Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Accurate Concentration Recovery for Quantitative Magnetic Particle Imaging Reconstruction via Nonconvex Regularization.

Magnetic particle imaging (MPI) uses nonlinear response signals to noninvasively detect magnetic nanoparticles in space, and its quantitative properties hold promise for future precise quantitative treatments. In reconstruction, the system matrix based method necessitates suitable regularization terms, such as Tikhonov or non-negative fused lasso (NFL) regularization, to stabilize the solution. While NFL regularization offers clearer edge information than Tikhonov regularization, it carries a biased estimate of the l1 penalty, leading to an underestimation of the reconstructed concentration and adversely affecting the quantitative properties. In this paper, a new nonconvex regularization method including min-max concave (MC) and total variation (TV) regularization is proposed. This method utilized MC penalty to provide nearly unbiased sparse constraints and adds the TV penalty to provide a uniform intensity distribution of images. By combining the alternating direction multiplication method (ADMM) and the two-step parameter selection method, a more accurate quantitative MPI reconstruction was realized. The performance of the proposed method was verified on the simulation data, the Open-MPI dataset, and measured data from a homemade MPI scanner. The results indicate that the proposed method achieves better image quality while maintaining the quantitative properties, thus overcoming the drawback of intensity underestimation by the NFL method while providing edge information. In particular, for the measured data, the proposed method reduced the relative error in the intensity of the reconstruction results from 28% to 8%.

Assembly of Functional Co(II) Metal-Organic Frameworks through a Mixed Ligand Strategy: Structure and Photocatalytic Degradation Properties.

Four Co(II)-based metal-organic frameworks (MOFs) were constructed by a mixed ligand strategy under solvothermal conditions. The controllable modification of the bridging groups in the secondary building units was realized by changing the anions in MOFs 1-3. The MOF 4 with 3D framework structure was obtained by regulating the solvent ratio following the synthesis process of MOF 3. Furthermore, the MOFs 1-4 exhibited efficient photocatalytic activity for the degradation of malachite green (MG) dye without any photosensitizer or cocatalyst under a low-energy light source, the decolorization ratio of MG all reached more than 96.0% within 60 min, and maximal degradation was obtained to be 99.4% (MOF 4). The recycling experiments showed that the degradation rate of MG was still higher than 91% after 10 cycles. In the MOF 4 as representation, the photocatalytic process was explored systematically. The possible mechanism of catalytic degradation was discussed, which proved the existence of efficient oxidation active factors (•O2-, •OH, and h+). The possible intermediates and degradation pathways were investigated based on high-performance liquid chromatography tandem mass spectrometry. Additionally, MOFs 1-4 also exhibited excellent photocatalytic activity for the degradation of methylene blue, methyl violet, rhodamine B, and basic red 9.

The short- and long-term effects of community-family-doctor-based type 2 diabetes self-management interventions.

OBJECTIVES: The popularity of contracted family doctor services in China has been growing in recent years, but community-family-doctor-based type 2 diabetes mellitus (T2DM) intervention programs have yet to be adequately studied. This study was to evaluate the short- and long-term effects of community-family-doctor-based self-management interventions for T2DM and to explore strategies for long-term glycemic control. STUDY DESIGN: This was a randomized controlled trial. METHODS: A total of 144 eligible participants were randomly assigned to intervention and control groups. The control group received only routine community diabetes care, and the intervention group received community-family-doctor-based interventions involving the same standard of care. The interventions lasted for 3 months, and the follow-up was continued for 15 months. Intention-to-treat analysis and generalized estimation equations were then used to determine the short- and long-term effects of the interventions on glycated hemoglobin (HbA1c), diabetes self-management, and medication adherence. RESULTS: There were statistically significantly greater improvements in all aspects of the intervention group after 3 months of intervention. Compared with baseline, changes in the attitude (ß = 0.384, 95% confidence interval [CI; 0.194, 0.574], P < 0.001), practice (ß = 1.751, 95% CI [0.762, 2.739], P = 0.001), and knowledge, attitudes, practice total scores (ß = 2.338, 95% CI [0.682, 3.995], P = 0.006) of patients in the intervention group were statistically significant after 15 months, and the HbA1c (8.19 ± 1.73%), knowledge (16.42 ± 3.21), and medication adherence (5.53 ± 1.76) scores were slightly better than those at baseline, although not statistically significant (P > 0.05). CONCLUSIONS: T2DM self-management interventions based on community family doctors improved patients' HbA1c, diabetes self-management, and medication adherence, did not do so significantly in the long term.

