the microbiota in preventing this disease. This study aimed to identify key biomarkers using metagenomics and untargeted metabolomics and verify their associations with atherosclerosis. METHODS: A total of 371 participants, including individuals with various CAD types and CAD-free controls, were enrolled. Subsequently, significant markers were identified in the stool samples through gut metagenomic sequencing and untargeted metabolomics. In vivo and in vitro experiments were performed to investigate the mechanisms underlying the association between these markers and atherosclerosis. RESULTS: Faecal omics sequencing revealed that individuals with a substantial presence of Faecalibacterium prausnitzii had the lowest incidence of CAD across diverse CAD groups and control subjects. A random forest model confirmed the significant relationship between F. prausnitzii and CAD incidence. Notably, F. prausnitzii emerged as a robust, independent CAD predictor. Furthermore, our findings indicated the potential of the gut microbiota and gut metabolites to predict CAD occurrence and progression, potentially impacting amino acid and vitamin metabolism. F. prausnitzii mitigated inflammation and exhibited an antiatherosclerotic effect on ApoE-/- mice after gavage. This effect was attributed to reduced intestinal LPS synthesis and reinforced mechanical and mucosal barriers, leading to decreased plasma LPS levels and an antiatherosclerotic outcome. CONCLUSIONS: Sequencing of the samples revealed a previously unknown link between specific gut microbiota and atherosclerosis. Treatment with F. prausnitzii may help prevent CAD by inhibiting atherosclerosis.

New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation.

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 âˆ¼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 âˆ¼ 16.83 ± 0.54 µM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 µM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 µM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway.

Dihydroartemisinin (DHA) has recently attracted increasing attention for its low toxicity and high antitumor activity. DHA has been reported to have synergistic anticancer effects with a variety of drugs in the clinic; however, the molecular mechanism by which DHA inhibits tumorigenesis and improves oxaliplatin cytotoxicity in colon cancer cells is still not well understood. In this study, we found that DHA can inhibit cell proliferation and colony formation in a dose-dependent manner. Prohibitin 2 (PHB2) is a potential target by which DHA exerts its antitumor and cytotoxic effects. The function and molecular mechanism of PHB2 in colon cancer tumorigenesis were fully studied to determine the regulatory mechanism between DHA and PHB2. We found that PHB2, a mitochondrial inner membrane scaffold protein, has a higher expression level in colon cancer tissues than in adjacent nontumor tissues and is mainly localized in mitochondria. Overexpression of PHB2 can promote cell proliferation and colony formation in vitro and accelerate tumor growth in vivo. We also found that the expression level of PHB2 was inversely related to the cytotoxicity of DHA and oxaliplatin in colon cancer cells. The molecular mechanism of PHB2 in tumorigenesis and cancer therapy was further studied. The results showed that 20 µM DHA can downregulate PHB2 expression in a ubiquitylation-dependent manner and subsequently block PHB2-induced RCHY1 upregulation and p53 and p21 downregulation. In this process, RCHY1 is necessary for PHB2 to play a tumor-promoting role. Thus, PHB2 and RCHY1 are effective targets for colon cancer therapy, and DHA has synergistic anticancer effects with oxaliplatin via promoting PHB2 degradation in colon cancer cells.

Circulating sTREM-1 as a predictive biomarker of pediatric multisystemic inflammatory syndrome (MIS-C).

