Beyond success: unveiling the hidden potential of radiotherapy and immunotherapy in solid tumors.

Immunotherapy, particularly with immune checkpoint inhibitors, has significantly transformed cancer treatment. Despite its success, many patients struggle to respond adequately or sustain long-lasting clinical improvement. A growing consensus has emerged that radiotherapy (RT) enhances the response rate and overall efficacy of immunotherapy. Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results, establishing itself as a dynamic and thriving area of research, clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results, suggesting the need for a more nuanced understanding. This review provides a balanced and updated analysis of the combination of immunotherapy and RT. We summarized the preclinical mechanisms through which RT boosts antitumor immune responses and mainly focused on the outcomes of recently updated clinical trials, including those that may not have met expectations. We investigated the optimization of the therapeutic potential of this combined strategy, including key challenges, such as fractionation and scheduling, lymph node irradiation, and toxicity. Finally, we offered insights into the prospects and challenges associated with the clinical translation of this combination therapy, providing a realistic perspective on the current state of research and potential future directions.

Deuterium Isotope Effect in Single Molecule Photophysics and Photochemistry of Hypericin.

The peripherical protons of the dye molecule hypericin can undergo structural interconversion (tautomerization) between different isomers through separated by a low energy barrier with rates that depends sensitively on the interaction with local chemical environment defined by the nature of host material. We investigate the deuterium (D) isotope effect of hypericin tautomerism at the single-molecule level to avoid ensemble averaging in different polymer matrices by a combined spectroscopic and computational approach. In the 'innocent' PMMA matrix only intramolecular isotope effects on the internal conversion channel and tautomerization are observed; while PVA specifically interacts with the probe via H- and D-bonding. This establishes a single molecular picture on intra- and intermolecular nano-environment effects to control chromophore photophysics and -chemistry.

How do "words poorly expressed emotion" affect mental health? The mediating role of affect labelling effect.

Previous studies have found that people with high negative emotional granularity(NEG) tend to have better health levels. It is generally believed that this is due to the selection and application of explicit emotion regulation strategies that affect mental health. However, no research has yet examined a more fundamental process, the role of affect labelling, an implicit emotion regulation strategy. This study focuses on the aforementioned issues and uses the experience sampling method to categorise participants into groups with high and low NEG. Using an affect labelling paradigm with ERP(event-related potential) technology, the study measures the effects of affect labelling in participants. Furthermore, it assesses the mental health levels of the participants through questionnaires to explore whether the affect labelling effect serves as a mediator between NEG and mental health. The results show that: (1) The high-NEG group exhibited significantly lower LPP wave amplitudes under affect labelling compared to under non-affect labelling, whereas the low-NEG group did not show significant differences. The results indicate that only the high-NEG group can produce the affect labelling effect. (2) The affect labelling effect mediates the relationship between NEG and mental health, meaning that NEG predicts mental health through the affect labelling effect.

Incorporating nonparametric methods for estimating causal excursion effects in mobile health with zero-inflated count outcomes.

In mobile health, tailoring interventions for real-time delivery is of paramount importance. Micro-randomized trials have emerged as the "gold-standard" methodology for developing such interventions. Analyzing data from these trials provides insights into the efficacy of interventions and the potential moderation by specific covariates. The "causal excursion effect," a novel class of causal estimand, addresses these inquiries. Yet, existing research mainly focuses on continuous or binary data, leaving count data largely unexplored. The current work is motivated by the Drink Less micro-randomized trial from the UK, which focuses on a zero-inflated proximal outcome, i.e., the number of screen views in the subsequent hour following the intervention decision point. To be specific, we revisit the concept of causal excursion effect, specifically for zero-inflated count outcomes, and introduce novel estimation approaches that incorporate nonparametric techniques. Bidirectional asymptotics are established for the proposed estimators. Simulation studies are conducted to evaluate the performance of the proposed methods. As an illustration, we also implement these methods to the Drink Less trial data.

Analysis of key circRNA events in the AOP framework of TCS acting on zebrafish based on the data-driven.