The association of intraocular efavirenz concentrations and HIV-1 viral load among persons with HIV.

OBJECTIVE: Efavirenz (EFV) is commonly used in combination antiretroviral therapy (cART). However, in our previous study, many persons living with human immunodeficiency virus (HIV) exhibited ocular complications despite undergoing effective cART. Here, we aimed to determine the intraocular EFV concentrations in the vitreous and analyze the factors affecting viral load in the vitreous in patients with HIV-associated retinopathies. DESIGN: Observational, retrospective study. METHODS: Fourteen patients receiving EFV in combination with an antiretroviral therapy who underwent pars plana vitrectomy (PPV) were enrolled between January 2019 and August 2022. The patients were divided into two groups based on presence or absence of retinal detachment (RD). Patient characteristics and HIV-1 RNA levels in plasma and vitreous were recorded during PPV. Paired blood plasma and vitreous samples were obtained for EFV concentration analysis using using ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) . RESULTS: The median age of the enrolled patients was 48 years (interquartile range [IQR], 32.25-53.25), including 12 men and 2 females. Median vitreous and plasma EFV concentrations were 141.5 (IQR, 69.63-323.75) and 2,620 ng/mL (1,680-4,207.5), respectively. Median ratio of vitreous/plasma EFV concentrations in the paired samples among all participants was 0.053 (0.018-0.118). Median vitreous/plasma EFV concentrations significantly differed between the non-RD and RD groups (0,04 vs 0.12, p = 0.042) .ConclusionsThe vitreous EFV concentrations were insufficient to inhibit viral replication in intraocular tissues, which may be due to poor penetration of the blood-retinal barrier. High vitreous EFV concentrations were associated with retinal detachment, indicating a correlation between the EFV concentration and the severity of blood-retinal barrier disruption. It implied that EFV was not a suitable antiviral drug to inhibit the HIV-1 replication in ocular tissues.

Relationship between shift work, night work, and headache and migraine risk: A meta-analysis of observational studies.

BACKGROUND: To date, there is insufficient research on whether shift work and night work increase the risk of experiencing headaches and migraines. OBJECTIVES: This study aimed to evaluate the potential association between shift work, night shift work, and headache/migraine. METHODS: We conducted a thorough search of the PubMed, Embase, and Web of Science databases up until October 2023 to identify relevant studies. Our inclusion criteria focused on observational studies that investigated the association between shift work exposure and headache/migraine outcomes. We extracted adjusted risk estimates from each study and calculated pooled odds ratios using either fixed or random-effects models. Our methodology followed the Meta-Analysis Group guidelines for observational studies in epidemiology. To ensure accuracy and consistency, two investigators independently reviewed the retrieved records and extracted data based on the predefined inclusion criteria. RESULTS: This meta-analysis included a total of seven studies involving 422,869 participants. The pooled analysis revealed a significant association between shift work and an increased risk of headaches (HR = 1.32, 95% CI: 1.15-1.52, P < 0.001). Specifically, individuals working night shifts had a 44% higher risk of developing headaches (HR = 1.44, 95% CI: 1.09-1.90, P = 0.011). Furthermore, shift work was also found to be associated with a higher incidence of migraines (HR = 1.63, 95% CI: 1.27-2.08, P < 0.001). Interestingly, night shift work was associated with a decreased incidence of migraines (HR = 0.74, 95% CI: 0.57-0.96, P = 0.024). CONCLUSION: Our study found a noteworthy association between shift work/night work and the occurrence of headaches and migraines. However, it is important to note that our study does not establish a causal relationship. Future research should investigate potential common vulnerability factors, such as genetics or health behaviors. This knowledge can help inform the implementation of preventive measures and interventions to mitigate the health risks associated with shift work.