The exacerbation of the inflammatory response caused by SARS-CoV-2 in adults promotes the production of soluble mediators that could act as diagnostic and prognostic biomarkers for COVID-19. Among the potential biomarkers, the soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) has been described as a predictor of inflammation severity. The aim was to evaluate sTREM-1 and cytokine serum concentrations in pediatric patients during the acute and convalescent phases of COVID-19. This was a prospective study that included 53 children/adolescents with acute COVID-19 (Acute-CoV group); 54 who recovered from COVID-19 (Post-CoV group) and 54 controls (Control group). Preexisting chronic conditions were present in the three groups, which were defined as follows: immunological diseases, neurological disorders, and renal and hepatic failures. The three groups were matched by age, sex, and similar preexisting chronic conditions. No differences in sTREM-1 levels were detected among the groups or when the groups were separately analyzed by preexisting chronic conditions. However, sTREM-1 analysis in the seven multisystemic inflammatory syndrome children (MIS-C) within the Acute-Cov group showed that sTREM-1 concentrations were higher in MIS-C vs non-MIS-C acute patients. Then, the receiver operating curve analysis (ROC) performed with MIS-C acute patients revealed a significant AUC of 0.870, and the sTREM-1 cutoff value of > 5781 pg/mL yielded a sensitivity of 71.4 % and a specificity of 91.3 % for disease severity, and patients with sTREM-1 levels above this cutoff presented an elevated risk for MIS-C development in 22.85-fold (OR = 22.85 [95 % CI 1.64-317.5], p = 0.02). The cytokine analyses in the acute phase revealed that IL-6, IL-8, and IL-10 concentrations were elevated regardless of whether the patient developed MIS-C, and those levels decreased in the convalescent phase, even when compared with controls. Spearman correlation analysis generated positive indexes between sTREM-1 and IL-12 and TNF-α concentrations, only within the Acute-CoV group. Our findings revealed that sTREM-1 in pediatric patients has good predictive accuracy as an early screening tool for surveillance of MIS-C cases, even in patients with chronic underlying conditions.

Mutated CYP17A1 promotes atherosclerosis and early-onset coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized. METHODS: In the present study, we identified a rare nonsense variant in the CYP17A1 gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice. RESULTS: The mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, the CYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore, CYP17A1 knockout mice or CYP17A1 + ApoE double knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models, CYP17A1 was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent in CYP17A1 knockout mice with impaired glucose tolerance and insulin resistance. CONCLUSIONS: Through our study of cells, mice and humans, we identified CYP17A1 as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism of CYP17A1 C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed. Video Abstract.

(±)-Salvicatone A: A Pair of C27-Meroterpenoid Enantiomers with Skeletons from the Roots and Rhizomes of Salvia castanea Diels f. tomentosa Stib.

(±)-Salvicatone A (1), a C27-meroterpenoid featuring a unique 6/6/6/6/6-pentacyclic carbon skeleton with a 7,8,8a,9,10,10a-hexahydropyren-1 (6H)-one motif, was isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Its structure was characterized by comprehensive spectroscopic analyses along with computer-assisted structure elucidation, including ACD/structure elucidator and quantum chemical calculations with 1H/13C NMR and electronic circular dichroism. Biogenetically, compound 1 was constructed from decarboxylation following [4 + 2] Diels-Alder cycloaddition reaction between caffeic acid and miltirone analogue. Bioassays showed that (-)-1 and (+)-1 inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophage cells with an IC50 value of 6.48 ± 1.25 and 15.76 ± 5.55 µM, respectively. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking and molecular dynamics simulations study, implied that (-)-1 and (+)-1 may potentially bind to retinoic acid receptor-related orphan receptor C to exert anti-inflammatory activities.

Age and outcomes following personalized antiplatelet therapy in chronic coronary syndrome patients: a post hoc analysis of the randomized PATH-PCI trial.