Triclosan (TCS) is a broad-spectrum antibiotic widely used in various personal care products. Research has found that exposure to TCS can cause toxic effects on organisms including neurotoxicity, cardiotoxicity, disorders of lipid metabolism, and abnormal vascular development, and the corresponding toxic mechanisms are gradually delving into the level of abnormal expression of miRNA regulating gene expression. Although the downstream mechanism of TCS targeting miRNA abnormal expression to induce toxicity is gradually improving, its upstream mechanism is still in a fog. Starting from the abnormal expression data of circRNA in zebrafish larvae induced by TCS, this study conducted a hierarchical analysis of the expression levels of all circRNAs, differential circRNAs, and trend circRNAs, and identified 29 key circRNA events regulating miRNA abnormal expression. In combination with GO and KEGG, the effects of TCS exposure were analyzed from the function and signaling pathway of the corresponding circRNA host gene. Furthermore, based on existing literature evidence about the biological toxicity induced by TCS targeting miRNA as data support, a competing endogenous RNAs (ceRNA) network characterizing the regulatory relationship between circRNA and miRNA was constructed and optimized. Finally, a comprehensive Adverse Outcome Pathway (AOP) framework of multiple levels of events including circRNA, miRNA, mRNA, pathway, and toxicity endpoints was established to systematically elucidate the toxic mechanism of TCS. Moreover, the rationality of the AOP framework was verified from the expression level of miRNA and adverse outcomes such as neurotoxicity, cardiotoxicity, oxidative stress, and inflammatory response by knockdown of circRNA48. This paper not only provides the key circRNA events for exploring the upstream mechanism of miRNA regulating gene expression but also provides an AOP framework for comprehensively demonstrating the toxicity mechanism of TCS on zebrafish, which is a theoretical basis for subsequent hazard assessment and prevention and control of TCS.

An electrochemical microbiosensor for serotonin based on surface imprinted layer coordinated bimetal functionalized acupuncture needle.

Serotonin (5-hydroxytryptamine, 5-HT) is a pivotal monoamine neurotransmitter, which is widely distributed in human brain for biological, physical and psychopathological processes. The content of 5-HT can support diagnose of various diseases. To selectively detect 5-HT is very important in clinical medicine. Here, a novel microbiosensor for 5-HT is studied on acupuncture needle. Molecularly imprinted film enwrapped 5-HT was electropolymerized onto bimetallic gold/platinum (Au/Pt) nanoparticles on acupuncture needle microelectrode (ANME). Au/Pt nanostructure exhibited active sites to catalyze the oxidation of 5-HT and bind the generated polymer. 5-HT can be enwrapped by the functional monomer of pyrrole (Py) in the process of electropolymerization with suitably electroactive conformation. Comparing with interfaces of single metal or molecularly imprinted layer, synergistic microbiosensor exhibit better performance for 5-HT. 5-HT can be adsorbed and catalytically oxidized by the imprinted cavities. Under optimized conditions, the peak current linearly increases with the concentration of 5-HT from 0.03 to 500 µM, and a detection limit of 0.0106 µM is obtained. The performance of this microbiosensor is competitive with previous studies. Furthermore, the prepared microbiosensor showed effective application to analyze 5-HT in human serum and urine. Interestingly, the microbiosensor expressed the real-time monitoring ability to 5-HT from stimulated PC12 cells by K+. The microbiosensor also exhibited high selectivity, stability and reproducibility, which is promising in view of the low price, fast response and simple operation.

2.5A mechanistic study on the tolerance of PAM distal end mismatch by SpCas9.

The therapeutic application of CRISPR-Cas9 is limited due to its off-target activity. To have a better understanding of this off-target effect, we have focused on its mismatch-prone PAM distal end. The off-target activity of SpCas9 depends directly on the nature of mismatches, which in turn results in deviation of the active site of SpCas9 due to structural instability in the RNA-DNA duplex strand. In order to test the hypothesis, we have designed an array of mismatched target sites at the PAM distal end and performed in vitro and cell line-based experiments, which showed a strong correlation for Cas9 activity. We found that target sites having multiple mismatches in the 18th to 15th position upstream of the PAM showed no to little activity. For further mechanistic validation, Molecular Dynamics simulations were performed, which revealed that certain mismatches showed elevated root mean square deviation (RMSD) values that can be attributed to conformational instability within the RNA-DNA duplex. Therefore, for successful prediction of the off-target effect of SpCas9, along with complementation-derived energy, the RNA-DNA duplex stability plays a crucial role.