The implication of instructional design for deciduous tooth identification in a dental morphology course for undergraduate dental students.

Background/purpose: The pediatric dentistry courses are lacking in our six-year undergraduate dental education. The purpose of this study was to evaluate the implication of instructional design for deciduous tooth identification in a dental morphology course for undergraduate dental students through students' perspectives. Materials and methods: A total of 34 s-year dental students who took this dental morphology course were invited to fill out the questionnaire for survey of instructional design for deciduous tooth identification after the class. Results: Of the 34 dental students, 32 of them participated in the survey with a valid response rate of 94.1%. The results showed that most students found the learning activity of instructional design for deciduous tooth identification to be helpful for improving their knowledge about deciduous dentition. Most of them also had positive attitude towards this instructional design. Conclusion: Since the proportion of pediatric dentistry courses in the undergraduate dental education is very low and children's oral problems are indeed faced by all dentists, it is important to add learning units of pediatric dentistry-related knowledge in different undergraduate dental professional courses or to propose strategies to promote students' awareness of self-directed learning about pediatric dentistry. This study may serve as a model for other undergraduate dental courses in Taiwan.

Revealing the Effect of the [CoO]6 Microstructure in Pseudocapacitance by Controlled Delithium of LiCoO2.

Revealing the in-depth structure-property relationship and designing specific capacity electrodes are particularly important for supercapacitors. Despite many efforts made to tune the composition and electronic structure of cobalt oxide for pseudocapacitance, insight into the [CoO]6 octahedron from the microstructure is still insufficient. Herein, we present a tunable [CoO]6 octahedron microstructure in LiCoO2 by a chemical delithiation process. The c-strained strain of the [CoO]6 octahedron is induced to form higher valence Co ions, and the (003) crystalline layer spacing increases to allow more rapid participation of OH- in the redox reaction. Interestingly, the specific capacity of L0.75CO2 is nearly four times higher than that of LiCoO2 at 10 mA g-1. The enhanced activity originated from the asymmetric strain [CoO]6 octahedra, resulting in enhanced electronic conductivity and Co-O hybridization for accelerated redox kinetics. This finding provides new insights into the modification strategy for pseudocapacitive transition metal oxides.

Non-Infectious Uveitis and Pregnancy, is There an Optimal Treatment? Uveitis Course and Safety of Uveitis Treatment in Pregnancy.

In pregnancy, a plethora of factors causes changes in maternal immunity. Uveitis flare-ups are more frequent in the first trimester and in undertreated patients. Management of non-infectious uveitis during pregnancy remains understudied. A bibliographic review to consolidate existing evidence was performed by a multidisciplinary group of Ophthalmologists, Gynaecologists and Rheumatologists. Our group recommends initial management with minimum-required doses of corticosteroids, preferably locally, to treat intraocular inflammation whilst ensuring good neonatal outcomes. If ineffective, clinicians should consider addition of Cyclosporine, Azathioprine or Certolizumab pegol, which are seemingly safe in pregnancy. Other therapies (such as Methotrexate, Mycophenolate Mofetil and alkylating agents) are teratogenic or have a detrimental effect on the foetus. Furthermore, careful multidisciplinary preconception discussions and close follow-up are recommended, monitoring for flare-ups and actively tapering medication doses, with a primary endpoint focused on protecting ocular tissues from inflammation, whilst giving minimal risk of poor pregnancy and foetal outcomes.

Combination of time domain-system matrix and x-space methods to reconstruct magnetic particle images with isotropic resolution.

