Substrate-Controlled Divergent Synthesis of Benzimidazole-Fused Quinolines and Spirocyclic Benzimidazole-Fused Isoindoles.

A Rh(III)-catalyzed annulation of 2-arylbenzimidazoles with α-diazo carbonyl compounds via C-H activation/carbene insertion/intramolecular cyclization is explored. The switchable product selectivity is achieved by the use of distinct α-diazo carbonyl compounds. Benzimidazole-fused quinolines are obtained through [4 + 2] annulation exclusively when 2-diazocyclohexane-1,3-diones are used, where they act as a C2 synthon. Alternatively, diazonaphthalen-1(2H)-ones merely function as a one-carbon unit synthon to generate a quaternary center through [4 + 1] cyclization to afford spirocyclic benzimidazole-fused isoindole naphthalen-2-ones. A thorough mechanistic study reveals the course of the reaction.

TSH Trajectories During Levothyroxine Treatment in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Cohort.

CONTEXT: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. OBJECTIVE: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. METHODS: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. RESULTS: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. CONCLUSION: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

Real-world applications of the new grading system in lung adenocarcinoma: A study of 907 patients focusing on revealing the relationship between pathologic grade and genetic status.

BACKGROUND: The status of the lung adenocarcinoma (LUAD) grading system and the association between LUAD differentiation, driver genes, and clinicopathological features remain to be elucidated. METHODS: We included patients with invasive non-mucinous LUAD, evaluated their differentiation, and collected available clinicopathological information, gene mutations, and analyzed clinical outcomes. RESULTS: Among the 907 patients with invasive non-mucinous LUAD, 321 (35.4 %) were poorly differentiated, 422 (46.5 %) were moderately differentiated, and 164 (18.1 %) were well differentiated. EGFR mutation was more common in the LUADs accompanied without CGP (complex glandular pattern) than LUADs with CGP (p < 0.001). Correlation analysis between mutations and clinical characteristics showed that EGFR gene mutation (p < 0.001), KRAS gene mutation (p < 0.05), and ALK gene rearrangement (p < 0.001) were significantly related to the degree of tumor differentiation, and the KRAS and ALK gene mutation frequencies were higher in the low-differentiation group than in the high and medium differentiation groups. The EGFR mutation frequency was higher in the well/moderately differentiated adenocarcinoma group. CONCLUSIONS: Our study adds to the evidence regarding the role of the grading system in prognosis. EGFR, KRAS, and ALK are related to the degree of tumor differentiation.

Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer.

This review comprehensively explores the challenge of drug resistance in cancer by focusing on the pivotal PI3K/AKT/mTOR pathway, elucidating its role in oncogenesis and resistance mechanisms across various cancer types. It meticulously examines the diverse mechanisms underlying resistance, including genetic mutations, feedback loops, and microenvironmental factors, while also discussing the associated resistance patterns. Evaluating current therapeutic strategies targeting this pathway, the article highlights the hurdles encountered in drug development and clinical trials. Innovative approaches to overcome resistance, such as combination therapies and precision medicine, are critically analyzed, alongside discussions on emerging therapies like immunotherapy and molecularly targeted agents. Overall, this comprehensive review not only sheds light on the complexities of resistance in cancer but also provides a roadmap for advancing cancer treatment.

Investigation of subclinical ocular inflammation in the aqueous humor of patients with myopia following bilateral sequential collamer lens implantation.

