Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Engaging and (the Illusion of) Learning? Examining the Relationship Between Different Social Media Activities and Reproductive Health Knowledge.

Social media have become fundamental platforms for learning about health, including reproductive health knowledge. However, little is known about what specific user activity is conducive to learning about reproductive health and by what means. Drawing upon the cognitive mediation model, this study examines how different social media activities function in terms of elaboration and knowledge gain. Our hypothesized model was largely supported by a nationwide online survey with 1,000 Chinese women residing in both rural and urban areas. The results revealed the crucial role of information elaboration in bridging different social media activities with both subjective and factual reproductive health knowledge. Interestingly, public reposting of reproductive health information was found to be positively related to subjective knowledge but negatively related to factual knowledge, suggesting the emergence of an illusion of knowing among our participants. Multigroup SEM analyses revealed that the positive roles of scanning and private sharing in encouraging elaboration were more pronounced among users with lower levels of need for cognition. The findings are expected to contribute to a more nuanced understanding of health learning based on users' social media activities and intrinsic motivations for learning.

"I Know News Will Find Me": Examining the Relationship Between the "News-Finds-Me" Perception and COVID-19 Misperceptions.

In the current media environment, some individuals have shifted from actively monitoring news toward passively waiting for the media to alert them about news to a certain extent, forming a "news-finds-me" (NFM) perception. Drawing on a cross-sectional survey (N = 906) of adults from the United States, this study investigates the relationship between the NFM perception and COVID-19 misperceptions. Findings demonstrated a positive association between NFM perception and misperceptions. Moreover, information avoidance mediated the relationship between NFM and misperception. Finally, need for cognition (NFC) was a significant moderator, such that among those with greater NFC, the indirect effect of NFM perception on misperceptions became weaker. Findings of this study can contribute to the literature of NFM perception in health contexts and provide useful guidelines for combating misinformation and misperceptions in the algorithm-generated information environment.

Communication Matters: The Role of Patient-Centered Communication in Improving Old Adults' Health Competence and Health Outcomes.

Research has demonstrated links between patient-centered communication (PCC) and patients' health outcomes. However, little is known about the underlying processes that may mediate the relationship. This study is one of the first to examine the influence of PCC on older adults' health outcomes, as well as the mediation role of health competence, from a longitudinal perspective. With a general basis of Street et al.'s pathway model, we proposed and tested mediation pathways linking patient-centered communication to the older population's general and mental health, mediated by health competence. Data from 2011, 2017 and 2020 iterations of the Health Information National Trends Survey (HINTS) were used for this study. This study focused on older adults aged 60 and above. Results indicated that after controlling participants' age, gender, education, income and race, PCC is related to the older people's health outcomes either directly or indirectly, irrespective of time series. Specifically, health competence was found to significantly mediate the associations between PCC and the older adults' general health or mental health over the three iterations. Noteworthily, findings from this study also revealed that different dimensions of PCC might exert different influences on older patients' health competence and health outcomes.

Counteracting sexual and reproductive health misperceptions: Investigating the roles of stigma, misinformation exposure, and information overload.

OBJECTIVE: Sexual and reproductive health (SRH) misperceptions constitute a critical precursor to undesired health outcomes for women. Drawing on the model of stigma management communication and exposure effects, we aimed to investigate the underlying processes of SRH misperceptions. METHODS: A nationwide survey was conducted via quota sampling with Chinese women (N = 1000). Structural equation modeling with maximum likelihood estimation and 5000 bootstrapping resamples were used to test the hypotheses. RESULTS: Stigma perceptions positively predicted information avoidance (ß = 0.207, p < 0.001), which, in turn, was positively associated with misperceptions (ß = 0.195, p < 0.001). Misinformation exposure significantly predicted misperceptions (ß = 0.607, p < 0.001), and this relationship was mediated by information avoidance (ß = 0.020, 95% CI [0.007, 0.040]). Moreover, information overload strengthened the relationship between misinformation exposure and information avoidance (ß = 0.153, p < 0.001) as well as the relationship between misinformation exposure and misperceptions (ß = 0.077, p = 0.006). CONCLUSION: Stigma and misinformation exposure play prominent roles in the formation of SRH misperceptions. Information overload facilitates the misinformation-misperception transformation. PRACTICE IMPLICATIONS: To counteract SRH misperceptions, health education should alleviate SRH stigma perceptions and strategically design messages to avoid information avoidance and overload.

LDLR heterozygous deletion reduces hamster testicular cholesterol toxicity via AMPK/Sirt1/PGC-1α pathway.