Objective. Imaging of superparamagnetic iron oxide nanoparticles based on their non-linear response to alternating magnetic fields shows promise for imaging cells and vasculature in healthy and diseased tissue. Such imaging can be achieved through x-space reconstruction typically along a unidirectional Cartesian trajectory, which rapidly convolutes the particle distribution with a 'anisotropic blurring' point spread function (PSF), leading to images with anisotropic resolution.Approach. Here we propose combining the time domine-system matrix and x-space reconstruction methods into a forward model, where the output of the forward model is the PSF-blurred x-space reconstructed image. We then treat the blur as an inverse problem solved by Kaczmarz iteration.Main results. After we have proposed the method optimization, the normal resolution of simulation and device images has been increased from 3.5 mm and 5.25 mm to 1.5 mm and 3.25 mm, which has reached the level in the tangential resolution. Quantitative indicators of image quality such as PSNR and SSIM have also been greatly improved.Significance. Simulation and imaging of real phantoms indicate that our approach provides better isotropic resolution and image quality than the x-space method alone or other methods for removing PSF blur. Using our proposed method to optimize the image quality of x-space reconstructed images using unidirectional Cartesian trajectories, it will promote the clinical application of MPI in the future.

Sleep and its association with dental caries or myopia in first graders.

AIM: First grade is a transition from pre-school to school-age. The change in lifestyle behaviours such as sleep may have a physiological response, which contributes to the presence or absence of two highly incident diseases: dental caries or myopia. The aim of the study was to examine the association between sleep and myopia as well as sleep and dental caries in first graders. DESIGN: It is a cross-sectional study. METHODS: This was a recruitment phase of an interventional study. A total of 338 children whose caregivers completed a Children's Sleep Habits Questionnaire. Caregivers also provided information regarding myopia and caries status of children and their parents. Binary logistic regression was applied to analyse the potential risk factors. RESULTS: Dental caries and myopia rates were 45.9% and 9.5%, respectively. After adjusting for children's gender, children's age, fathers with caries and mothers with caries, the odds ratio for dental caries in children who slept less than 9 h when compared to those who slept for nine and more hours was 1.94. Mothers with caries were 3.37 times more likely to have children with caries than mothers without caries. However, sleep was not associated with myopia in first graders. CONCLUSION: Sleeping less than 9 h and maternal caries were risk factors of children developing dental caries. Future sleep and myopia studies can be conducted on higher graders who may present prolonged exposure and accumulations of myopic risk factors. IMPLICATIONS: Screening of children with insufficient sleep is needed for nurses to enable the early identification of high-risk groups for dental caries in school settings. Family nurses are encouraged to work with family members to implement tailored sleep interventions, in order to facilitate better sleep and oral health practices in both school and home settings. REGISTRATION: This study protocol was registered on ClinicalTrials.gov (Registration number: Redacted).

Prediction of 5-year overall survival of diffuse large B-cell lymphoma on the pola-R-CHP regimen based on 2-year event-free survival and progression-free survival.

This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS ) or PFS (HRPFS ) and the HR for OS (HROS ) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

HMOX1-overexpressing mesenchymal stem cell-derived exosomes facilitate diabetic wound healing by promoting angiogenesis and fibroblast function.