Assessment of antibacterial activity, modes of action, and synergistic effects of Origanum vulgare hydroethanolic extract with antibiotics against avian pathogenic Escherichia coli.

This study evaluates the antibacterial effectiveness of Origanum vulgare hydroethanolic extract, both independently and in combination with antibiotics, against Escherichia coli strains associated with avian colibacillosis-a significant concern for the poultry industry due to the rise of antibiotic-resistant E. coli. The urgent demand for new treatments is addressed by analyzing the extract's phytochemical makeup via High-Performance Liquid Chromatography (HPLC), which identified sixteen phenolic compounds. Antibacterial activity was determined through agar diffusion and the measurement of minimum inhibitory and bactericidal concentrations (MIC and MBC), showing moderate efficacy (MIC: 3.9 to 7.8 mg/ml, MBC: 31.2 to 62.4 mg/ml). Combining the extract with antibiotics like ampicillin and tetracycline amplified antibacterial activity, indicating a synergistic effect and highlighting the importance of combinatory treatments against resistant strains. Further analysis revealed the extract's mechanisms of action include disrupting bacterial cell membrane integrity and inhibiting ATPase/H+ proton pumps, essential for bacterial survival. Moreover, the extract effectively inhibited and eradicated biofilms, crucial for preventing bacterial colonization. Regarding cytotoxicity, the extract showed no hemolytic effect at 1 to 9 mg/ml concentrations. These results suggest Origanum vulgare extract, particularly when used with antibiotics, offers a promising strategy for managing avian colibacillosis, providing both direct antibacterial benefits and moderating antibiotic resistance, thus potentially reducing the economic impact of the disease on the poultry industry.

New phenols and one aminobenzoic acid derivative isolated from the roots of Rhus chinensis Mill.

Four new phenols and one new aminobenzoic acid derivative, with five known phenols were isolated from the roots of Rhus chinensis Mill. Their structures were elucidated by UV, IR, HRESIMS, 1D and 2D NMR spectra, as well as optical rotations. Compound 4 significantly inhibited mouse ear inflammation (inhibitory rate of 44.03%), and significantly extended the time of pain response (extension rate of 48.55%), showing significant anti-inflammatory and analgesic effects in vivo.

Effect of exercise duration on toluene-induced locomotor sensitization in mice: a focus on the Renin Angiotensin System.

RATIONALE: Exercise attenuates addictive behavior; however, little is known about the contribution of exercise duration to this positive effect. The Renin Angiotensin System (RAS) has been implicated both in addictive responses and in the beneficial effects of exercise; though, its role in the advantageous effects of exercise on toluene-induced addictive responses has not been explored. OBJECTIVES: To evaluate the impact of different exercise regimens in mitigating the expression of toluene-induced locomotor sensitization and to analyze changes in RAS elements' expression at the mesocorticolimbic system after repeated toluene exposure and following voluntary wheel running in toluene-sensitized animals. METHODS: Toluene-induced addictive-like response was evaluated with a locomotor sensitization model in mice. Toluene-sensitized animals had access to running wheels 1, 2, 4 or 24 h/day for 4 weeks; thereafter, locomotor sensitization expression was evaluated after a toluene challenge. RAS elements (ACE and ACE2 enzymes; AT1, AT2 and Mas receptors) expression was determined by Western blot in the VTA, NAc and PFCx of toluene-sensitized mice with and without exercise. RESULTS: Individual differences in toluene-induced locomotor sensitization development were observed. Access to wheel running 1 and 2 h/day reduced but 4 and 24 h/day completely blocked locomotor sensitization expression. Repeated toluene exposure changed RAS elements' expression in the VTA, NAc and PFCx, while exercise mainly modified ACE and AT1 in air-exposed and toluene-sensitized mice. CONCLUSIONS: Inhalant-exposed animals show different sensitization phenotypes. Exercise duration determined its efficacy to attenuate the addictive-like response. Toluene exposure and exercise each modified RAS, the latter also modifying toluene-induced changes.

