Correlated gene modules uncovered by high-precision single-cell transcriptomics.

Correlations in gene expression are used to infer functional and regulatory relationships between genes. However, correlations are often calculated across different cell types or perturbations, causing genes with unrelated functions to be correlated. Here, we demonstrate that correlated modules can be better captured by measuring correlations of steady-state gene expression fluctuations in single cells. We report a high-precision single-cell RNA-seq method called MALBAC-DT to measure the correlation between any pair of genes in a homogenous cell population. Using this method, we were able to identify numerous cell-type specific and functionally enriched correlated gene modules. We confirmed through knockdown that a module enriched for p53 signaling predicted p53 regulatory targets more accurately than a consensus of ChIP-seq studies and that steady-state correlations were predictive of transcriptome-wide response patterns to perturbations. This approach provides a powerful way to advance our functional understanding of the genome.

Electrochemically-driven actuators: from materials to mechanisms and from performance to applications.

Soft actuators, pivotal for converting external energy into mechanical motion, have become increasingly vital in a wide range of applications, from the subtle engineering of soft robotics to the demanding environments of aerospace exploration. Among these, electrochemically-driven actuators (EC actuators), are particularly distinguished by their operation through ion diffusion or intercalation-induced volume changes. These actuators feature notable advantages, including precise deformation control under electrical stimuli, freedom from Carnot efficiency limitations, and the ability to maintain their actuated state with minimal energy use, akin to the latching state in skeletal muscles. This review extensively examines EC actuators, emphasizing their classification based on diverse material types, driving mechanisms, actuator configurations, and potential applications. It aims to illuminate the complicated driving mechanisms of different categories, uncover their underlying connections, and reveal the interdependencies among materials, mechanisms, and performances. We conduct an in-depth analysis of both conventional and emerging EC actuator materials, casting a forward-looking lens on their trajectories and pinpointing areas ready for innovation and performance enhancement strategies. We also navigate through the challenges and opportunities within the field, including optimizing current materials, exploring new materials, and scaling up production processes. Overall, this review aims to provide a scientifically robust narrative that captures the current state of EC actuators and sets a trajectory for future innovation in this rapidly advancing field.

Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization.

Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.

PM2.5 exposure increases dry eye disease risks through corneal epithelial inflammation and mitochondrial dysfunctions.

Dry eye disease (DED) is the most common disease affecting vision and quality of life. PM2.5 was a potential risk of DED. Herein, we conducted animal exposure and cell-based studies to evaluate the pathogenic effect of PM2.5 exposure on the ocular surface and DED etiological mechanisms. C57 mice were exposed to filtered air and PM2.5 aerosol. We assessed health conditions and inflammation of the ocular surface by corneal fluorescein staining and immunohistochemistry. In parallel, cultured human corneal epithelial cells (HCETs) were treated with PM2.5, followed by characterization of cell viability, intracellular ATP level, mitochondrial activities, and expression level of DED relevant mRNA and proteins. In mice, PM2.5 exposure induced severe superficial punctate keratopathy and inflammation in their cornea. In HCETs, cell proliferation and ROS generation followed dose-response and time-dependent manner; meanwhile, mitochondrial ROS (mtROS) level increased and mitochondrial membrane potential (MMP) level decreased. Inflammation cascade was triggered even after short-term exposure. The reduction of ATP production was alleviated with Nrf2 overexpression, NF-κB P65 knockdown, or ROS clearance. Nrf2 overexpression and P65 knockdown reduced inflammatory reaction through decreasing expression of P65 and increasing of Nrf2, respectively. They partly alleviated changes of ROS/mtROS/MMP. This research proved that PM2.5 would cause DED-related inflammation reaction on corneal epithelial cells and further explored its mechanism: ROS from mitochondrial dysfunctions of corneal epithelial cells after PM2.5 exposure partly inhibited the expression of anti-inflammatory protein Nrf2 led the activation of inflammatory protein P65 and its downstream molecules, which finally caused inflammation reaction.

A cross-cultural study of language and cognition: Numeral classifiers and solid object categorization.

