Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.

Structural insights into the interactions between lloviu virus VP30 and nucleoprotein.

The family Filoviridae comprises many notorious viruses, such as Ebola virus (EBOV) and Marburg virus (MARV), that can infect humans and nonhuman primates. Lloviu virus (LLOV), a less well studied filovirus, is considered a potential pathogen for humans. The VP30 C-terminal domain (CTD) of these filoviruses exhibits nucleoprotein (NP) binding and plays an essential role in viral transcription, replication and assembly. In this study, we confirmed the interactions between LLOV VP30 CTD and its NP fragment, and also determined the crystal structure of the chimeric dimeric LLOV NP-VP30 CTD at 2.50 Å resolution. The structure is highly conserved across the family Filoviridae. While in the dimer structure, only one VP30 CTD binds the NP fragment, which indicates that the interaction between LLOV VP30 CTD and NP is not strong. Our work provides a preliminary model to investigate the interactions between LLOV VP30 and NP and suggests a potential target for anti-filovirus drug development.

Feasibility Investigation of Ipsilateral Reoperations by Thoracoscopy for Major Lung Resection.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has become the preferred approach for minimizing harm from thoracic operations. There is no report, however, which has discussed the feasibility of VATS in ipsilateral reoperation of major lung resection. METHODS: The present study included patients who had undergone ipsilateral reoperation of major lung resection by VATS from October 2009 to May 2017. Referring clinical data were recruited for analysis. RESULTS: Fourteen patients were recruited in the present study, including nine patients who underwent lobectomy and five who underwent segmentectomy during the second operation. Different hila were found in 6 patients, and pleural adhesions appeared in 10 patients. The average intraoperative blood loss was 203.6 ± 121.7 mL, and the mean operating room time was 2.2 ± 0.5 hours. There were no intraoperative deaths, and only one patient required conversion to thoracotomy. The average drainage time was 5.9 ± 4.6, and the mean hospital stay was 6.7 ± 4.2 days. CONCLUSION: Though it is technically demanding to safely handle the changed hilum structure caused by the last operation, major lung resection by VATS is feasible for ipsilateral reoperation in appropriate candidates.

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. METHODS: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed. The levels of proteins were detected using western blot. Bioinformatics analysis and luciferase reporter assays were applied to the analysis of the relationship between SNHG16, miR-4518 and PRMT5. Cell viability and apoptosis were measured using MTT and apoptosis ELISA assay, respectively. RESULTS: SNHG16 was highly expressed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. Knockdown of SNHG16 inhibits the viability and induces apoptosis of glioma cells. Further investigation revealed that SNHG16 could up-regulate the expression of miR-4518 targeted gene PRMT5 via acting as an endogenous sponge of miR-4518. Moreover, SNHG16 also affects the expression of Bcl-2 family proteins and the activation of PI3K/Akt signaling pathway. CONCLUSION: Our study revealed a novel SNHG16-miR-4518-PRMT5 pathway regulatory axis in glioma pathogenesis. SNHG16 could be used as a potential therapeutic target in the treatment of glioma.

Recombinant Expression and Bioactivity Comparison of Four Typical Fungal Immunomodulatory Proteins from Three Main Ganoderma Species.

BACKGROUND: More than a dozen of fungal immunomodulatory proteins (FIPs) have been identified to date, most of which are from Ganoderma species. However, little is known about the similarities and differences between different Ganoderma FIPs' bioactivities. In the current study, two FIP genes termed FIP-gap1 and FIP-gap2 from G. applanatum, along with LZ-8 and FIP-gsi, another two representative Ganoderma FIP genes from G. lucidum and G. sinense were functionally expressed in Pichia. Subsequently, bioactivities of four recombinant Ganoderma FIPs were demonstrated and compared. RESULTS: All the four Ganoderma FIP genes could be effectively expressed in P. pastoris GS115 at expression levels ranging from 197.5 to 264.3 mg L- 1 and simply purified by one step chromatography using HisTrap™ FF prepack columns. Amino acid sequence analysis showed that they all possessed the FIP conserved fragments. The homologies of different Ganoderma FIPs were from 72.6 to 86.4%. In vitro haemagglutination exhibited that FIP-gap1, FIP-gsi and LZ-8 could agglutinate human, sheep and mouse red blood cells but FIP-gap2 agglutinated none. Besides, the immunomodulation activities of these Ganoderma FIPs were as: rFIP-gap2 > rFIP-gap1 > rLZ-8 and rFIP-gsi in terms of proliferation stimulation and cytokine induction on murine splenocytes. Additionally, the cytotoxic activity of different FIPs was: rFIP-gap1 > rLZ-8 > rFIP-gsi > rFIP-gap2, examined by their inhibition of three human carcinomas A549, Hela and MCF-7. CONCLUSIONS: Taken together, four typical Ganoderma FIP genes could be functionally expressed in P. pastoris, which might supply as feasible efficient resources for further study and application. Both similarities and differences were indeed observed between Ganoderma FIPs in their amino acid sequences and bioactivities. Comprehensively, rFIP-gaps from G. applanatum proved to be more effective in immunomodulation and cytotoxic assays in vitro than rLZ-8 (G. lucidum) and rFIP-gsi (G. sinense).