It is particularly important to establish more effective and safer antiplatelet treatment strategies according to age. The present subanalysis of the PATH-PCI trial was to determine the safety and efficacy of any dual-antiplatelet therapy (DAPT) strategy in different age groups. We randomized 2285 chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) into a standard group or a personalized group from December 2016 to February 2018. The personalized group received personalized antiplatelet therapy (PAT) based on a novel platelet function test (PFT). The standard group received standard antiplatelet therapy (SAT). Then, all patients were divided according to age (under the age of 65 years and aged 65 years or over) to investigate the association and interaction of age on clinical outcomes at 180 days. In the patients under the age of 65 years, the incidence of NACEs was decreased in the personalized group compared to the standard group (5.1% vs. 8.8%, HR: 0.603, 95% CI: 0.409-0.888, P = .010). The rates of MACCEs (3.3% vs. 7.7%, HR: 0.450, 95% CI: 0.285-0.712, P = .001), MACEs (2.2% vs. 5.4%, HR: 0.423, 95% CI: 0.243-0.738, P = .002) also decreased. We did not find a significant difference in bleeding between the groups. In the patients aged 65 years or over, no difference in the primary endpoint was found (4.9% vs. 4.2%, P = .702), and comparable rates of survival were observed with the two strategies (all Ps > 0.05). The present study shows that PAT according to PFT was comparable to SAT at the 180-day follow-up for both ischemic and bleeding endpoints in CCS patients aged 65 years or over who underwent PCI. In patients under the age of 65 years, PAT can reduce ischemic events but does not increase bleeding, and it is an effective and safe treatment strategy. It may be necessary for young CCS patients after PCI to undergo PAT early after PCI.

What is the context? The PATH-PCI trial reported that personalized antiplatelet therapy (PAT) based on a novel platelet function test (PFT) can greatly reduce the incidence of ischemic events.Antiplatelet strategies may have very different effects on clinical outcomes in patients in China who are undergoing PCI at different ages.What is new? PL-12 is a new point-of-care platelet function analyzer that is used to test the platelet maximum aggregation rate (MAR).We explored the efficacy and safety of different antiplatelet strategies in chronic coronary syndrome (CCS) patients in different age groups.What is the impact? PAT according to PFT was comparable to standard antiplatelet therapy (SAT) at the 180-day follow-up for both ischemic and bleeding endpoints in CCS patients aged 65 years or over who underwent PCI.In patients under the age of 65 years, PAT can reduce ischemic events but not increase bleeding.PAT may be an effective and safe treatment strategy in CCS patients under the age of 65 years who underwent PCI.Abbreviation: PCI: percutaneous coronary intervention; CCS: chronic coronary syndrome; DAPT: dual antiplatelet therapy; PAT: personalized antiplatelet therapy; SAT: standard antiplatelet therapy; PFT: platelet function test; NACEs: net adverse clinical events; MACCEs: major adverse cardiac and cerebrovascular events; MACEs: major adverse cardiovascular events.

Epidemic trends of dyslipidemia in young adults: a real-world study including more than 20,000 samples.

BACKGROUND: There is an urgent need to learn more about the epidemiological features of dyslipidemia in youth to address the high burden of cardiovascular disease. METHODS: This experiment was an observational, cross-sectional study. The samples were collected from 22,379 college students at Xinjiang Medical University. RESULT: The overall prevalence of dyslipidemia was 13.17%, which was significantly higher in men (23%) than in women (7.2%), p < 0.01. Similarly, the prevalence rate of obesity in men (11.4%) was significantly higher than that in women (3.4%). The composition of blood lipids, such as triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C), began to increase gradually from the age of 22 and showed a sharp increase after the age of 30; however, a reverse trend was present in high density lipoprotein cholesterol (HDL-C). In terms of the proportion of dyslipidemia in both men and women, low HDL-C accounted for the largest proportion (74%), followed by elevated TGs (14.5%). The overall distribution of rates of dyslipidemia and excess weight showed a U-shaped trend with increasing age, with the lowest rates seen in the 20-24 age group. CONCLUSION: Our study sheds light on the epidemiological features of dyslipidemia in young adults and enriches the limited data available on dyslipidemia, providing a reference for the close monitoring and control of risk factors to reduce the occurrence and progression of atherosclerotic cardiovascular disease events.

NT-proBNP change is useful for predicting weaning failure from invasive mechanical ventilation among postsurgical patients: a retrospective, observational cohort study.