One of the central issues in cognition is identifying universal and culturally specific patterns of thought. In this study, we examined how one aspect of culture, a linguistic part of speech known asclassifiers, are related to categorization of solid objects. In Experiment 1, we used a numeral classifier elicitation task to examine the classifiers used by speakers of Hmong, Japanese, and Mandarin Chinese (N = 34) with 135 nouns that referred to solid objects. In Experiment 2, adult speakers of English, Japanese, Mandarin Chinese, and Hmong (N = 64) rated the similarity of 39 pictured objects that depicted a subset of the nouns. All groups classified the objects into natural kinds and artifacts, with the category of humans anchoring both divisions. The main difference that emerged from the study was that speakers of Japanese and English rated humans and animals as more similar to each other than Hmong speakers; Mandarin speakers' ratings of the similarity between humans and animals fell in between those of Hmong and English speakers. However, the pattern of categorization of humans and animals found among speakers of the classifier languages contradicted their patterns of classifier use. The findings help to tease apart the effects of language from other cultural factors that impact cognition.

LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway.

The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.

Meta-analysis of metabolic syndrome and its individual components with risk of atrial fibrillation in different populations.

BACKGROUND: Recent studies have reported the effects of metabolic syndrome (MetS) and its components on atrial fibrillation (AF), but the results remain controversial. Therefore, we performed a meta-analysis to evaluate the relationship between MetS and AF risk. METHODS: Studies were searched from the Cochrane library, PubMed, and Embase databases through May 2020. Adjusted hazard ratios (HRs) and its corresponding 95% confidence intervals (CIs) were extracted and then pooled by using a random effects model. RESULTS: A total of 6 observational cohort studies were finally included. In the pooled analysis, MetS was associated with an increased risk of AF (HR 1.57; 95% CI 1.40-1.77; P < 0.01). And the components of MetS including abdominal obesity (HR 1.37; 95% CI 1.36-1.38; P < 0.01), elevated blood pressure (HR 1.56; 95% CI 1.46-1.66; P < 0.01), elevated fasting glucose (HR 1.18; 95% CI 1.15-1.21; P < 0.01) and low high density cholesterol (HDL) (HR 1.18; 95% CI 1.06-1.32; P < 0.01) was also associated with an increased risk of AF, while high triglyceride (HR 0.99; 95% CI 0.87-1.11, P = 0.82) was not. CONCLUSIONS: Our present meta-analysis suggested that MetS, as well as its components including abdominal obesity, elevated blood pressure, elevated fasting glucose and low HDL cholesterol were associated with an increase in the risk of AF.

Interconversions between Uranium Mono-metallofullerenes: Mechanistic Implications and Role of Asymmetric Cages.

The isolation and structural characterization of three new monometallic uranium metallofullerenes, U@D2(21)-C84, U@Cs(15)-C86, and U@C1(11)-C86, allowed us to complete an interconversion map for all the characterized uranium mono-metallofullerenes. The topological analysis reveals that asymmetric fullerene cages, which may be formed by roll and wrap processes directly from graphene, are the starting points for a series of highly symmetric fullerene structures via top-down and bottom-up growth mechanisms. Moreover, some asymmetric intermediates, such as C1(28324)-C80, can serve as precursors to form either larger cages in consecutive growing processes or smaller cages during cascade shrinking processes. This work provides evidence for both top-down and bottom-up processes happening simultaneously during the arcing processes. This study also sheds light on the prediction of possible cage structures for minor products produced in low yields in the soot.

Fullerenes as Nanocontainers That Stabilize Unique Actinide Species Inside: Structures, Formation, and Reactivity.