Ultra-sensitive film sensor based on Al2O3-Au nanoparticles supported on PDDA-functionalized graphene for the determination of acetaminophen.

An electrochemical sensor of acetaminophen based on poly(diallyldimethylammonium chloride) (PDDA)-functionalized reduced graphene-loaded Al2O3-Au nanoparticles coated onto glassy carbon electrode (Al2O3-Au/PDDA/reduced graphene oxide (rGO)/glass carbon electrode (GCE)) were prepared by layer self-assembly technique. The as-prepared electrode-modified materials were characterized by scanning electron microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy. The electrocatalytic performances of Al2O3-Au/PDDA/rGO-modified glassy carbon electrode toward the acetaminophen were investigated by cyclic voltammetry and differential pulse voltammetry. The modified electrodes of graphene oxide (GO)/GCE, PDDA/rGO/GCE, and Al2O3-Au/PDDA/rGO/GCE were constructed for comparison and learning the catalytic mechanism. The research showed Al2O3-Au/PDDA/rGO/GCE having good electrochemical performance, attributing to the synergetic effect that comes from the special nanocomposite structure and physicochemical properties of Al2O3-Au nanoparticles and graphene. A low detection limit of 6 nM (S/N = 3) and a wide linear detection range from 0.02 to 200 µM (R (2) = 0.9970) was obtained. The preparation of sensor was successfully applied for the detection of acetaminophen in commercial pharmaceutical pills. Graphical abstract Schematic diagram of synthesis of Al2O3-Au/PDDA/rGO/GCE.

ZIF-Co3O4@ZIF-Derived Urchin-Like Hierarchically Porous Carbon as Efficient Bifunctional Oxygen Electrocatalysts.

Co3O4 nanoparticles were sandwiched into interlayers between ZIF-8 and ZIF-67 to form ZIF-Co3O4@ZIF precursors. Pyrolysis of ZIF-Co3O4@ZIF yielded an urchin-like hierarchically porous carbon (Co@CNT/NC), the thorns of which were carbon nanotubes embedded Co nanoparticles. With large specific surface area and hierarchically porous structure, as-prepared Co@CNT/NC exhibited excellent bifunctional oxygen electrocatalytic performances. It has good ORR performance with E1/2 of 0.85 V, which exceeds the Pt/C half-wave potential (E1/2=0.83 V). In addition, Co@CNT/NC has an OER performance close to that of RuO2. To further demonstrate the effect of Co modifying on the properties, the samples were subjected to acid washing treatment. Co-based nanoparticles were proved to After acid washing, there was obvious loss of Co particles in Co@CNT/NC, resulting in poor oxygen electrocatalysis. So, the pyrolysis products of ZIF-8-Co3O4@ZIF-67 retained large specific surface area and porous structure can be retained, and on the other hand, the carbon tube structure and original polyhedron framework. Besides, existence of Co nanoparticle@carbon nanotube provided more active sites and improved the ORR and OER performances.

Nitrogen, sulfur co-coordinated iron single-atom catalysts with the optimized electronic structure for highly efficient oxygen reduction in Zn-air battery and fuel cell.

Atomically dispersed iron-nitrogen-carbon (FesbndNsbndC) materials have been considered ideal catalysts for the oxygen reduction. Unfortunately, designing and adjusting the electronic structure of single-atom Fe sites to boost the kinetics and activity still faces grand challenges. In this work, the coordination environment engineering is developed to synthesize the FeSA/NSC catalyst with the tailored N, S co-coordinated Fe atomic site (Fe-N3S site). The structural characterizations and theoretical calculations demonstrate that the incorporation of sulfur can optimize the charge distribution of Fe atoms to weaken the adsorption of OH* and facilitate the desorption of OH*, thus leading to enhanced kinetics process and intrinsic activity. As a result, the S-modified FeSA/NSC exhibits outstanding catalytic activity with the half-wave potentials (E1/2) of 0.915 V and 0.797 V, as well as good stability, in alkaline and acidic electrolytes, respectively. Impressively, the excellent performance of FeSA/NSC is further confirmed in Zn-air batteries (ZABs) and fuel cells, with high peak power densities (146 mW cm-2 and 0.259 W cm-2).