BACKGROUND: The aqueous humor, a transparent fluid secreted by the ciliary body, supports the lens of the eyeball. In this study, we analyzed the cytokine and chemokine profiles within the aqueous humor of the contralateral eye post-implantation of an implantable collamer lens (ICL) to evaluate potential subclinical inflammation in the second eye subsequent to ICL implantation in the first eye. METHODS: Aqueous humor samples were procured from both eyes of 40 patients (totaling 80 eyes) prior to bilateral ICL insertion. Subsequently, a comprehensive statistical analysis was conducted using the Luminex assay to quantify 30 different cytokines in these samples. RESULTS: Compared to the first eye, the aqueous humor of the second eye demonstrated decreased concentrations of IFN-γ (P = 0.038), IL-13 (P = 0.027), IL-17/IL-17 A (P = 0.012), and IL-4 (P = 0.025). No significant differences were observed in other cytokine levels between the two groups. Patients were then categorized based on the postoperative rise in intraocular pressure (IOP) in the first eye. The group with elevated IOP displayed elevated levels of EGF in the aqueous humor of the first eye (P = 0.013) and higher levels of PDGF-AB/BB in the aqueous humor of the second eye (P = 0.032) compared to the group with normal IOP. Within the elevated IOP group, the levels of EGF (P = 0.013) and IL-17/IL-17 A (P = 0.016) in the aqueous humor were lower in the second eye than in the first eye. In the normal IOP group, cytokine levels did not differ notably between eyes. CONCLUSION: Following sequential ICL implantation, it appears that a protective response may be activated to mitigate subclinical inflammation in the second eye induced by the initial implantation in the first eye. Additionally, the increase in IOP subsequent to surgery in the first eye may correlate with the presence of inflammatory mediators in the aqueous humor.

Update on Musculoskeletal Pain Management.

Pain is the most common complaint reported to orthopedists in the outpatient clinic, emergency room, or booth. Numerous publications report the inadequate management of both acute and chronic pain by health professionals. This updated article aims to provide information about musculoskeletal pain, its classification, evaluation, diagnosis, and the multimodal therapeutic approach for each case. For acute pain, adequate control allows for earlier rehabilitation to work and reduces the rates of pain chronification. For chronic pain, the goal is to reduce its intensity and improve the quality of life. Currently, some procedures are increasingly used and aided by imaging tests for diagnostic and therapeutic purposes.

Clickable Polymerization-Induced Emission Luminogens Toward Color-Tunable Modification of Non-Traditional Intrinsic Luminescent Polymers.

Non-traditional intrinsic luminescent (NTIL) polymer is an emerging field, and its color-tunable modification is highly desirable but still rarely investigated. Here, a click chemistry approach for the color-tunable modifications of NTIL polymers by introducing clickable polymerization-induced emission luminogen (PIEgen), is demonstrated. Through Cu-catalyzed azide-alkyne cycloaddition click chemistry, a series of PIEgens is successful prepared, which is further polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Interestingly, after clickable modification, these monomers are nonemissive in both solution and aggregation states; while, the corresponding polymers exhibit intriguing aggregation-induced emission (AIE) characteristics, confirming their PIEgen characteristics. By varying alkynyl substitutions, color-tunable NTIL polymers are achieved with emission wavelength varying from 448 to 498 nm, revealing a series of PIEgens and verifying the importance of modification of NTIL polymers. Further luminescence energy transfer application is carried out as well. This work therefore designs a series of clickable PIEgens and opens a new avenue for the modification of NTIL polymers via click chemistry, which may cause inspirations to the research fields including luminescent polymer, NTIL, click chemistry, AIE and modification.

Antiplatelet effects of the CEACAM1-derived peptide QDTT.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) restricts platelet activation via platelet collagen receptor GPVI/FcRγ-chain. In this study, screening against collagen-induced platelet aggregation was performed to identify functional CEACAM1 extracellular domain fragments. CEACAM1 fragments, including Ala-substituted peptides, were synthesized. Platelet assays were conducted on healthy donor samples for aggregation, cytotoxicity, adhesion, spreading, and secretion. Mice were used for tail bleeding and FeCl3-induced thrombosis experiments. Clot retraction was assessed using platelet-rich plasma. Extracellular segments of CEACAM1 and A1 domain-derived peptide QDTT were identified, while N, A2, and B domains showed no involvement. QDTT inhibited platelet aggregation. Ala substitution for essential amino acids (Asp139, Thr141, Tyr142, Trp144, and Trp145) in the QDTT sequence abrogated collagen-induced aggregation inhibition. QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.