Many scholars have suggested that exosomes (Exos) can carry active molecules to induce angiogenesis and thus accelerate diabetic wound healing. Heme oxygenase-1 (HO-1) encoded by the gene HMOX1 promotes wound healing in DM by enhancing angiogenesis. Nevertheless, whether HMOX1 regulates wound healing in DM through mesenchymal stem cell-derived exosomes (MSC-Exos) remains to be further explored. The primary isolated- and cultured-cells expressed MSC-specific marker proteins, and had low immunogenicity and multi-differentiation potential, which means that MSCs were successfully isolated in this study. Notably, HO-1 protein expression was significantly higher in Exo-HMOX1 than in Exos, indicating that HMOX1 could be delivered to Exos as an MSCs-secreted protein. After verifying the -Exo structure, fibroblasts, keratinocytes, and human umbilical vein endothelial cells (HUVECs) were incubated with Exo-HMOX1 or Exo, and the findings displayed that Exo-HMOX1 introduction promoted the proliferation and migration of fibroblasts, keratinocytes and the angiogenic ability of HUVECs in vitro study. After establishing diabetic wound model mice, PBS, Exo, and Exo-HMOX1 were subcutaneously injected into multiple sites on the 1st, 3rd, 7th, and 14th day, DM injected with Exo-HMOX1 showed faster wound healing, re-epithelialization, collagen deposition, and angiogenesis than those in PBS and Exo groups in vitro study. In summary, Exo-HMOX1 could enhance the activity of fibroblasts, keratinocytes, and HUVEC, and accelerate wound healing by promoting angiogenesis in DM.

In vitro ischemic preconditioning mediates the Ca2+/CaN/NFAT pathway to protect against oxygen-glucose deprivation-induced cellular damage and inflammatory responses.

Oxygen-glucose deprivation (OGD) is a critical model for studying hypoxic-ischemic cerebrovascular disease in vitro. This paper is to investigate the protection of OGD-induced cellular damage and inflammatory responses by OGD preconditioning in vitro, to provide a theoretical basis for OGD preconditioning to improve the prevention and prognosis of ischemic stroke. OGD or OGD preconditioning model was established by culturing the PC12 cell line in vitro, followed by further adding A23187 (calcium ion carrier) or CsA (calcium ion antagonist). Cell viability was detected by MTT, apoptosis by Hoechst 33,258 staining, the levels of TNF-α and IL-1ß mRNA by RT-qPCR and ELISA, and the levels of CaN, NFAT, COX-2 by RT-qPCR and Western blot. Cell viability was decreased, and apoptosis, inflammatory cytokines, and CaN, NFAT, and COX-2 levels were notably increased upon OGD, while OGD pretreatment significantly increased cell viability and decreased apoptosis, inflammation, and the Ca2+/CaN/NFAT pathway. Treatment with A23187 decreased cell viability, promoted apoptosis, and significantly increased TNF-α, IL-1ß, CaN, NFAT, and COX-2 levels, while CsA treatment reduced the opposite results. In vitro OGD preconditioning mediates the Ca2+/CaN/NFAT pathway to protect against OGD-induced cellular damage and inflammatory responses.

Cadherin-5 facilitated the differentiation of human induced pluripotent stem cells into sinoatrial node-like pacemaker cells by regulating ß-catenin.

Our study was conducted to investigate whether cadherin-5 (CDH5), a vascular endothelial cell adhesion glycoprotein, could facilitate the differentiation of human induced pluripotent stem cells (hiPSCs) into sinoatrial node-like pacemaker cells (SANLPCs), following previous findings of silk-fibroin hydrogel-induced direct conversion of quiescent cardiomyocytes into pacemaker cells in rats through the activation of CDH5. In this study, the differentiating hiPSCs were treated with CDH5 (40 ng/mL) between Day 5 and 7 during cardiomyocytes differentiation. The findings in the present study demonstrated that CDH5 stimulated the expression of pacemaker-specific markers while suppressing markers associated with working cardiomyocytes, resulting in an increased proportion of SANLPCs among hiPSCs-derived cardiomyocytes (hiPSC-CMs) population. Moreover, CDH5 induced typical electrophysiological characteristics resembling cardiac pacemaker cells in hiPSC-CMs. Further mechanistic investigations revealed that the enriched differentiation of hiPSCs into SANLPCs induced by CDH5 was partially reversed by iCRT14, an inhibitor of ß-catenin. Therefore, based on the aforementioned findings, it could be inferred that the regulation of ß-catenin by CDH5 played a crucial role in promoting the enriched differentiation of hiPSCs into SANLPCs, which presents a novel avenue for the construction of biological pacemakers in forthcoming research.