A robotic system for transthoracic puncture of pulmonary nodules based on gated respiratory compensation.

BACKGROUND AND OBJECTIVE: With the urgent demands for rapid and precise localization of pulmonary nodules in procedures such as transthoracic puncture biopsy and thoracoscopic surgery, many surgical navigation and robotic systems are applied in the clinical practice of thoracic operation. However, current available positioning methods have certain limitations, including high radiation exposure, large errors from respiratory, complicated and time-consuming procedures, etc. METHODS: To address these issues, a preoperative computed tomography (CT) image-guided robotic system for transthoracic puncture was proposed in this study. Firstly, an algorithm for puncture path planning based on constraints from clinical knowledge was developed. This algorithm enables the calculation of Pareto optimal solutions for multiple clinical targets concerning puncture angle, puncture length, and distance from hazardous areas. Secondly, to eradicate intraoperative radiation exposure, a fast registration method based on preoperative CT and gated respiration compensation was proposed. The registration process could be completed by the direct selection of points on the skin near the sternum using a hand-held probe. Gating detection and joint optimization algorithms are then performed on the collected point cloud data to compensate for errors from respiratory motion. Thirdly, to enhance accuracy and intraoperative safety, the puncture guide was utilized as an end effector to restrict the movement of the optically tracked needle, then risky actions with patient contact would be strictly limited. RESULTS: The proposed system was evaluated through phantom experiments on our custom-designed simulation test platform for patient respiratory motion to assess its accuracy and feasibility. The results demonstrated an average target point error (TPE) of 2.46 ± 0.68 mm and an angle error (AE) of 1.49 ± 0.45° for the robotic system. CONCLUSIONS: In conclusion, our proposed system ensures accuracy, surgical efficiency, and safety while also reducing needle insertions and radiation exposure in transthoracic puncture procedures, thus offering substantial potential for clinical application.

Case report: One case of refractory membranous nephropathy with hypokalemia after rituximab infusion was switched to obinutuzumab without recurrence of hypokalemia.

Rituximab (RTX) is a monoclonal antibody commonly used to treat PLA2R-associated membranous nephropathy (MN). This report presents a case of refractory MN in a patient who experienced severe hypokalemia, a rare but clinically significant condition, after the 5th RTX infusion. Clinicians should be aware of the potential for hypokalemia and its management during or after RTX infusion. After the onset of hypokalemia, the patient received treatment with obinutuzumab and achieved partial remission of renal disease without experiencing further hypokalemia. Obinutuzumab may be a viable alternative therapy for refractory membranous nephropathy that develops side effects after rituximab therapy or is refractory to it, but further studies are necessary to determine its efficacy and safety.

Tailoring the d-band electronic structure of deficient LaMn0.3Co0.7O3-δ perovskite nanofibers for boosting oxygen electrocatalysis in Zn-Air batteries.

The development and design of efficient bifunctional electrocatalysts towards oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are crucial for rechargeable Zinc-air batteries (ZABs). Optimizing the d-band structure of active metal center in perovskite oxides is an effective method to enhance ORR/OER activity by accelerating the rate-determining step. Herein, we report a deficient method to optimize the d-band structure of Co ions in LaMn0.3Co0.7O3-δ (LMCO-2) perovskite nanofibers, which regulates the mutual effect between B-site Co ions and reactive oxygen intermediates. It is proved by experiment and theoretical calculation that the d-band center (Md) of transition metal ions in LMCO-2 is moved up and the electron filling number of eg orbital in B site is 1.01, thus leading to the reduction of Gibbs free energy required for ORR rate-determining step (OH*→H2O*) to 0.22 eV and promoting reaction proceeds. In this manner, LMCO-2 showed good bifunctional oxygen electrocatalytic activity, with a half-wave potential of 0.71 V vs. RHE. Furthermore, the high specific capacity of 811.54 mAh g-1 and power density of 326.56 mW cm-2 were obtained by using LMCO-2 as the cathode catalyst for ZABs. This study proved the feasibility of d-band structure regulation to enhance the electrocatalytic activity of perovskite oxides.