Cholesterol is an important part of the human diet. The relationship and molecular mechanisms between intracellular cholesterol and male infertility are unclear. The purpose of this study was to evaluate the role of low-density lipoprotein receptor (LDLR) in male infertility. Both wild-type (WT) and LDLR heterozygous deletion (LDLR+/-) male Golden Syrian hamsters were fed either a high-fat diet (HFD) or a normal diet (ND). Plasma biochemistry, serum hormone, testicular histopathology, mRNA and protein expression of AMPK/Sirt1/PGC-1α in both testicular tissue and isolated Leydig cells (LCs) were measured. Compared with the ND animals, the WT HFD hamsters developed dyslipidemia at three weeks with lipid droplets deposited in LCs, testosterone decreased at four weeks (0.440 ± 0.264 ng/ml vs. 2.367 ± 1.236 ng/ml), the number of the Sertoli cells decreased (21.578 ± 2.934/one tubule vs. 25.733 ± 3.424/one tubule), the seminiferous epithelium became thinner (0.0813 ± 0.01729 mm vs. 0.0944 ± 0.0138 mm), testicular atrophy and AMPK/Sirt1/PGC-1α pathway downregulated at five weeks. All these changes persisted until the end of the study. LDLR+/- alleviated all of the above changes by downregulating the cellular influx of cholesterol induced by HFD except for higher hyperlipidemia. In summary, excessive intracellular cholesterol inactivates AMPK/Sirt1/PGC-1α pathway firstly in LCs and then in both Sertoli and spermatids. Cholesterol toxicity was LDLR dependent.

BJTJ-1837, a novel FXI activation-blocking antibody.

Background: Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. Objectives: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Methods: Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. Results: A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. Conclusion: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.

Promoting condom negotiation self-efficacy among young women in China: the effects of traditional sexual values and descriptive norms.

This study attempts to design effective messages to promote condom negotiation self-efficacy and safer sex intent among young women in China. An online experiment with 2 (descriptive norm: present versus absent) × 2 (traditional sexual value: high versus low) between-subjects factorial design was conducted on a purposive sample of 241 female Chinese college students. The results demonstrated that culturally tailored messages incorporating descriptive norms information on the popularity of condom negotiation can increase participants' self-efficacy (F(1,237) = 9.01, partial η2 = 0.04, P = 0.003) but not safer sex intent (F(1,237) = 2.80, partial η2 = 0.01, P = 0.096). Participants with a lower level of traditional sexual values had similar levels of condom negotiation self-efficacy as those with a higher level of values: F(1,237) = 2.85, partial η2 = 0.01, P = 0.09. There were no significant interaction effects of traditional sexual value and descriptive norm on condom negotiation self-efficacy and safer sex intent. The findings contribute to the cultural sensitivity perspective in health education in an Eastern context and have implications for public health practitioners and policymakers.

Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with Antiproliferative Activity.

A normal phosphorylation state is essential for the function of proteins. Biased regulation frequently results in morbidity, especially for the hyperphosphorylation of oncoproteins. The hyperphosphorylation of ASK1 at Thr838 leads to a persistently high activity state, which accelerates the course of gastric cancer. Under normal conditions, PP5 specifically dephosphorylates p-ASK1T838 in cells, thereby weakening ASK1 to a low-basal activity state. However, in tumor types, PP5 shows low activity with a self-inhibition mechanism, making p-ASK1T838 remain at a high level. Thus, we aim to design phosphatase recruitment chimeras (PHORCs) through a proximity-mediated effect for specifically accelerating the dephosphorylation of p-ASK1T838. Herein, we describe DDO3711 as the first PP5-recruiting PHORC, which is formed by connecting a small molecular ASK1 inhibitor to a PP5 activator through a chemical linker, to effectively decrease the level of p-ASK1T838 in vitro and in vivo. DDO3711 shows preferable antiproliferative activity (IC50 = 0.5 µM) against MKN45 cells through a direct binding and proximity-mediated mechanism, while the ASK1 inhibitor and the PP5 activator, used alone or in combination, exhibit no effect on MKN45 cells. Using DDO3711, PHORCs are identified as effective tools to accelerate the dephosphorylation of POIs and provide important evidence to achieve precise phosphorylation regulation, which will promote confidence in the further regulation of abnormally phosphorylated oncoproteins.

Healing of the Torn Anterior Horn of Rabbit Medial Meniscus to Bone after Transtibial Pull-Out Repair and Autologous Platelet-Rich Plasma Gel Injection.