Fullerene carbon cages can encapsulate a wide variety of atoms, ions, clusters, or small molecules inside, resulting in stable compounds with unusual structures and electronic properties. These compounds are collectively defined as endohedral fullerenes. The most studied endohedral fullerenes are those containing metal atoms or ions inside, and these are referred to as endohedral metallofullerenes (EMFs). For EMFs, the inner isolated space of the fullerene cages can lead to the stabilization of unique clusters, which are otherwise not synthetically accessible. This offers an excellent environment and opportunity for investigating the nature of previously unobserved metal-metal, metal-non-metal, and metal-fullerene interactions, which are of fundamental interest and importance. Up until now, most of the work in this field has been mainly focused on the rare-earth metals and related elements (groups II, III, and IV). The encapsulation of other elements of the periodic table could potentially lead to totally new structures and bonding motifs and to material properties beyond those of the existing EMFs. Actinides were originally explored as encapsulated elements in fullerenes when Smalley et al. ( Science 1992 , 257 , 1661 ) reported mass spectral evidence of actinide endohedral fullerenes back in 1992. However, the full characterization of these actinide endohedral fullerenes, including single crystal X-ray diffractometric analyses, was not reported until very recently, in 2017. In this Account, we highlight some recent advances made in the field of EMF compounds, focusing primarily on the molecular and electronic structures of novel actinide-based EMFs, new evidence for the formation mechanisms of EMFs, and the influence of the entrapped species on the reactivity and regiochemistry of EMF compounds. We recently reported that some monometallic actinide EMFs represent the first examples of tetravalent metals encapsulated inside fullerenes that exhibit considerably stronger host-guest interactions when compared to those observed for the lanthanide EMFs. These unusually strong metal-cage interactions, along with very high mobilities of the actinides inside the fullerene cages at high temperatures, result in the stabilization of unexpected non-IPR (isolated pentagon rule) fullerene cages encapsulating only one metal ion. Strikingly, such covalent stabilization factors had never been previously observed, although Sm@C2v(19138)-C76 was the first reported mono-EMF with a non-IPR cage, see details below. In addition, we showed that a long sought-after actinide-actinide bond was obtained upon encapsulation of U2 inside an Ih(7)-C80 fullerene cage. More interestingly, we demonstrated that actinide multiple bonds, which are very difficult to prepare by conventional synthetic methods, are stabilized when trapped inside fullerene cages. A totally unexpected and previously unreported uranium carbide cluster, U═C═U, was fully characterized inside an EMF, U2C@Ih(7)-C80, which, for the first time, clearly exhibits two unsupported axial U═C double bonds that are ∼2.03 Šlong. We also discovered that synthetic bis-porphyrin nanocapsules exhibit exquisitely selective complexation of some of these uranium endohedral compounds, providing the basis for a nonchromatographic EMF purification method for actinide EMFs. Regarding EMF formation mechanisms, we suggested that novel carbide EMF structures, that is, Sc2C2@Cs(hept)-C88, are likely key intermediates in a bottom-up fullerene growth process. Additionally, the structural correlation between chiral carbon cages during a bottom-up growth process was shown to be enantiomer-dependent. The influence of the encapsulated clusters on the chemical reactivity of EMFs is discussed at the end, which showed that the regioselectivities of multiple additions to the fullerene cages are remarkably controlled by the encapsulated metal clusters.

Synthesis and Characterization of Non-Isolated-Pentagon-Rule Actinide Endohedral Metallofullerenes U@ C1(17418)-C76, U@ C1(28324)-C80, and Th@ C1(28324)-C80: Low-Symmetry Cage Selection Directed by a Tetravalent Ion.

For the first time, actinide endohedral metallofullerenes (EMFs) with non-isolated-pentagon-rule (non-IPR) carbon cages, U@C80, Th@C80, and U@C76, have been successfully synthesized and fully characterized by mass spectrometry, single crystal X-ray diffractometry, UV-vis-NIR and Raman spectroscopy, and cyclic voltammetry. Crystallographic analysis revealed that the U@C80 and Th@C80 share the same non-IPR cage of C1(28324)-C80, and U@C76 was assigned to non-IPR U@ C1(17418)-C76. All of these cages are chiral and have never been reported before. Further structural analyses show that enantiomers of C1(17418)-C76 and C1(28324)-C80 share a significant continuous portion of the cage and are topologically connected by only two C2 insertions. DFT calculations show that the stabilization of these unique non-IPR fullerenes originates from a four-electron transfer, a significant degree of covalency, and the resulting strong host-guest interactions between the actinide ions and the fullerene cages. Moreover, because the actinide ion displays high mobility within the fullerene, both the symmetry of the carbon cage and the possibility of forming chiral fullerenes play important roles to determine the isomer abundances at temperatures of fullerene formation. This study provides what is probably one of the most complete examples in which carbon cage selection occurs through thermodynamic control at high temperatures, so the selected cages do not necessarily coincide with the most stable ones at room temperature. This work also demonstrated that the metal-cage interactions in actinide EMFs show remarkable differences from those previously known for lanthanide EMFs. These unique interactions not only could stabilize new carbon cage structures, but more importantly, they lead to a new family of metallofullerenes for which the cage selection pattern is different to that observed so far for nonactinide EMFs. For this new family, the simple ionic A q+@C2 n q- model makes predictions less reliable, and in general, unambiguously discerning the isolated structures requires the combination of accurate computational and experimental data.