BACKGROUND: To evaluate the predictive value of N-terminal prohormone B-type natriuretic peptide (NTproBNP) for weaning failure among patients undergoing major surgeries during spontaneous breathing trial (SBT), compared to traditional weaning parameters. METHODS: The observational cohort study retrospectively included postsurgical patients who received IMV and underwent a 2 h SBT. According to weaning outcome, NTproBNP level at initiation (NTproBNP1) and at end of 2 h SBT(NTproBNP2), the ΔNTproBNP%, RSBI and MV were compared between weaning failure and weaning success group. Multiple logistical regression and ROC curve were used to evaluate the capability of NTproBNP to predict weaning failure. RESULTS: Out of the 323 included postsurgical patients, 45 (13.9%) patients had failed weaning. The ΔNTproBNP% was a better predictor for weaning failure (AUC 0.744;95%CI,0.693-0.791) than NTproBNP1(AUC 0.639; 95%CI,0.580-0.694)), NTproBNP2(AUC 0.742, 95%CI,0.688-0.792) and other traditional weaning index such as RSBI (AUC 0.651; 95%CI, 0.597-0.703) and MV (AUC 0.552; 95%CI,0.496-0.607). The cutoff value of ΔNTproBNP% for predicting weaning failure was 23.3% with the sensitivity75.76% and specificity73.38%. The multiple logistic regression analysis found that ΔNTproBNP%>23.3% was an independent predictor of weaning failure. CONCLUSION: ΔNTproBNP% may be a useful marker for predict weaning failure for postsurgical patients, and it's better to be more careful to withdraw from invasive mechanical ventilation for those postsurgical patients with ΔNTproBNP% >23.3%. The corresponding interventions to optimize cardiac function should be actively given to these patients.

Reversible phosphorylation of Rpn1 regulates 26S proteasome assembly and function.

The fundamental importance of the 26S proteasome in health and disease suggests that its function must be finely controlled, and yet our knowledge about proteasome regulation remains limited. Posttranslational modifications, especially phosphorylation, of proteasome subunits have been shown to impact proteasome function through different mechanisms, although the vast majority of proteasome phosphorylation events have not been studied. Here, we have characterized 1 of the most frequently detected proteasome phosphosites, namely Ser361 of Rpn1, a base subunit of the 19S regulatory particle. Using a variety of approaches including CRISPR/Cas9-mediated gene editing and quantitative mass spectrometry, we found that loss of Rpn1-S361 phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress as well as mitochondrial dysfunction. A screen of the human kinome identified several kinases including PIM1/2/3 that catalyze S361 phosphorylation, while its level is reversibly controlled by the proteasome-resident phosphatase, UBLCP1. Mechanistically, Rpn1-S361 phosphorylation is required for proper assembly of the 26S proteasome, and we have utilized a genetic code expansion system to directly demonstrate that S361-phosphorylated Rpn1 more readily forms a precursor complex with Rpt2, 1 of the first steps of 19S base assembly. These findings have revealed a prevalent and biologically important mechanism governing proteasome formation and function.

The Neonatal-Perinatal Medicine fellowship application webinar series: a novel approach to helping applicants succeed.

BACKGROUND: In 2022, 13,586 candidates applied to subspecialty fellowships. Formal resources to inform candidates on subspecialty-specific fellowship application are limited. Candidates rely on residency application experience, informal advice, and online research for navigating the application process. Thus, a need exists for formal subspecialty-specific fellowship application guidance. The American Academy of Pediatrics Organization of Neonatal-Perinatal Medicine Training Program Directors (ONTPD) and Trainees and Early Career Neonatologists (TECaN) created a webinar-based curriculum to help educate trainees about the application process and recruit diverse fellowship applicants. METHODS: In 2022, ONTPD and TECaN co-hosted and implemented a four-part national webinar series focused on different aspects of the Neonatal-Perinatal Medicine (NPM) fellowship application and interview processes. Webinars were advertised through list-servs and social media, conducted in two time zones, and recorded for asynchronous viewing. Registration, demographic data, and questions for webinar panelists were collected via electronic survey. Program evaluation data was collected after each webinar and following the fellowship match. RESULTS: In the 2022 appointment year, 310 candidates participated in the NPM fellowship match and 250 individuals registered for the webinar series. A quarter (26%) of registrants identified as underrepresented in medicine. Most registrants reported minimal or no knowledge of the fellowship application (64%, 158/248) and interview (81%, 201/248) processes. The majority of registrants (70%, 173/248) were planning on applying to fellowship in 2022, and 91% of post-webinar respondents (43/47) felt the webinars were moderately or extremely helpful, a finding that was sustained beyond the match (37/42). Almost all respondents rated the quality of the webinars as good or higher and were likely or very likely to recommend them to peers (39/42). There was considerable variability amongst respondents in the number of fellowship programs applied to, interviewed at, and ranked, and factors influencing rank list. CONCLUSION: We describe a virtual curriculum to prepare trainees for the NPM fellowship application and interview process. This webinar series provides needed education to fellowship candidates, bridges the gap between candidate knowledge and program director expectations, is generalizable to other specialties, and can be replicated with minimal resources.

Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction.

Sirtuin 2 (SIRT2), as a member of the sirtuin family, has representative features of evolutionarily highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. In addition, SIRT2, as the only sirtuin protein colocalized with tubulin in the cytoplasm, has its own functions and characteristics. In recent years, studies have increasingly shown that SIRT2 can participate in the regulation of gene expression and regulate signal transduction in the metabolic pathway mainly through its post-translational modification of target genes; thus, SIRT2 has become a key centre in the metabolic pathway and participates in the pathological process of metabolic disorder-related diseases. In this paper, it is discussed that SIRT2 can regulate all aspects of gene expression, including epigenetic modification, replication, transcription and translation, and post-translational modification, which enables SIRT2 to participate in energy metabolism in life activities, and it is clarified that SIRT2 is involved in metabolic process-specific signal transduction mechanisms. Therefore, SIRT2 can be involved in metabolic disorder-related inflammation and oxidative stress, thereby triggering the occurrence of metabolic disorder-related diseases, such as neurodegenerative diseases, tumours, diabetes, and cardiovascular diseases. Currently, although the role of SIRT2 in some diseases is still controversial, given the multiple roles of SIRT2 in regulating physiological and pathological signal transduction, SIRT2 has become a key target for disease treatment. It is believed that with increasing research, the clinical application of SIRT2 will be promoted.

Mean platelet volume as a predictive biomarker for in-hospital mortality in patients receiving invasive mechanical ventilation.

BACKGROUND: Although mean platelet volume (MPV) has been reported to be associated with poor prognosis of various critical illness, the relationship between MPV and in-hospital mortality among patients undergoing invasive mechanical ventilation (IMV) is unclear. METHODS: A retrospective observational study including patients receiving IMV was conducted from January, 2014 to January, 2019. The patients were divided into two groups by MPV cutoff value. The receiver operating characteristics curve was used to evaluate the predictive ability of MPV for in-hospital mortality. Univariate and multivariate Cox regression analysis were conducted to analyze the value of MPV for predicting in-hospital mortality. Kaplan-Meier cumulative incidence curve was employed to observe the incidence of in-hospital mortality. RESULTS: A total of 274 patients were enrolled in the study, and 42 patients (15.3%) died in hospital. MPV > 11.4 fl was a valuable predictor for in-hospital mortality (AUC0.848; 95%CI, 0.800-0.889) with sensitivity 66.7%, and specificity = 86.21%. MPV > 11.4 fl was an independent risk factor for in-hospital mortality (adjusted HR 2.640, 95%CI, 1.208-5.767, P = 0.015). Compared to the group of MPV ≤ 11.4 fl, patients with MPV > 11.4 fl had increased mortality (log-rank test = 40.35, HR = 8.723, P < 0.0001). The relationship between MPV and in-hospital mortality was stronger in female patients than in male patients. CONCLUSION: MPV > 11.4 fl is a more useful marker for predicting in-hospital mortality among critically ill patients receiving IMV, especially in female patients. Attention to the MPV marker is simple and profitable with immediate applicability in daily clinical practice.