Scaffold-Free Tracheal Engineering via a Modular Strategy Based on Cartilage and Epithelium Sheets.

Tracheal defects lead to devastating problems, and practical clinical substitutes that have complex functional structures and can avoid adverse influences from exogenous bioscaffolds are lacking. Herein, a modular strategy for scaffold-free tracheal engineering is developed. A cartilage sheet (Cart-S) prepared by high-density culture is laminated and reshaped to construct a cartilage tube as the main load-bearing structure in which the chondrocytes exhibit a stable phenotype and secreted considerable cartilage-specific matrix, presenting a native-like grid arrangement. To further build a tracheal epithelial barrier, a temperature-sensitive technique is used to construct the monolayer epithelium sheet (Epi-S), in which the airway epithelial cells present integrated tight junctions, good transepithelial electrical resistance, and favorable ciliary differentiation capability. Epi-S can be integrally transferred to inner wall of cartilage tube, forming a scaffold-free complex tracheal substitute (SC-trachea). Interestingly, when Epi-S is attached to the cartilage surface, epithelium-specific gene expression is significantly enhanced. SC-trachea establishes abundant blood supply via heterotopic vascularization and then is pedicle transplanted for tracheal reconstruction, achieving 83.3% survival outcomes in rabbit models. Notably, the scaffold-free engineered trachea simultaneously satisfies sufficient mechanical properties and barrier function due to its matrix-rich cartilage structure and well-differentiated ciliated epithelium, demonstrating great clinical potential for long-segmental tracheal reconstruction.

A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model.

A practical strategy for engineering a trachea-like structure that could be used to repair or replace a damaged or injured trachea is an unmet need. Here, we fabricated bioengineered cartilage (BC) rings from three-dimensionally printed fibers of poly(ɛ-caprolactone) (PCL) and rabbit chondrocytes. The extracellular matrix (ECM) secreted by the chondrocytes combined with the PCL fibers formed a "concrete-rebar structure," with ECM deposited along the PCL fibers, forming a grid similar to that of native cartilage. PCL fiber-hydrogel rings were then fabricated and alternately stacked with BC rings on silicone tubes. This trachea-like structure underwent vascularization after heterotopic transplantation into rabbits for 4 weeks. The vascularized bioengineered trachea-like structure was then orthotopically transplanted by end-to-end anastomosis to native rabbit trachea after a segment of trachea had been resected. The bioengineered trachea-like structure displayed mechanical properties similar to native rabbit trachea and transmural angiogenesis between the rings. The 8-week survival rate in transplanted rabbits was 83.3%, and the respiratory rate of these animals was similar to preoperative levels. This bioengineered trachea-like structure may have potential for treating tracheal stenosis and other tracheal injuries.

Extracellular Vesicles in Tissue Engineering: Biology and Engineered Strategy.

Extracellular vesicles (EVs), acting as an important ingredient of intercellular communication through paracrine actions, have gained tremendous attention in the field of tissue engineering (TE). Moreover, these nanosized extracellular particles (30-140 nm) can be incorporated into biomaterials according to different principles to facilitate signal delivery in various regenerative processes directly or indirectly. Bioactive biomaterials as the carrier will extend the retention time and realize the controlled release of EVs, which further enhance their therapeutic efficiency in tissue regeneration. Herein, the basic biological characteristics of EVs are first introduced, and then their outstanding performance in exerting direct impacts on target cells in tissue regeneration as well as indirect effects on promoting angiogenesis and regulating the immune environment, due to specific functional components of EVs (nucleic acid, protein, lipid, etc.), is emphasized. Furthermore, different design ideas for suitable EV-loaded biomaterials are also demonstrated. In the end, this review also highlights the engineered strategies, which aim at solving the problems related to natural EVs such as highly heterogeneous functions, inadequate tissue targeting capabilities, insufficient yield and scalability, etc., thus promoting the therapeutic pertinence and clinical potential of EV-based approaches in TE.

A Simple and Efficient Strategy for Preparing a Cell-Spheroid-Based Bioink.