Stabilization of Giant Fullerenes C2(41)-C90, D3(85)-C92, C1(132)-C94, C2(157)-C96, and C1(175)-C98 by Encapsulation of a Large La2C2 Cluster: The Importance of Cluster-Cage Matching.

Successful isolation and unambiguous crystallographic assignment of a series of higher carbide cluster metallofullerenes present new insights into the molecular structures and cluster-cage interactions of endohedral metallofullerenes. These new species are identified as La2C2@C2(41)-C90, La2C2@D3(85)-C92, La2C2@C1(132)-C94, La2C2@C2(157)-C96, and La2C2@C1(175)-C98. This is the first report for these new cage structures except for D3(85)-C92. Our experimental and theoretical results demonstrate that La2C92-106 are more inclined to exist stably in the carbide form La2C2@C90-104 rather than as the dimetallofullerenes La2@C92-106, which are rationalized by considering a synergistic effect of inserting a C2 unit into the cage, which ensures strong metal-cage interactions by partially neutralizing the charges from the metal ions and by fulfilling the coordination requirement of the La3+ ions as much as possible.

Circulating miRNAs as Potential Biomarkers of Age-Related Macular Degeneration.

Backgroud: Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness of the elder people. This research was intended to demonstrate the different expression of microRNAs (miRNA) in AMD patients and whether they can be used as biomarkers for AMD. METHODS: MiRNAs expression was measured by microarray of 6 AMD cases and 6 gender matched controls. In a larger-sample case-control study with 126 AMD cases and 140 controls, whole blood samples were detected for the differences of miRNA expression. RESULTS: A total of 216 differentially expressed miRNAs (111 increased and 105 decreased miRNAs) were detected from circulating miRNA microarray. Expanded case-control study results showed that the expression of miR-27a-3p, miR-29b-3p and miR-195-5p was increased significantly. Moreover, the level of miR-27a is higher in patients with wet AMD compared to patients with dry AMD. All 3 miRNAs showed a potential diagnostic value for AMD. CONCLUSION: Circulating miRNA levels were significantly varied in AMD patients. Three miRNAs, miR-27a-3p, miR-29b-3p and the miR-195-5p, might be potential diagnostic biomarkers for AMD.

Isolation and Crystallographic Characterization of La2C2@Cs(574)-C102 and La2C2@C2(816)-C104: Evidence for the Top-Down Formation Mechanism of Fullerenes.

Tubular higher fullerenes are prototypes of finite-length end-capped carbon nanotubes (CNTs) whose structures can be accurately characterized by single-crystal X-ray diffraction crystallography. We present here the isolation and crystallographic characterization of two unprecedented higher fullerenes stabilized by the encapsulation of a La2C2 cluster, namely, La2C2@Cs(574)-C102, which has a perfect tubular cage corresponding to a short (10, 0) zigzag carbon nanotube, and La2C2@C2(816)-C104 which has a defective cage with a pyracylene motif inserting into the cage waist. Both cages provide sufficient spaces for the large La2C2 cluster to adopt a stretched and nearly planar configuration, departing from the common butterfly-like configuration which has been frequently observed in midsized carbide metallofullerenes (e.g., Sc2C2@C80-84), to achieve strong metal-cage interactions. More meaningfully, our crystallographic results demonstrate that the defective cage of C2(816)-C104 is a starting point to form the other three tubular cages known so far, i.e., D5(450)-C100, Cs(574)-C102, and D3d(822)-C104, presenting evidence for the top-down formation mechanism of fullerenes. The fact that only the large La2C2 cluster has been found in giant fullerene cages (C>100) and the small clusters M2C2 (M = Sc, Y, Er, etc.) are present in midsized fullerenes (C80-C86) indicates that geometrical matching between the cluster and the cage, which ensures strong metal-cage interactions, is an important factor controlling the stability of the resultant metallofullerenes, in addition to charge transfer.