What is the context? The study focuses on Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its role in platelet activation, particularly through the GPVI/FcRγ-chain pathway.The research aims to identify specific fragments of CEACAM1's extracellular domain that could restrict platelet activation, without increasing bleeding risk.What is new? The researchers identified a peptide called QDTT derived from the A1 domain of CEACAM1's extracellular segment. This peptide demonstrated the ability to inhibit platelet aggregation, secretion, and GP IIb/IIIa activation.The study also revealed that specific amino acids within the QDTT sequence were essential for its inhibitory effects on collagen-induced aggregation.What is the impact? The findings suggest that the A1 domain-derived peptide QDTT from CEACAM1 could serve as a potential basis for developing novel antiplatelet drugs. This peptide effectively limits platelet activation and aggregation without significantly prolonging bleeding time, indicating a promising approach to managing thrombosis and related disorders while minimizing bleeding risks.

Utilization, quality, and spending for pediatric Medicaid enrollees with primary care in health centers vs non-health centers.

BACKGROUND: Limited research has explored the performance of health centers (HCs) compared to other primary care settings among children in the United States. We evaluated utilization, quality, and expenditures for pediatric Medicaid enrollees receiving care in HCs versus non-HCs. METHODS: This national cross-sectional study utilized 2012 Medicaid Analytic eXtract (MAX) claims to examine children 0-17 years with a primary care visit, stratified by whether majority (> 50%) of primary care visits were at HCs or non-HCs. Outcome measures include utilization (primary care visits, non-primary care outpatient visits, prescription claims, Emergency Department (ED) visits, hospitalizations) and quality (well-child visits, avoidable ED visits, avoidable hospitalizations). For children enrolled in fee-for-service Medicaid, we also measured expenditures. Propensity score-based overlap weighting was used to balance covariates. RESULTS: A total of 2,383,270 Medicaid-enrolled children received the majority of their primary care at HCs, while 18,540,743 did at non-HCs. In adjusted analyses, HC patients had 20% more primary care visits, 15% less non-primary care outpatient visits, and 21% less prescription claims than non-HC patients. ED visits were similar across the two groups, while HC patients had 7% lower chance of hospitalization than non-HC. Quality of care outcomes favored HC patients in main analyses, but results were less robust when excluding managed care beneficiaries. Total expenditures among the fee-for-service subpopulation were lower by $239 (8%) for HC patients. CONCLUSIONS: In this study of nationwide claims data to evaluate healthcare utilization, quality, and spending among Medicaid-enrolled children who receive primary care at HCs versus non-HCs, findings suggest primary care delivery in HCs may be associated with a more cost-effective model of healthcare for children.

Versatile Polymerization-Induced Emission Polymers from Barbier Polymerization of Cinnamic Esters with Tunable Emission.

Cinnamic ester is a common and abundant chemical substance, which can be extracted from natural plants. Compared with traditional esters, cinnamic ester contains α,ß-unsaturated carbonyl structure with multiple reactive sites, resulting in more abundant reactivities and chemical structures. Here, a versatile polymerization-induced emission (PIE) is successfully demonstrated through Barbier polymerization of cinnamic ester. Attributed to its abundant reactivities of α,ß-unsaturated carbonyl structure, Barbier polymerization of cinnamic esters with different organodihalides gives polyalcohol and polyketone via 1,2-addition and 1,4-addition, respectively, which is also confirmed by small molecular model reactions. Meanwhile, these organodihalides dependant polyalcohol and polyketone exhibit different non-traditional intrinsic luminescence (NTIL) from aggregation-induced emission (AIE) type to aggregation-caused quenching (ACQ) type, where novel PIE luminogens (PIEgens) are revealed. Further potential applications in explosive detection are carried out, where it achieves TNT detection sensitivity at ppm level in solution and ng level on the test paper. This work therefore expands the structure and functionality libraries of monomer, polymer and NTIL, which might cause inspirations to different fields including polymer chemistry, NTIL, AIE and PIE.

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.

Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.

Predictive value of the HB/RDW ratio for the risk of all-cause death in patients with heart failure with different ejection fractions.