Mean platelet volume is useful for predicting weaning failure: a retrospective, observational study.

BACKGROUND: To evaluate the usefulness of mean platelet volume (MPV), a marker of inflammation and stress, for predicting weaning failure in patients undergoing invasive mechanical ventilation (IMV) compared to traditional inflammation markers. METHODS: The retrospective observational study including patients who received IMV and underwent spontaneous breathing trial (SBT) was conducted in ICU at Beijing Chao-Yang hospital in China from January, 2013 to December, 2019. According to the weaning outcome, MPV, leukocyte count and C-reaction protein(CRP) were compared between weaning failure and weaning success group. Receiver-operating characteristics (ROC) curves and multivariate logistical regression analysis were constructed to analyze the value of these inflammatory markers for predicting weaning failure. RESULTS: A total of 261 patients were enrolled in the study and 54 patients (20.7%) experienced weaning failure (45 SBT failure and 9 extubation failure after successful SBT). MPV was a better predictor for weaning failure (AUC 0.777;95%CI, 0.722-0.826) than leukocyte count (AUC 0.6;95%CI,0.538-0.66) and CRP (0.627;95%CI,0.565-0.685). The cutoff value of MPV for predicting weaning failure was 11.3 fl with sensitivity 55.56%, specificity 87.92%, and diagnostic accuracy 81.22%. According to multivariate logistic regression analyses, MPV > 11.3 fl was an independent risk factor for predicting weaning failure. CONCLUSIONS: MPV could be a more valuable marker for predicting weaning failure. and the patients with MPV > 11.3 fl should be attentively evaluated before weaning since they are at high risk of weaning failure, and it would be auspicable for those patients to undergo a noninvasive ventilation or high-flow nasal cannula oxygen therapy after extubation or even an early tracheostomy.

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors.

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives (3a-3t) were synthesised and screened against α-glucosidase and α-amylase.Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

The ASK-SEAT: a competency-based assessment scale for students majoring in clinical medicine.

BACKGROUND: To validate a competency-based assessment scale for students majoring in clinical medicine, ASK-SEAT. Students' competency growth across grade years was also examined for trends and gaps. METHODS: Questionnaires were distributed online from May through August in 2018 to Year-2 to Year-6 students who majored in clinical medicine at the Shantou University Medical College (China). Cronbach alpha values were calculated for reliability of the scale, and exploratory factor analysis employed for structural validity. Predictive validity was explored by correlating Year-4 students' self-assessed competency ratings with their licensing examination scores (based on Kendall's tau-b values). All students' competency development over time was examined using the Mann-Whitney U test. RESULTS: A total of 760 questionnaires meeting the inclusion criteria were analyzed. The overall Cronbach's alpha value was 0.964, and the item-total correlations were all greater than 0.520. The overall KMO measure was 0.966 and the KMO measure for each item was greater than 0.930 (P < 0.001). The eigenvalues of the top 3 components extracted were all greater than 1, explaining 55.351, 7.382, and 5.316% of data variance respectively, and 68.048% cumulatively. These components were aligned with the competency dimensions of skills (S), knowledge (K), and attitude (A). Significant and positive correlations (0.135 < Kendall's tau-b < 0.276, p < 0.05) were found between Year-4 students' self-rated competency levels and their scores for the licensing examination. Steady competency growth was associated with almost all indicators, with the most pronounced growth in the domain of skills. A lack of steady growth was seen in the indicators of "applying the English language" and "conducting scientific research & innovating". CONCLUSIONS: The ASK-SEAT, a competency-based assessment scale developed to measure medical students' competency development shows good reliability and structural validity. For predictive validity, weak-to-moderate correlations are found between Year-4 students' self-assessment and their performance at the national licensing examination (Year-4 students start their clinical clerkship during the 2nd semester of their 4th year of study). Year-2 to Year-6 students demonstrate steady improvement in the great majority of clinical competency indicators, except in the indicators of "applying the English language" and "conducting scientific research & innovating".