Effect of bradykinin on TGF-ß1-induced retinal pigment epithelial cell proliferation and extracellular matrix secretion.

BACKGROUND: To evaluate the effect of bradykinin (BK) on TGF-ß1-induced retinal pigment epithelial (RPE) cell proliferation and extracellular matrix secretion and to elucidate the relationship between BK and the Erk/Akt signaling pathway. METHODS: The effects of BK on TGF-ß1-induced RPE cell proliferation were examined via CCK-8 assay. Cell culture supernatant collagen I concentrations were measured via ELISA. Fibronectin (Fn), matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA and protein expression levels were measured via q-PCR and Western blotting, respectively. Changes in Akt/Erk phosphorylation induced by BK and HOE-140 were evaluated via Western blotting. RESULTS: TGF-ß1 stimulated ARPE-19 cell proliferation, which was inhibited by BK, whose effects were inhibited by HOE-140. BK inhibited TGF-ß1-induced collagen I, Fn and MMP-2 secretion in RPE cells, and these effects were inhibited by HOE-140. BK also inhibited TGF-ß1-induced Akt phosphorylation in RPE cells, and these effects were blocked by HOE-140. BK had no significant effect on Erk-mediated signaling. CONCLUSIONS: The findings from this study indicate that BK could be novel therapeutic targets for the treatment of PVR.

Anomalous Compression of D5(450)-C100 by Encapsulating La2C2 Cluster instead of La2.

We demonstrate that a finite-length (10,0) carbon nanotube (CNT) with two fullerene caps, namely D5(450)-C100, is an ideal prototype to study the mechanical responses of small CNTs upon endohedral metal doping. Encapsulation of a large La2C2 cluster inside D5(450)-C100 induces a 5% axial compression of the cage, as compared with the structure of La2@D5(450)-C100. Detailed crystallographic analyses reveal quantitively the flexibility of the [10]cyclacene-sidewall segment and the rigidity of the pentagon-dominating caps for the first time. The internal C2-unit acts as a molecular spring that attracts the surrounding cage carbon atoms through strong interactions with the two moving lanthanum ions. This is the first crystallographic observation of the axial compression of CNTs caused by the internal stress, which enhances our knowledge about the structural deformation of novel carbon allotropes at the atomic level.

In-depth understanding of the chemical properties of rarely explored carbide cluster metallofullerenes: a case study of Sc2 C2 @C3v (8)-C82 that reveals a general rule.

The chemical properties of carbide-cluster metallofullerenes (CCMFs) remain largely unexplored, although several new members of CCMFs have been discovered recently. Herein, we report the reaction between Sc2 C2 @C3v (8)-C82 , which is viewed as a prototypical CCMF because of its high abundance, and 3-triphenylmethyl-5-oxazolidinone (1) to afford the corresponding pyrrolidino derivative Sc2 C2 @C3v (8)-C82 (CH2 )2 NTrt (2; Trt=triphenylmethyl). Single-crystal X-ray crystallography studies of 2 revealed that the reaction takes place at a [6,6]-bond junction, which is directly over the encapsulated C2 unit and is far from either of the two scandium atoms. On the basis of theoretical calculations and by considering previously reports, we have found that a hexagonal carbon ring on the cage of Sc2 C2 @C3v (8)-C82 is highly reactive toward different reagents due to the overlap of high p-orbital axis vector (POAV) angles and large LUMO coefficients. We propose that this highly concentrated area of reactivity is generated by the encapsulation of the Sc2 C2 cluster because this region is absent from the empty fullerene C3v (8)-C82 . Moreover, the absorption and electrochemical results confirm that derivative 2 is more stable than pristine Sc2 C2 @C3v (8)-C82 , thus illuminating its potential applications.

Synthesis and photophysical properties of a Sc3N@C80 -corrole electron donor-acceptor conjugate.

