Two laser-assisted hatching methods of embryos in ART: a systematic review and meta-analysis.

BACKGROUND: Laser-assisted hatching (LAH) stands as the predominant technique for removing the zona pellucida (ZP) in embryos, primarily consisting of two methods: drilling laser-assisted hatching (D-LAH) and thinning laser-assisted hatching (T-LAH). Presently, both methods have limitations, and their comparative efficacy for embryo implantation and clinical pregnancy remains uncertain. AIM: Evaluate the impact of D-LAH and T-LAH on clinical pregnancy rates within assisted reproductive technology (ART). METHODS: We systematically searched electronic databases including PubMed, Web of Science, and Cochrane Library until July 20, 2022. This study encompassed observational studies and randomized controlled trials (RCTs). A 95% confidence interval (CI) was utilized for assessing the risk ratio (RR) of pregnancy outcomes. The level of heterogeneity was measured using I2 statistics, considering a value exceeding 50% as indicative of substantial heterogeneity. RESULTS: The meta-analysis scrutinized 9 studies involving 2405 clinical pregnancies from D-LAH and 2239 from T-LAH. Findings suggested no considerable variation in the clinical pregnancy rates between the two techniques (RR = 0.93, 95% CI: 0.79-1.10, I2 = 71%, P = 0.41). Subgroup analyses also revealed no substantial differences. However, D-LAH exhibited a notably higher occurrence of singleton pregnancies compared to T-LAH (RR = 2.28, 95% CI: 1.08-4.82, I2 = 89%, P = 0.03). There were no noteworthy distinctions observed in other secondary outcomes encompassing implantation rate, multiple pregnancies, ongoing pregnancy, miscarriage, premature birth, and live birth. CONCLUSION: Both the primary findings and subgroup analyses showed no marked variance in clinical pregnancy rates between D-LAH and T-LAH. Therefore, patients with varying conditions should select their preferred LAH technique after assessing their individual situation. However, due to the restricted number of studies involved, accurately gauging the influence of these laser techniques on clinical outcomes is challenging, necessitating further RCTs and high-quality studies to enhance the success rate of ART. TRIAL REGISTRATION: PROSPERO: CRD42022347066.

Sustainable natural chlorogenic acid as a functional molecular sensor toward viscosity detection in liquids.

Liquids are perishable at ease during the long-term transportation and storage processes, non-invasive and in situ inspection method is urgent to be developed. In consideration of the important role of viscosity, one kind of sustainable natural product chlorogenic acid (CA) extracted from honeysuckle has been used as a versatile optical sensor for viscosity determination during the liquid spoilage process. The natural molecule was conducted by the O-diphenyl and carboxylic acid ester groups in coincidence, a typical twisted intramolecular charge transfer phenomenon was formed. This sensor features wide adaptability, high selectivity, good sensitivity, and excellent photo stability in various liquids. And CA displays a larger Stokes shift, high viscosity sensitive coefficient (0.62), and narrower energy band. The rotatable conjugate structure can be acted as the recognition site, and the bright fluorescent signal of CA is specifically activated when in the high viscous micro-environment. Inspired by this objective phenomenon, CA has been applied to detect the thickening efficiency of various food thickeners. More importantly, the viscosity fluctuations during the deterioration stage of liquids can be screened through non-invasive and in situ monitoring. We expected that more natural products can be developed as molecular tools for liquids safety investigation, and fluorescent analytical methods can be expanded toward interdisciplinary research.

Utilization of photo-luminescent technique toward viscosity detection in the liquid food system with triphenylamine-michaelitic acid molecular sensor.