INTRODUCTION: The prognostic value of the ratio of haemoglobin to red cell distribution width (HRR) in different types of heart failure (HF) is not well known. METHOD AND RESULTS: We analysed the long-term prognostic value of HRR in patients with HF using the Cox proportional risk model and Kaplan‒Meier method. We reviewed consecutive 972 HF patients. The overall mortality rate was 45.68%. Mortality was 52.22% in the HFrEF group and 40.99% in the HFpEF+HFmrEF group. Cox regression showed that when HRR increased by 1 unit, the risk of all-cause death in all HF patients decreased by 22.8% (HR: 0.772, 95% CI (0.724, 0.823, p<0.001), in the HFpEF+HFmrEF group it decreased by 15.5% (HR: 0.845, 95% CI (0.774, 0.923), p<0.001), and in the HFrEF group it decreased by 36.1% (HR: 0.639, 95% CI (0.576, 0.709), p<0.0001). Subgroup analysis showed that there were interactions between the EF and HRR groups. The group in which HRR best predicted all-cause death from HF was Group 1 (EF<40%, HRR<9.45), followed by Group 2 (EF<40%, HRR≥9.45) and Group 3 (EF≥40%, HRR<9.45). HRR had no predictive value in Group 4 (EF≥40%, HRR≥9.45). CONCLUSION: HRR is an important predictor of all-cause mortality in patients with HF, especially HFrEF. There is an interaction between HRR group and LVEF group.

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

A Deep-Learning Model for Diagnosing Fresh Vertebral Fractures on Magnetic Resonance Images.

BACKGROUND: The accurate diagnosis of fresh vertebral fractures (VFs) was critical to optimizing treatment outcomes. Existing studies, however, demonstrated insufficient accuracy, sensitivity, and specificity in detecting fresh fractures using magnetic resonance imaging (MRI), and fall short in localizing the fracture sites. METHODS: This prospective study comprised 716 patients with fresh VFs. We obtained 849 Short TI Inversion Recovery (STIR) image slices for training and validation of the AI model. The AI models employed were yolov7 and resnet50, to detect fresh VFs. RESULTS: The AI model demonstrated a diagnostic accuracy of 97.6% for fresh VFs, with a sensitivity of 98% and a specificity of 97%. The performance of the model displayed a high degree of consistency when compared to the evaluations by spine surgeons. In the external testing dataset, the model exhibited a classification accuracy of 92.4%, a sensitivity of 93%, and a specificity of 92%. CONCLUSIONS: Our findings highlighted the potential of AI in diagnosing fresh VFs, offering an accurate and efficient way to aid physicians with diagnosis and treatment decisions.

Exploring Patients' Intentions for Usage of Video Telemedicine Follow-Up Services: Cross-Sectional Study.

Background: Data suggest that regarding completion rates and lower readmission rates, video telemedicine follow-up is as efficient as in-person consultations. However, evidence of patients' intention to adopt such service is lacking. The objective of this study was to determine the essential factors influencing Chinese patients' intention to adopt video telemedicine follow-up. Methods: The researchers extended the technology acceptance model (TAM) by incorporating trust, subjective norms (SNs), perceived risk (PR), and perceived disease threat (PDT). A survey was conducted with 793 Chinese patients, and the collected data were analyzed using the partial least-squares approach. Results: The study revealed that trust emerged as the strongest factor influencing patients' behavioral intention (BI) to use video telemedicine follow-up, followed by SNs, perceived ease of use (PEOU), and perceived usefulness (PU). PR and PDT had no significant influence on patients' intention to adopt video telemedicine follow-up. PEOU mediated the relationship between trust, SNs, and BI, and PU mediated the relationship between trust and BI. The study also found that gender, age, and usage experience moderated certain relationships in the model. Conclusions: Our findings support the use of the extended TAM in understanding individual's motivations for using video telemedicine follow-up in China. In addition, this study contributes to the existing literature on telemedicine promotion by identifying significant mediation mechanisms. These findings have practical implications for planning, creating, and implementing improved video telemedicine follow-up services.

Barbier Polymerization-Induced Emission towards Fully Substituted Polyethylene Analogues with Non-Traditional Intrinsic Luminescence.