Embedding endohdedral metallofullerenes (EMFs) into electron donor-acceptor systems is still a challenging task owing to their limited quantities and their still largely unexplored chemical properties. In this study, we have performed a 1,3-dipolar cycloaddition reaction of a corrole-based precursor with Sc3 N@C80 to regioselectively form a [5,6]-adduct (1). The successful attachment of the corrole moiety was confirmed by mass spectrometry. In the electronic ground state, absorption spectra suggest sizeable electronic communications between the electron acceptor and the electron donor. Moreover, the addition pattern occurring at a [5,6]-bond junction is firmly proven by NMR spectroscopy and electrochemical investigations performed with 1. In the electronically excited state, which is probed in photophysical assays with 1, a fast electron-transfer yields the radical ion pair state consisting of the one-electron-reduced Sc3 N@C80 and of the one-electron-oxidized corrole upon its exclusive photoexcitation. As such, our results shed new light on the practical work utilizing EMFs as building blocks in photovoltaics.

Comparative efficacy of five approved Janus kinase inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis: a systematic review and network meta-analysis of randomized controlled trials.

Background: The European League of Rheumatology(EULAR)guidelines recommend Janus kinase (JAK) inhibitors for patients with moderate to severe rheumatoid arthritis (RA) who are insensitive or under-responsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). But there was no recommendation for which one was preferred in five currently approved JAK inhibitors. The objective of this network meta-analysis study was to evaluate the efficacy of five JAK inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis. Methods: The randomized controlled trials (RCTs) of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy or combined with csDMARD in the treatment of active RA were searched in database of PubMed, Embase, Web of Science and Cochrane Library, up to December 2023. The control group included placebo or csDMARD. Outcome indicators included American College of Rheumatology 20% response (ACR20), ACR50, ACR70 and the percentage of patients achieving 28-joint disease activity score using C-reactive protein (DAS28(CRP))<2.6 at 12 weeks and 24 weeks. The statistical analysis was performed by Stata14 and RevMan5.4. Data processing, network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots and funnel plots were generated. Risk ratio (RR) and 95% confidence interval (95%CI) as effect sizes to analyze the statistics. Results: This study included thirty-six RCTs with 16,713 patients. All JAK inhibitors were more effective than placebo in ACR20 (RRs ranging between 1.74 and 3.08), ACR50 (RRs ranging between 2.02 and 7.47), ACR70 (RRs ranging between 2.68 and 18.13), DAS28(CRP) < 2.6 (RRs ranging between 2.70 and 7.09) at 12 weeks. Upadacitinib 30 mg and upadacitinib 15 mg showed relatively good efficacy according to their relative SUCRA ranking. All JAK inhibitors were more effective than csDMARD or placebo in ACR20 (RRs ranging between 1.16 and 1.86), ACR50 (RRs ranging between 1.69 and 2.84), ACR70 (RRs ranging between 1.50 and 4.47), DAS28(CRP) < 2.6 (RRs ranging between 2.28 and 7.56) at 24 weeks. Upadacitinib 15 mg + csDMARD and baricitinib 4 mg + csDMARD showed relatively good efficacy according to their relative SUCRA ranking. The safety analysis results such as serious infection, malignancy, major adverse cardiovascular event (MACE), and venous thromboembolic events (VTE) showed no statistical difference. Conclusion: This NMA study indicated that all JAK inhibitors performed better than placebo. Based on the results of this study, upadacitinib 30 mg, upadacitinib 15 mg, upadacitinib 15 mg + csDMARD and baricitinib 4 mg + csDMARD were recommended treatment options with relatively good efficacy and safety. However, attention should be paid to monitoring the occurrence of adverse events in high-risk RA patients with medication. Combination therapy with csDMARD might be more suitable for the maintenance of long-term efficacy. However, in clinical practice, it is still necessary to select the appropriate therapeutic regimen based on the actual clinical situation.

Efficacy and safety of rivaroxaban versus warfarin in the management of unusual site deep vein thrombosis: a retrospective cohort study.