A noninvasive and effective viscosity inspection method is expected to ease the burden of continued increased health problems caused by liquid food safety. In this study, we proposed the viscosity of the liquid food micro-environment as a marker and further developed a versatile optical sensor, DPTMDD, for monitoring liquid food micro-environmental viscosity alterations. This sensor was strategically constructed by the triphenylamine-thiophene derivate and michaelitic acid, rotatable conjugate structure was utilized as the recognition site. The molecular sensor was synthesized in a one-step facile way, and DPTMDD displayed a longer emission wavelength (592 nm), low detection limit (1.419 cP), and larger Stokes shift (193.7 nm in glycerol and 177.8 nm in water) with narrower energy band, endowing the sensor with the capacity of achieving high signal-to-noise ratio imaging. Meanwhile, DPTMDD exhibits high adaptability, selectivity, sensitivity, and good photo-stability in various liquid foods, bright fluorescent signal (37.5-fold) of DPTMDD is specifically activated in the high viscosity media. Thickening efficiencies can be identified as well. More importantly, the viscosity fluctuations during the metamorphic stages of liquid foods are also screened through in situ monitoring. We expected that this unique strategy will reinvigorate the continued perfection of liquid food safety investigation systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05699-y.

Triphenylamine indanedione as an AIE-based molecular sensor with one-step facile synthesis toward viscosity detection of liquids.

Viscosity is one of the most important physical parameters in a liquid, noninvasive, and effective viscosity inspection method toward liquid safety that needs to be developed urgently. In this study, two kinds of novel molecular sensors, namely, DPBID and DPTMID, were strategically constructed by the triphenylamine indanedione derivates; the rotatable conjugate structure was utilized as the recognition site and fluorescence quencher. This couple of molecular sensors was synthesized in a one-step facile manner. DPTMID displayed longer emission wavelength and larger Stokes shift (195 nm in water, 138 nm in glycerol) with a narrower energy band. Moreover, DPTMID exhibited high selectivity, sensitivity, and significant fluorescence signal enhancement toward a higher viscous microenvironment. The molecular sensor displayed good photostability, selectivity, and universality in various commercial liquids and featured with typical aggregation-induced emission (AIE). With the aid of DPTMID, the thickening effects of liquid thickeners can be captured. More importantly, DPTMID was explored to visualize the viscosity fluctuations during the metamorphic stages of liquids, and it was found that the microenvironment viscosity level is closely related to the spoilage degree of liquids. The method with rapid detection, high sensitivity, cheap equipment, and fast results output toward food quality and safety inspection can be achieved through this study.

A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy.

OBJECTIVES: To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. METHODS: Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. RESULTS: A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. CONCLUSION: Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs). METHODS: PubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: 26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03). CONCLUSION: The existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents.

A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC50 of 0.10 mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC50 of 0.18 mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4 µg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.

Synchronous Mutual Learning Network and Asynchronous Multi-Scale Embedding Network for miRNA-Disease Association Prediction.

MicroRNA (miRNA) serves as a pivotal regulator of numerous cellular processes, and the identification of miRNA-disease associations (MDAs) is crucial for comprehending complex diseases. Recently, graph neural networks (GNN) have made significant advancements in MDA prediction. However, these methods tend to learn one type of node representation from a single heterogeneous network, ignoring the importance of multiple network topologies and node attributes. Here, we propose SMDAP (Sequence hierarchical modeling-based Mirna-Disease Association Prediction framework), a novel GNN-based framework that incorporates multiple network topologies and various node attributes including miRNA seed and full-length sequences to predict potential MDAs. Specifically, SMDAP consists of two types of MDA representation: following a heterogeneous pattern, we construct a transfer learning-like synchronous mutual learning network to learn the first MDA representation in conjunction with the miRNA seed sequence. Meanwhile, following a homogeneous pattern, we design a subgraph-inspired asynchronous multi-scale embedding network to obtain the second MDA representation based on the miRNA full-length sequence. Subsequently, an adaptive fusion approach is designed to combine the two branches such that we can score the MDAs by the downstream classifier and infer novel MDAs. Comprehensive experiments demonstrate that SMDAP integrates the advantages of multiple network topologies and node attributes into two branch representations. Moreover, the area under the receiver operating characteristic curve is 0.9622 on DB1, which is a 5.06% increase from the baselines. The area under the precision-recall curve is 0.9777, which is a 7.33% increase from the baselines. In addition, case studies on three human cancers validated the predictive performance of SMDAP. Overall, SMDAP represents a powerful tool for MDA prediction.