Cell spheroids are a promising bioprinting building block that can mimic several physiological conditions in embryonic development. However, it remains challenging to efficiently prepare cell-spheroid-based bioink (Sph-bioink) with favorable printability and spheroid fusion ability. In this work, a poly(N-isopropylacrylamide) (PNIPAAm)-based porous hydrogel is developed as an "all-in-one" platform for Sph-bioink preparation. On the one hand, the nonadhesive porous structure in hydrogels is an effective tool for fabricating adipose-derived stem cell (ASC) spheroids in high yield, and the hydrogel itself also serves as a "carrier" for conveniently transferring cell spheroids to the bioprinter. On the other hand, the integration of redox/thermo-responsiveness allows the hydrogel to shift from a solid spheroid-making tool to an extrudable bioprinting medium that is sensitive to temperature. These features enabled a simple procedure for preparing Sph-bioink, in which the cell spheroids were densely packed to retain fusion capability. The present study also demonstrates that ASC spheroids formed in hydrogels have good biological preservation and superior chondrogenic differentiation, and verified the feasibility of using Sph-bioink to build custom-shaped mature cartilage. In conclusion, this strategy provides a simple, efficient, and standardized approach for Sph-bioink preparation, making it possible to produce tissue-engineered constructs with accelerated maturation and functionalization.

Development and validation of a deep learning model to predict the survival of patients in ICU.

BACKGROUND: Patients in the intensive care unit (ICU) are often in critical condition and have a high mortality rate. Accurately predicting the survival probability of ICU patients is beneficial to timely care and prioritizing medical resources to improve the overall patient population survival. Models developed by deep learning (DL) algorithms show good performance on many models. However, few DL algorithms have been validated in the dimension of survival time or compared with traditional algorithms. METHODS: Variables from the Early Warning Score, Sequential Organ Failure Assessment Score, Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation (APACHE) II, and APACHE IV models were selected for model development. The Cox regression, random survival forest (RSF), and DL methods were used to develop prediction models for the survival probability of ICU patients. The prediction performance was independently evaluated in the MIMIC-III Clinical Database (MIMIC-III), the eICU Collaborative Research Database (eICU), and Shanghai Pulmonary Hospital Database (SPH). RESULTS: Forty variables were collected in total for model development. 83 943 participants from 3 databases were included in the study. The New-DL model accurately stratified patients into different survival probability groups with a C-index of >0.7 in the MIMIC-III, eICU, and SPH, performing better than the other models. The calibration curves of the models at 3 and 10 days indicated that the prediction performance was good. A user-friendly interface was developed to enable the model's convenience. CONCLUSIONS: Compared with traditional algorithms, DL algorithms are more accurate in predicting the survival probability during ICU hospitalization. This novel model can provide reliable, individualized survival probability prediction.

Interactions Between Immunomodulatory Biomaterials and Immune Microenvironment: Cues for Immunomodulation Strategies in Tissue Repair.

The foreign body response (FBR) caused by biomaterials can essentially be understood as the interaction between the immune microenvironment and biomaterials, which has severely impeded the application of biomaterials in tissue repair. This concrete interaction occurs via cells and bioactive substances, such as proteins and nucleic acids. These cellular and molecular interactions provide important cues for determining which element to incorporate into immunomodulatory biomaterials (IMBs), and IMBs can thus be endowed with the ability to modulate the FBR and repair damaged tissue. In terms of cellular, IMBs are modified to modulate functions of immune cells, such as macrophages and mast cells. In terms of bioactive substances, proteins and nucleic acids are delivered to influence the immune microenvironment. Meanwhile, IMBs are designed with high affinity for spatial targets and the ability to self-adapt over time, which allows for more efficient and intelligent tissue repair. Hence, IMB may achieve the perfect functional integration in the host, representing a breakthrough in tissue repair and regeneration medicine.

Three-dimensional printing template for intraoperative localization of pulmonary nodules in the pleural cavity.

Objectives: Localization of pulmonary nodules is challenging. However, traditional localization methods have high radiation doses and a high risk of complications. We developed a noninvasive 3-dimensional printing navigational template for intraoperative localization. It can reduce puncture-related complications and simplify the localization process. This study will verify the feasibility of this method. Methods: Patients with peripheral pulmonary nodules were included in this study. The computed tomography scan sequences were obtained to design a digital template model, which was then imported into a 3-dimensional printer to produce a physical navigational template. Finally, the navigational template is placed into the patient's pleural cavity for intraoperative localization. The precision of the nodule localization and associated complications were evaluated. Results: Twelve patients were finally included in this study. Intraoperative navigational template localization was used in all patients. The success rate of intraoperative nodule localization was 100%, and the median time of localization was 19.5 minutes (range, 16-23.5 minutes). The deviation median of the navigational template was 2.1 mm (range, 1.1-2.7 mm). Among the included patients, no significant complications occurred during intraoperative localization. Conclusions: The 3-dimensional printing template for intraoperative localization is feasible, will cause no trauma to the patient, and has acceptable accuracy for application in nodules localization. This navigational template greatly simplifies the localization process and may potentially break the dependence of percutaneous localization on computed tomography scanning.