Background: Unusual site deep vein thrombosis (DVT) was defined as venous thromboembolism (VTE) occurring outside the conventional deep veins of the lower extremity or pulmonary arteries. However, the optimal anticoagulation therapy for unusual site DVT remained unclear. This study aims to evaluate the efficacy and safety of rivaroxaban in unusual site DVT. Methods: This retrospective cohort study enrolled consecutive patients at Nanjing Drum Tower Hospital between January 2011 and December 2021 who were diagnosed with unusual site DVT. Patients were divided into two groups based on their ultimate medication choice: the warfarin group and the rivaroxaban group. The demographic characteristics were recorded for all enrolled patients. Clinical outcomes included recurrent VTE, bleeding complications and major bleeding. Results: A total of 1,088 patients were divided into warfarin (n = 514) and rivaroxaban (n = 574) groups. After the stabilized inverse probability of treatment weighting, Hazard Ratios for warfarin vs. rivaroxaban of recurrent VTE, bleeding complications and major bleeding were 0.52(95% CI: 0.25-1.08), 0.30(95% CI: 0.14-0.60), and 0.33 (95% CI, 0.13-0.74), respectively. Risk of clinical outcomes in specified subgroups for age, gender, renal function, thrombosis sites and diagnosis were assessed. The interaction of gender and treatment on major bleeding was significant (P for interaction = 0.062). Otherwise, there was no significant interaction between the other subgroups and the treatment group in terms of clinical outcomes. Conclusion: Compared with warfarin, rivaroxaban exhibited comparable efficacy for the anticoagulant treatment of unusual site DVT, associated with a lower risk of bleeding complications and major bleeding.

Tirzepatide as a novel effective and safe strategy for treating obesity: a systematic review and meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the efficacy and safety of a new hypoglycemic drug, tirzepatide, for treating obesity based on indicators such as BMI, waist circumference, and body weight. Methods: A search formula was written using search terms such as "tirzepatide," "overweight," and "obesity." A comprehensive search was conducted on databases such as PubMed, Cochrane Library, Embase, and Web of Science using a computer. Random controlled trial (RCT) literature was selected based on inclusion and exclusion criteria. After extracting the data, literature bias risk assessment and meta-analysis were conducted using RevMan 5.4 software. The search deadline is from the establishment of each database to May 2023. Results: A total of 12 randomized controlled trials were included, with a total of 11,758 patients. Meta analysis results showed that compared with the glucagon like peptide-1 receptor agonist (GLP-1 RAs), placebo and insulin groups, tirzepatide could significantly reduce the BMI (body mass index) of patients [MD = -1.71, 95% CI (-2.46, -0.95), p < 0.00001], [MD = -3.99, 95% CI (-3.69, -2.45), p < 0.00001], [MD = -4.02, 95% CI (-4.72, -3.31), p < 00.00001]. In terms of decreasing waist circumference, tirzepatide has a more significant advantage [MD = -4.08, 95% CI (-5.77, -2.39), p < 0.00001], [MD = -7.71, 95% CI (-10.17, -5.25), p < 0.00001], [MD = -9.15, 95% CI (-10.02, -8.29), p < 0.00001]. In the analysis of body weight, tirzepatide showed a more significant reduction effect compared to the control group [MD = -5.65, 95% CI (-7.47, -3.82), p < 0.001], [MD = -10.06, 95% CI (-12.86, -7.25), p < 0.001], [MD = -10.63, 95% CI (-12.42, -8.84), p < 0.001]. In comparison with placebo, tirzepatide had a prominent advantage in weight loss ≥20% and ≥25% [RR = 30.43, 95% CI (19.56, 47.33), p < 0.00001], [RR = 37.25, 95% CI (26.03, 53.30), p < 0.00001]. Subgroup analysis showed a dose-dependent therapeutic effect. In terms of safety, compared with the placebo and insulin groups, the incidence of gastrointestinal adverse reactions was markedly higher in the tirzepatide group, slightly higher to the GLP-1 RAs group. The hypoglycemic (<70 mg/dL) risk of tirzepatide was slightly higher to that of placebo and GLP-1 RAs, but significantly lower than that of the insulin group [RR = 0.46, 95% CI (0.36, 0.58), p < 0.001]. The incidence of other adverse events, including pancreatitis, cholecystitis, major adverse cardiovascular events-4, hypersensitivity reactions, and neoplasms did not show significant statistical differences compared to the control group (p > 0.05). Conclusion: Tirzepatide, as a weight loss drug, significantly reduces BMI, waist circumference and body weight while gastrointestinal adverse reactions need to be vigilant. Overall, its efficacy is significant and its safety is high.