Triphenylamine-Modified Cinnamaldehyde Derivate as a Molecular Sensor for Viscosity Detection in Liquids.

Liquid safety is considered a serious public health problem; a convenient and effective viscosity determination method has been regarded as one of the powerful means to detect liquid safety. Herein, one kind of triphenylamine-modified cinnamaldehyde-based fluorescent sensor (3-(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl)acrylaldehyde (DPABA)) has been developed for sensing viscosity fluctuations in a liquid system, where a cinnamaldehyde derivative was extracted from one kind of natural plant cinnamon and acted as an acceptor, which has been combined with a triphenylamine derivate via the Suzuki coupling reaction within one facile step. Twisted intramolecular charge transfer (TICT) was observed, and the rotation could be restricted in the high-viscosity microenvironment; thus, the fluorescent signal was released at 548 nm. Featured with a larger Stokes shift (223.8 nm in water, 145.0 nm in glycerol), high adaptability, sensitivity, selectivity, and good photostability, the capability of high signal-to-noise ratio sensing was achieved. Importantly, this sensor DPABA has achieved noninvasively identifying thickening efficiency investigation, and viscosity fluctuations during the liquid deterioration program have been screened as well. We believed that this unique strategy can accelerate intelligent molecular platforms toward liquid quality and safety inspection.

Green extract rosemary acid as a viscosity-sensitive molecular sensor in liquid systems.

The liquid micro-environment plays a momentous role in the regulation of various activities, and the abnormal changes are often closely related to the deterioration phenomena in multiple beverages. The local viscosity fluctuation has long been regarded as a key indicator to reflect the micro-environmental status changes. Herein, we proposed a versatile optical sensor, rosmarinic acid (RA), one kind of green natural product extracted from rosemary, for monitoring liquid micro-environmental viscosity alterations. RA displays a larger Stokes shift (123.8 nm) with narrow-band energy and exhibits wide adaptability, high selectivity, good sensitivity, and excellent photostability in various commercial liquids. When in high viscous media, a bright fluorescent signal of RA is specifically activated, and a high signal-to-noise ratio signal was released (58-fold). With the assistance of the fluorescence analytical technique, we have successfully achieved tracking the viscosity fluctuations during the deterioration stage of liquids via an in situ and visualization method. Our study will spur additional research on the molecular tools extracted from natural products for liquid safety inspection, and a convenient and sustainable application pathway has been established.

Caffeic acid, a natural extract, as an activatable molecular probe for viscosity detection in a liquid system.

Liquids, functioning as nutrients and energy systems, regulate various functions during storage programs. Microenvironmental viscosity is one of the most important physical parameters associated with the extent of deterioration, and it is crucial to monitor the mutation of viscosity at a molecular level. Herein, we utilized caffeic acid (CaC), a natural product extracted from thistles, as a molecular probe for viscosity sensing. CaC contains phenol hydroxyl (electron-donor) and carboxyl (electron-acceptor) groups, with both moieties connected by conjugated single and double bonds, forming a typical twisted intramolecular charge transfer system. The fluorescent probe CaC, obtained from a natural product without any chemical processing, exhibits high sensitivity (x = 0.43) toward viscosity, with an obvious visualized turn-on signal. Moreover, it displays good photostability, selectivity, and wide universality in commercial liquids. Utilizing CaC, we have successfully visualized viscosity enhancement during the spoilage process, with a positive correlation between the degree of liquid spoilage and microenvironmental viscosity. Thus, this study will provide a convenient and efficient molecular probe for food safety inspection across the boundaries of traditional biological applications.

Activatable molecular rotor based on bithiophene quinolinium toward viscosity detection in liquids.