Cs2CO3-Promoted Alkylation of 3-Cyano-2(1H)-pyridones: Anticancer Evaluation and Molecular Docking.

Herein, a Cs2CO3-promoted N-alkylation of 3-cyano-2(1H)-pyridones containing alkyl groups with diverse alkyl halides to synthesize N-alkyl-2-pyridones over O-alkylpyridines is reported. Alkyl dihalides resulted in complex mixtures of N- and O-alkylated products. The primary factor influencing regioselectivity in these reactions is the electronic effects of substituents on the 2(1H)-pyridone ring, as evidenced by the preferential formation of O-alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(Oi-Pr)4-catalyzed amidation reactions to functionalize N-alkyl-2-pyridones containing propargyl and ester groups, leading to the synthesis of 1,2,3-triazoles and amides, respectively. Moreover, O-alkylpyridines 10b and 10d displayed remarkable selectivity toward the A-498 renal cancer cell line with growth inhibition percentages (%GI) of 54.75 and 67.64, respectively. The binding modes of compounds 10b and 10d to the PIM-1 kinase enzyme were determined through molecular docking studies.

Improved industrial induction time-based technique for evaluating kinetic hydrate inhibitors.

Kinetic hydrate inhibitor laboratory testing before field application is one of the key priorities in the oil and gas industry. The common induction-time-based technique is often used to evaluate and screen for kinetic hydrate inhibitors (KHIs). However, the main challenge relates to the stochastic nature of hydrate nucleation observed in fresh systems, which often results in scattered data on hydrate formation with unacceptable uncertainties. A much more precise KHI evaluation method, called crystal growth inhibition (CGI), provides comprehensive insights into the inhibitory behavior of a kinetic hydrate inhibitor, including both hydrate formation and decomposition. Given that industry does not require this much information, it is not feasible to expend either much time or cash on this strategy. This study aims to provide a cost-effective technique that presents maximum data accuracy and precision with relatively little time and cost expenditure. Hence, the impact of water-hydrate memory on improving the accuracy and repeatability of the results of the induction-time-based technique (IT method) was examined. First, the concept of water-hydrate memory, which contains information about how it is created, was reviewed, and then, the factors influencing it were identified and experimentally investigated, like the heating rate of hydrate dissociation and the water-hydrate memory target temperature during heating. Finally, a procedure was developed based on the background information in the earlier sections to compare the consistency of the results, originating from the conjunction of water-hydrate memory with the IT technique. The results of replications at KHI evaluation target temperatures of 12.3-12.4°C and 11.5-11.7°C showed that more repeatable data were obtained by applying water-hydrate memory, and a more conclusive decision was made in evaluating KHI performance than with an IT method. It seems that combining the IT method with water-hydrate memory, introduced as the "HME method", can lead to more definitive evaluations of KHIs. This approach is expected to gain in popularity, even surpassing the accurate but complex and time-consuming CGI method.

Associations of Early-Life Deprivation and Threat with Exploratory Behavior: Moderated Mediation Models of Sensation Seeking and Executive Function.

Exploratory behavior, as a crucial aspect of decision-making, plays an indispensable role in maximizing long-term benefits and is, therefore, essential in promoting adolescents' psychological well-being and social adaptation. Recent studies have shown that this adaptive behavior is influenced by previous early experiences. However, little was known about the associations between specific types of childhood maltreatment and exploratory behavior and the roles of individual motivational and cognitive factors in these relationships. The present study aimed to examine whether the subtypes of maltreatment, that is, threat and deprivation, would influence adolescents' exploratory behavior, the mediating role of sensation seeking, and the moderating role of executive function. Using a sample of 720 Chinese adolescents (Mage = 13.29, SDage = 0.82, 54.8% female), we found that sensation seeking fully mediated the relationship between threat and exploratory behavior. That is, adolescents who experienced threat were more likely to increase sensation seeking, which further promote exploratory activities. Moreover, executive function was a second-stage moderator of this full mediation pathway, with the mediating effect of sensation seeking between threat and exploratory behavior increasing with the enhancement of executive function. However, we did not observe the mediating effect of sensation seeking and the second-stage moderating effect of executive function on the relationship between deprivation and exploration. Considering the distinct impact mechanisms of threat and deprivation on exploratory behavior, our study provides empirical support for the Dimensional Model of Adversity and Psychopathology, and highlights the critical role of sensation seeking and the necessity of implementing executive function interventions for those experiencing threat experiences.