The properties of polyethylene are highly dependent on the variety and quantity of substitutions. Generally, polyethylene can only be fully substituted with fluorine atoms, mainly e. g., polytetrafluoroethylene and nafion, because atomic radius of fluorine atom is small enough. The preparation of fully substituted polyethylene analogues (FSPEA) and their non-traditional intrinsic luminescence (NTIL) are attractive, especially for substitutions with relatively larger atomic radii than a fluorine atom. Here, Barbier polymerization-induced emission (PIE) is demonstrated as a universal method for the molecular design of NTIL type FSPEAs with intriguing aggregation-induced emission (AIE) behaviors. Through Barbier polymerization of diphenyldichloromethane and different peroxyesters in the presence of Mg in one pot, a series of FSPEAs, including polytriphenylethanol (PTPE), polydiphenylfurylethanol (PDPFE), polydiphenylthiophenylethanol (PDPTE) and polydiphenylnaphthylethanol (PDPNE) have been successfully prepared. Further potential applications for explosive detection, artificial light-harvesting system and white phosphor-converted light-emitting diode are investigated. Therefore, this work opens up a new approach for the molecular design of FSPEA with non-conjugated luminescence, which may cause inspirations to different research fields like polyolefin and luminescent materials.

Phase separation in DNA double-strand break response.

DNA double-strand break (DSB) is the most dangerous type of DNA damage, which may lead to cell death or oncogenic mutations. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are two typical DSB repair mechanisms. Recently, many studies have revealed that liquid-liquid phase separation (LLPS) plays a pivotal role in DSB repair and response. Through LLPS, the crucial biomolecules are quickly recruited to damaged sites with a high concentration to ensure DNA repair is conducted quickly and efficiently, which facilitates DSB repair factors activating downstream proteins or transmitting signals. In addition, the dysregulation of the DSB repair factor's phase separation has been reported to promote the development of a variety of diseases. This review not only provides a comprehensive overview of the emerging roles of LLPS in the repair of DSB but also sheds light on the regulatory patterns of phase separation in relation to the DNA damage response (DDR).

Analysis of effective components of Agaricus blazei Murill extract by LC-MS and network pharmacology analysis in treatment of chronic myeloid leukemia / 中国药理学通报

Aim To explore the potential targets and related signaling pathways of Agaricus blazei Murill (AbM ) extract in the treatment of chronic myeloid leukemia (CML) based on liquid chromatography mass spectrometry ( LC-MS ), network pharmacology, molecular docking, and were further verified by experiments in vitro. Methods The active components of AbM extract were retrieved from LC-MS, Swiss Target Prediction database was used to predict related targets, and CML disease target genes were obtained from Gen- eCards and DisGeNET databases. After screening the common targets of drug and CML, the protein-protein interaction network of the common targets was performed by STRING, and GO and KEGG enrichment a- nalysis were done by DAVID database. Cytoscape software was used to construct the network of target protein. Molecular docking was carried out by DockThor, and the Pymol software was used to make a visual picture. The inhibitory effect of AbM extract on leukemia cells K562 was determined by CCK-8 experiment, and the effect of AbM extract on the expression and phosphorylation level of related proteins was verified by Western blot. Results The prediction results showed that 126 active components of AbM extract, and 172 common targets were collected. KEGG pathway analysis results showed that PI3K/Akt/mTOR signaling pathway might play an important role in the treatment of CML disease. The IC

Patients with Hepatitis C Undergoing Direct-Acting Antiviral Treatment Have a Lower SARS-CoV-2 Infection Rate.

This study retrospectively analyzed the medical records of 602 patients with first-time positive results for the HCV nucleic acid test between 1 May 2021 and 31 March 2023, exploring the association between DAA treatment and SARS-CoV-2 infection. The results showed that 9.8% of HCV patients were co-infected with SARS-CoV-2. Gender, age, vaccination status, and HCV genotype did not significantly affect SARS-CoV-2 infection. However, patients undergoing DAA treatment showed significantly lower rates of SARS-CoV-2 infection and mortality compared to those not undergoing DAA treatment. The analysis also compared patients undergoing different DAA treatments, with Epclusa and Maviret showing superior protection against SARS-CoV-2. Furthermore, this study explored the severity and mortality of SARS-CoV-2 infection in patients undergoing and having completed DAA treatment. It revealed that patients diagnosed with COVID-19 during DAA treatment experienced only mild symptoms, and none died, suggesting a potential protective effect of DAA treatment against severe outcomes of SARS-CoV-2 infection. The findings contribute to the understanding of the interplay between HCV, DAA treatment, and SARS-CoV-2 infection, highlighting the need for continued monitoring and healthcare measures for individuals with chronic conditions during the ongoing COVID-19 pandemic.