The development of non-invasive and effective viscosity inspection methods during the liquid deterioration process is urgently needed since viscosity is one of the most important physical parameters of liquids. Methods featuring rapid detection, high sensitivity, cheap equipment, and fast result output are greatly desired. In this study, a viscosity-sensitive molecular rotor (BTPEQ) with a large Stokes shift (187 nm), and long emission wavelength (648 nm) has been developed. The rotor is comprised of a bithiophene donor and quinolinium acceptor, and displays a typical twisted intramolecular-charge transfer (TICT) feature, with good photostability, selectivity, and universality in various commercial liquids. With the aid of BTPEQ, the thickening effects of liquid thickeners can be determined. More importantly, BTPEQ was explored to visualize the viscosity variations in liquids at different metamorphic stages, and it was found that the viscosity level in microenvironments is highly dependent on the liquid food metamorphic period. It is worth noting that this approach can facilitate the continued perfection of fluorescent analytical methods for food quality and safety inspection.

Genome architecture plasticity underlies DNA replication timing dynamics in cell differentiation.

During the S-phase of eukaryotic cell cycle, DNA is replicated in a dedicatedly regulated temporal order, with regions containing active and inactive genes replicated early and late, respectively. Recent advances in sequencing technology allow us to explore the connection between replication timing (RT), histone modifications, and three-dimensional (3D) chromatin structure in diverse cell types. To characterize the dynamics during cell differentiation, corresponding sequencing data for human embryonic stem cells and four differentiated cell types were collected. By comparing RT and its extent of conservation before and after germ layer specification, the human genome was partitioned into distinct categories. Each category is then subject to comparisons on genomic, epigenetic, and chromatin 3D structural features. As expected, while constitutive early and late replication regions showed active and inactive features, respectively, dynamic regions with switched RT showed intermediate features. Surprisingly, although early-to-late replication and late-to-early replication regions showed similar histone modification patterns in hESCs, their structural preferences were opposite. Specifically, in hESCs, early-to-late replication regions tended to appear in the B compartment and large topologically associated domains, while late-to-early replication regions showed the opposite. Our results uncover the coordinated regulation of RT and 3D genome structure that underlies the loss of pluripotency and lineage commitment and indicate the importance and potential roles of genome architecture in biological processes.

Apparent Diffusion Coefficient as a Noninvasive Biomarker for the Early Response in Hepatocellular Carcinoma After Transcatheter Arterial Chemoembolization Using Drug-eluting Beads.

BACKGROUND: Prognostic evaluation for Hepatocellular Carcinoma (HCC) after Transcatheter Arterial Chemoembolization (TACE) using Drug-Eluting Beads (DEBs) is essential for guiding the personalized treatment and follow-up strategy. Apparent Diffusion Coefficient (ADC) has been reported as a biomarker in conventional TACE. OBJECTIVE: This study aimed to evaluate the diagnostic value of ADCbaseline, ADC change, and ADCratio in predicting the early objective response for HCC after DEB-TACE. METHODS: This prospective single-center study included 32 consecutive patients undergoing dynamic contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging before and 1 month after DEB-TACE. After DEB-TACE, patients were grouped based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria into responders (complete response [CR], partial response [PR]) and nonresponders (stable disease [SD], progressive disease [PD]). The Mann- Whitney U test and receiver operating characteristic (ROC) curves were performed to assess the statistical differences in ADCbaseline, ADC change, and ADCratio between responders and nonresponders. RESULTS: At post-DEB-TACE follow-up MRI, 62.5% (n = 20, 11 CRs, and 9 PRs) of patients showed objective response, and 37.5% (n = 12, 7 SDs, and 5 PDs) did not respond to chemoembolization. Nonresponders had a significantly higher ADCbaseline value than responders (p < 0.001). The ROC for identifying the response to chemoembolization demonstrated that the threshold ADCbaseline value of 0.920 × 10-3 mm2/s had 100% sensitivity and 70% specificity. The ADC change and ADCratio of responders were higher than that of nonresponders (p < 0.001). CONCLUSION: ADCbaseline, ADC change, and ADCratio may be utilized as a noninvasive biomarker for predicting the early response of HCC to DEB-TACE.