The physiological significance of plasma-accessible carbonic anhydrase in the respiratory systems of fishes.

Carbonic anhydrase (CA) activity is ubiquitously found in all vertebrate species, tissues and cellular compartments. Most species have plasma-accessible CA (paCA) isoforms at the respiratory surfaces, where the enzyme catalyzes the conversion of plasma bicarbonate to carbon dioxide (CO2) that can be excreted by diffusion. A notable exception are the teleost fishes that appear to lack paCA at their gills. The present review: (i) recapitulates the significance of CA activity and distribution in vertebrates; (ii) summarizes the current evidence for the presence or absence of paCA at the gills of fishes, from the basal cyclostomes to the derived teleosts and extremophiles such as the Antarctic icefishes; (iii) explores the contribution of paCA to organismal CO2 excretion in fishes; and (iv) the functional significance of its absence at the gills, for the specialized system of O2 transport in most teleosts; (v) outlines the multiplicity and isoform distribution of membrane-associated CAs in fishes and methodologies to determine their plasma-accessible orientation; and (vi) sketches a tentative time line for the evolutionary dynamics of branchial paCA distribution in the major groups of fishes. Finally, this review highlights current gaps in the knowledge on branchial paCA function and provides recommendations for future work.

Analyzing the impact of remittance, FDI and inflation rate on GDP: A comparative study of Bangladesh, Pakistan and Sri-Lanka using VAR and BEKK-GARCH approach.

This study examines the impact, conditional correlation and volatility spillover effect of remittances, foreign direct investment and inflation rate on GDP in Bangladesh, Pakistan, and Sri-Lanka, three Asian nations that are particularly vulnerable. While numerous studies have examined the relationship between remittances, FDI and IR on GDP but this paper approaches advanced econometric techniques to capture spillover effect and the dynamic interactions between the variables. For estimation purposes the study employs different econometric techniques such as Augmented Dickey-Fuller (ADF) test, VAR model, Granger causality tests, Impulse Response function, Variance Decomposition and BEKK-GARCH model. Bangladesh and Sri Lanka's REM, FDI and IR have no significant effects on GDP according to the VAR model. BEKK-GARCH demonstrates that three countries have both unidirectional and bidirectional transmissions of volatility, with the exception of Pakistan's REM and Bangladesh's FDI. We find that VAR model may not be adequate in capturing the complex dynamics between variables, which can be better captured by BEKK-GARCH model. Our comparison research shows how these variables affect GDP differently and similarly in each of the three nations, giving policymakers information they can use to create customized policies that encourage economic growth.

Mutant dominant-negative rhodopsin∆I256 causes protein aggregates degraded via ERAD and prevents normal rhodopsin from proper membrane trafficking.

Dominant mutations in the rhodopsin gene (Rho) contribute to 25% of autosomal dominant retinitis pigmentosa (adRP), characterized by photoreceptor loss and progressive blindness. One such mutation, Rho ∆I256 , carries a 3-bp deletion, resulting in the loss of one of two isoleucines at codons 255 and 256. Our investigation, using recombinant expression in HEK293 and COS-7 cells, revealed that Rho ∆I256, akin to the known adRP mutation Rho P23H, induces the formation of rhodopsin protein (RHO) aggregates at the perinuclear region. Co-expression of Rho ∆I256 or Rho P23H with wild-type Rho WT, mimicking the heterozygous genotype of adRP patients, demonstrated the dominant-negative effect, as all isoforms were retained in perinuclear aggregates, impeding membrane trafficking. In retinal explants from WT mice, mislocalization of labeled adRP isoforms at the outer nuclear layer was observed. Further analysis revealed that RHO∆I256 aggregates are retained at the endoplasmic reticulum (ER), undergo ER-associated degradation (ERAD), and colocalize with the AAA-ATPase escort chaperone valosin-containing protein (VCP). These aggregates are polyubiquitinated and partially colocalized with the 20S proteasome subunit beta-5 (PSMB5). Pharmacological inhibition of proteasome- or VCP activity increased RHO∆I256 aggregate size. In summary, RHO∆I256 exhibits dominant pathogenicity by sequestering normal RHOWT in ER aggregates, preventing its membrane trafficking and following the ERAD degradation.