Three-dimensionally printed navigational template: a promising guiding approach for lung biopsy.

Background: Percutaneous transthoracic lung biopsy is customarily conducted under computed tomography (CT) guidance, which primarily depends on the conductors' experience and inevitably contributes to long procedural duration and radiation exposure. Novel technique facilitating lung biopsy is currently demanded. Methods: Based on the reconstructed anatomical information of CT scans, a three-dimensionally printed navigational template was customized to guide fine-needle aspiration (FNA). The needle insertion site and angle could be indicated by the template after proper placement according to the reference landmarks. From June 2020 to August 2020, patients with peripheral indeterminate lung lesions ≥30 mm in diameter were enrolled in a pilot trial. Cases were considered successful when the virtual line indicated by the template in the first CT scan was pointing at the target, and the rate of success was recorded. The insertion deviation, procedural duration, radiation exposure, biopsy-related complications, and diagnostic yield were documented as well. Results: A total of 20 patients consented to participate, and 2 withdrew. The remaining 18 participants consisting of 11 men and 7 women with a median age of 63 [inter-quartile range (IQR), 50-68] years and a median body mass index (BMI) of 23.5 (IQR, 20.8-25.8) kg/m2 received template-guided FNA. The median nodule size of the patients was 41.2 (IQR, 36.2-51.9) mm and 17 lesions were successfully targeted (success rate, 94.4%). One lesion was not reached through the designed trajectory due to an unpredictable alteration of the lesion's location resulting from pleural effusion. The median deviation between the actual position of the needle tip and the designed route was 9.4 (IQR, 6.8-11.7) mm. The median procedural duration was 10.7 (IQR, 9.7-11.8) min, and the median radiation exposure was 220.9 (IQR, 198.6-249.5) mGy×cm. No major biopsy-related complication was encountered. Definitive diagnosis of malignancy was reached in 13 of the 17 (76.5%) participants. Conclusions: The feasibility and safety of navigational template-guided FNA were preliminarily validated in lung biopsy cohort. Nonetheless, patients with pleural effusion were not recommended to undergo FNA guided by such technique. Trial Registration: This study was registered with ClinicalTrials.gov (identifier: NCT03325907).

Efficacy and Safety of Non-recommended Dose of New Oral Anticoagulants in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Introduction: The real-world treatment of atrial fibrillation (AF) often involves the prescription of new oral anticoagulants (NOACs) using dosing both lower and higher than recommended guidelines. Our study aimed to evaluate the efficacy and safety of non-recommended dosage of NOACs in AF patients. Methods: A systematic search was performed for relevant studies across multiple electronic databases (PubMed, Embase, Cochrane Library, Clinical Trials Registry) from inception to May 1, 2021. Multicenter randomized trials and observational studies were selected with key reporting measures for inclusion involved efficacy outcomes including stroke or systemic thromboembolism along with safety endpoints assessing major or clinically relevant bleeding events. Results: A total of 11 eligible studies were included involving 48,648 patients receiving recommended dose of NOACs and 50,116 patients receiving non-recommended dosage. Compared to AF patients treated with recommended dose regimens, administration of low dose of NOACs was associated with higher risk of stroke/systemic embolism (RR = 1.24, 95% CI 1.14-1.35, P < 0.00001), but without reducing bleeding risk (RR = 1.18, 95% CI 0.91-1.53, P = 0.21) and a higher risk of all-cause mortality (RR = 1.58, 95% CI 1.25-1.99, P = 0.0001). Moreover, high dose of NOACs was associated with higher risk of stroke and systemic embolism efficacy (RR = 1.71, 95% CI 1.06-2.76, P = 0.03) and a non-significant trend to a greater risk of major or clinically relevant bleeding (RR = 1.57, 95% CI 0.96-2.58, P = 0.07). Conclusions: AF patients treated with low dose of NOACs showed equivalent safety but with worse efficacy compared with recommended dose. High dose of NOACs was not superior to recommended dose regimens in preventing stroke/systemic embolism outcomes in AF patients.