Cell wall permeability of pinto bean cotyledon cells regulate in vitro fecal fermentation and gut microbiota.

Processing induced structural changes of whole foods for the regulation of the colonic fermentation rate and microbiota composition are least understood and often overlooked. In the present study, intact cotyledon cells from pinto beans were isolated as a whole pulse food model and subjected to a series of processing temperatures to modulate the structure, most dominantly the cell wall permeability. The cell wall permeability, observed with the diffusion of fluorescently labeled dextran (FITC-dextran), was increased as a function of the hydrothermal temperature, which is in line with the rise in the in vitro fecal fermentation rate and production of short-chain fatty acids (SCFAs) from the pinto bean cells. Further, the abundance of beneficial microbiota, such as Roseburia, Lachnospiraceae, Bacteroides, and Coprococcus, were significantly higher for cells processed at 100 °C compared to the 60 °C-treated ones. We conclude that cell wall provides an effective barrier for the microbial fermentation of intact cells. With an increase in cell wall permeability, microbes and/or microbial enzymes have easier access to intracellular starch for fermentation, leading to an increase in the production of metabolites and the abundance of beneficial microbes. Thus, desired colonic fermentation profiles can be achieved with the controlled processing of whole foods for enhanced gut health.

Oxygen-Challenge Blood Oxygen Level-Dependent Magnetic Resonance Imaging for Evaluation of Early Change of Hepatocellular Carcinoma to Chemoembolization: A Feasibility Study.

RATIONALE AND OBJECTIVES: To investigate the feasibility of oxygen-challenge blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) at 3T for evaluating the early change of blood oxygenation before and after transcatheter arterial embolization (TACE) in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty HCC patients with cirrhosis (HCC group, n = 30) and 30 healthy volunteers (control group, n = 30) were included in this study. Patients in the HCC group underwent BOLD before and 1 month after TACE. Oxygen was administered via a mask. Differences between pre- and post-O2 T2* values were evaluated using a pairwise t-test. Analysis of variance was performed to assess the statistical differences in the T2* values measured in HCC group pre-TACE and post-TACE and in healthy volunteers. RESULTS: In the HCC group, the pre- and post-O2 T2* values of the cancerous area before TACE were 26.03 ± 3.30 and 26.84 ± 3.42 msec, respectively, and both decreased significantly to 8.67 ± 1.76 and 8.82 ± 1.80 msec, respectively, at 1 month after TACE (p < 0.001). The respective pre- and post-O2 T2* values of the noncancerous area increased significantly from 14.96 ± 2.32 and 15.33 ± 2.28 msec at baseline to 16.38 ± 2.22 and 16.89 ± 2.24 msec at 1 month after TACE (p < 0.001). No significant response to BOLD was observed in the control group (p = 0.059). CONCLUSION: Oxygen-challenge BOLD MRI is feasible to assess post-TACE changes in HCC patients.

Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: We aimed to systematically assess a possible association of tofacitinib therapy with cardiovascular events (CVEs) and all-cause mortality. METHODS: Systematic searches of PubMed, Embase, and Cochrane Library were conducted from inception through March 2019. Randomized controlled trials in patients with immune-mediated inflammatory diseases (IMIDs) reporting safety data were included. Included studies compared tofacitinib with placebo or 5 mg tofacitinib with 10 mg tofacitinib. The primary and secondary outcome measures were all CVEs [major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs)] and all-cause mortality. RESULTS: 29 studies randomizing 13,611 patients were included. Compared with placebo, there was no significant increased risk of all CVEs (OR = 1.07, 95% CI 0.49-2.34), MACEs (OR 1.54, 95% CI 0.42-5.59), or all-cause mortality (OR = 1.13, 95% CI 0.26-4.95), but a decreased rate of VTEs (OR 0.03, 95% CI 0.00-0.21) in patients with IMIDs initiating tofacitinib. Meanwhile, paired comparison showed 10 mg tofacitinib twice daily was associated with a significantly lower incidence of all CVEs (OR = 0.56, 95% CI 0.33-0.96), MACEs (OR = 0.48, 95% CI 0.22-1.05), or all-cause mortality (OR = 0.47, 95% CI 0.19-1.17), but a trend toward an increase in VTEs risk (OR = 1.47, 95% CI 0.25-8.50), compared with the 5 mg regimen. CONCLUSION: Compared with placebo, there was no augmented risk of CVEs and all-cause mortality in patients with IMIDs following tofacitinib treatment in a short-term perspective, whereas 10 mg twice daily tofacitinib appeared to be associated with reduction in cardiovascular and all-cause mortality risks, except VTEs, relative to the 5 mg twice daily dose. Long-term studies and postmarketing risk monitoring are increasingly needed to develop a better understanding.