Did childhood adversity increase the vulnerability of university students to the negative mental health impact of the COVID-19 pandemic?

OBJECTIVE: To examine a potential synergistic effect of history of childhood adversity and COVID-19 pandemic exposure on the association with mental health concerns in undergraduate students. Participants: We used U-Flourish Survey data from 2019 (pre-pandemic) and 2020 (during-pandemic) first-year cohorts (n = 3,149) identified at entry to a major Canadian University. METHODS: Interactions between childhood adversity (physical and sexual abuse, and peer bullying) and COVID-19 pandemic exposure regarding mental health concern (depressive and anxiety symptoms, suicidality, and non-suicidal self-harm) were examined on an additive scale. RESULTS: We found a positive additive interaction between physical abuse and pandemic exposure in relation to suicidality (combined effect was greater than additive effect (risk difference 0.54 vs. 0.36)). Conversely, less than additive interactions between peer bullying and pandemic regarding depression and anxiety were observed. CONCLUSIONS: Childhood adversities have diverse reactions to adult stressor depending on the nature of the childhood adversity and the mental health outcomes.

Prussian blue nanoparticles coated with tumor cell membranes for precise photothermal therapy and subsequent inflammation reduction.

The utilization of photothermal agents (PTAs) in photothermal therapy (PTT) is faced with challenges such as immune clearance and inadequate concentration, which consequently result in residual tumors and an increased risk of recurrence and metastasis. Conversely, excessive treatment can lead to heightened inflammation and inevitable harm to adjacent healthy tissues. To address these issues, we developed a nanosystem (M@PB) consisting of Prussian blue coated with tumor cell membrane for precise photothermal therapy (PTT) and subsequent reduction of inflammation. This system not only evades immune attack due to the homologous biological characteristics of the encapsulating cell membrane but also exhibits active targeting capabilities towards homologous tumors. Furthermore, it effectively reduces excessive phototoxicity by leveraging the distinctive photothermal and anti-inflammatory characteristics of PB nanoparticles. The resulting M@PB nanosystem demonstrates effective photothermal ablation under 808 nm laser irradiation while mitigating the inflammatory response through inhibiting of local production of inflammatory mediators. Our study provides valuable insights into achieving targeted PTT with high efficiency while minimizing post-treatment inflammatory responses.

Synergistic Effect of P and Co Dual Doping Endows CuNi with High-Performance Hydrogen Evolution Reaction.

The rational design of highly active and durable non-noble electrocatalysts for hydrogen evolution reaction (HER) is significantly important but technically challenging. Herein, a phosphor and cobalt dual doped copper-nickel alloy (P, Co-CuNi) electrocatalyst with high-efficient HER performance is prepared by one-step electrodeposition method and reported for the first time. As a result, P, Co-CuNi only requires an ultralow overpotential of 56 mV to drive the current density of 10 mA cm-2, with remarkable stability for over 360 h, surpassing most previously reported transition metal-based materials. It is discovered that the P doping can simultaneously increase the electrical conductivity and enhance the corrosion resistance, while the introduction of Co can precisely modulate the sub-nanosheets morphology to expose more accessible active sites. Moreover, XPS, UPS, and DFT calculations reveal that the synergistic effect of different dopants can achieve the most optimal electronic structure around Cu and Ni, causing a down-shifted d-band center, which reduces the hydrogen desorption free energy of the rate-determining step (H2O + e- + H* → H2 + OH-) and consequently enhances the intrinsic activity. This work provides a new cognition toward the development of excellent activity and stability HER electrocatalysts and spurs future study for other NiCu-based alloy materials.

[Head-to-head trials in rheumatoid arthritis]. / Head-to-Head-Therapiestudien zur rheumatoiden Arthritis.

BACKGROUND: Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available. AIM OF THE WORK: This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which a DMARD was at least included in an active comparison arm. RESULTS: A total of 23 studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study. DISCUSSION: There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK 1/JAK 3 inhibitor or are a class effect of all JAK inhibitors.