Efficacy and safety of secukinumab in active rheumatoid arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis of phase III randomized controlled trials.

OBJECTIVES: To address the efficacy and safety of secukinumab in comparison with placebo in active rheumatoid arthritis (RA) patients who had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: Databases of PubMed, Embase, and Web of Science were searched to identify the relevant randomized controlled trials (RCTs). Risk ratio (RR) and 95% confidence interval (95% CI) were calculated with the Mantel-Haenszel random effects method. Statistical heterogeneity was assessed using the Cochran Q and I2 tests. RESULTS: A total of 1292 patients from three phase III RCT studies were included. Compared with placebo, secukinumab 150 mg was superior at 24 weeks in terms of ACR20 with RR (1.66, 95% CI 1.33, 2.08; P < 0.0001; I2 = 0%), ACR50 (1.88, 95% CI 1.29, 2.72; P = 0.0009; I2 = 0%), and ACR70 (2.15, 95% CI 1.15, 4.02; P = 0.02; I2 = 0%). Consistent effects were also observed in pooled group of 150 mg and 75 mg secukinumab. For secukinumab 75 mg alone, ACR20 response rate was significantly higher compared with placebo (RR 1.62, 95% CI 1.29, 2.03; P < 0.00001; I2 = 0%). Although ACR50 and ACR70 response rates showed a favorable trend to be higher, no statistical difference was observed (RR 1.68, 95% CI 0.99, 2.85, P = 0.05, I2 = 47%; RR 1.81, 95% CI 0.78, 4.21, P = 0.17, I2 = 34%, respectively). Compared with the placebo group, there was no increased risk of adverse effects (AEs) and serious AEs at 16 weeks in the pooled secukinumab group. CONCLUSIONS: In active RA patients with an inadequate response to TNF inhibitors, secukinumab may be a therapeutic option. Secukinumab 150 mg showed significantly better clinical efficacy with no increased risk of AEs and serious AEs compared with placebo. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT01770379, NCT01350804, NCT01377012 Key Points • Secukinumab 150 mg showed significantly better clinical efficacy in active RA patients with an inadequate response to TNF inhibitors. • No increased risk of AEs and serious AEs in secukinumab group compared with placebo.

Cysteine-rich 61 (Cyr61): a biomarker reflecting disease activity in rheumatoid arthritis.

BACKGROUND: Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients. METHODS: A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses. RESULTS: A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P <  0.001). In addition, the Cyr61 level in active RA patients was significantly lower than that in patients in remission/low disease activity, and it was inversely correlated with composite disease activity scores and almost all of the components in statistic. Further study in the validation cohort (n = 77) showed a significant increase of the Cyr61 level at 12 weeks in ACR responders (ACR20/50/70), while no significant change of the Cyr61 level from baseline was observed in non-responders. CONCLUSIONS: Serum Cyr61 levels were remarkably increased in RA patients compared with those in healthy controls. The Cyr61 concentration was inversely correlated with RA disease activity and upregulated in those therapeutic responders. TRIAL REGISTRATION: Combination Therapy Prevents the Relapse of RA, NCT02320630 . Registered 19 December 2014.