OBJECTIVES: The transtibial pull-out repair (TP) is a relatively new method for treating meniscal root tear; however, the clinical evaluation of its healing effect remains controversial. Due to ethical constraints and limitations of imaging techniques in humans, here we dynamically observe the healing effects of TP and TP with platelet-rich plasma gel (PRG) at the histological level using an animal model. METHODS: Platelet-rich plasma (PRP) and PRG of rabbits were prepared. Platelet-derived growth factor (PDGF) and transforming growth factor-ß1 (TGF-ß1) levels in PRP and PRG were determined using an enzyme-linked immunosorbent assay. A rabbit model of anterior horn tear of the medial meniscus and TP surgery were created. PRG was injected between the anterior horn of the medial meniscus and the tibial tunnel. Rabbits were divided into three groups: the anterior horn tear group (Tear group), the anterior horn tear + TP group (TP group), and the anterior horn tear + TP + PRG group (TP + PRG group). The healing effect was observed dynamically using histopathological studies and biomechanical experiments. RESULTS: The platelet content in PRP significantly increased to approximately 4.57 times that of whole blood. PDGF and TGF-ß1 concentrations in PRG increased to 2.46 and 4.15 times those in PRP, respectively. Hematoxylin and eosin (H&E) and Masson staining showed that the number of inflammatory cells in healing tissue decreased and the collagen fibers significantly increased in TP and TP + PRG groups at 4, 8, and 12 weeks postoperatively compared to those in Tear group. Neatly arranged, interlaced, and dense collagen fibers were found between the anterior horn and bone at 12 weeks. H&E and toluidine blue staining showed that the injury to the femoral condyle cartilage was alleviated. The healing performance in TP + PRG group was better and faster than that in TP group. The maximum tensile fracture strength of the meniscus progressively increased at 8 and 12 weeks postoperatively. CONCLUSIONS: Anterior horn injury of the medial meniscus in rabbits can be repaired using the TP technique, and the addition of autologous PRG to the bone tunnel promotes early healing of the meniscus and bone postoperatively. Meanwhile, both treatments can reduce the secondary damage to the cartilage due to osteoarthritis.

Associations Between COVID-19 Information Acquisition and Vaccination Intention: The Roles of Anticipated Regret and Collective Responsibility.

While public health communication has been suggested to be a key for improving acceptance of COVID-19 vaccination, this study tested mediation pathways through which three types of vaccine information acquisition, i.e. seeking, scanning, and discussing, affect COVID-19 vaccination intention. The pathways comprise two mediators, i.e. anticipated regret due to inaction and collective responsibility. Results suggest that information seeking and discussing may have encouraged the intention to get vaccinated, but mainly indirectly through the two mediators. Information seeking and discussing may have elicited anticipated regret and collective responsibility, which in turn increased vaccination intention. The paths from information scanning were smaller in effect sizes and statistically unacknowledged. Implications and limitations are discussed.

The more engaging, the more enjoyable? Age matters in predicting perceived enjoyment with different Facebook activities.

Drawing upon uses and gratifications perspectives and socioemotional selectivity theory, this study examined the differences in the use of Facebook features among younger, middle-aged, and older adults. Furthermore, it explored the association between Facebook activities and users' perceived enjoyment for different age groups. An online survey was conducted with 647 Facebook users in the United States. An exploratory factor analysis identified four types of Facebook activities: broadcasting, directed communication, content consumption, and information regulation. The results revealed that younger users' broadcasting, content consumption, and information regulation activities substantially differed from those of older users. In addition, broadcasting and content consumption activities were more popular among younger users and more predictive of their enjoyment. Directed communication was more powerful in predicting middle-aged and older users' enjoyment. However, younger and middle-aged users' engagement with information regulation activities was negatively related to their enjoyment of Facebook. The study findings provide more nuanced knowledge regarding user experiences on social media platforms among specified age groups and practical insights into the improvement of social media by addressing their different needs.

Severe Acute Respiratory Syndrome Coronavirus 2 Epitope Mapping for Antibodies.

Epitope mapping of the interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Abs is challenging because of complexity in protein three-dimensional structures. Protein structure fingerprint technology was applied for epitope mapping of 44 SARS-CoV-2 Abs with three-dimensional structure complexes. The results defined how the epitopes were distributed on SARS-CoV-2 and how the patterns of six CDRs from Abs participated in neutralization. Also, the residue-residue recognition revealed that certain residues had higher frequencies on the interfaces between SARS-CoV-2 and Abs, and the activity correlated with the physicochemical properties of the residues at the interface. Thus, epitope mapping provides significant lead information for development of epitope-based designs for Abs, vaccines, and diagnostic reagents. This is a bioinformatics project of structural data analysis; no animals or cells were used.

Comprehensive folding variations for protein folding.

The revelation of protein folding is a challenging subject in both discovery and description. Except for acquirement of accurate 3D structure in protein stable state, another big hurdle is how to discover structural flexibility for protein innate character. Even if a huge number of flexible conformations are known, difficulty is how to represent these conformations. A novel approach, protein structure fingerprint, has been developed to expose the comprehensive local folding variations, and then construct folding conformations for entire protein. The backbone of five amino acid residues was identified as a universal folden, and then a set of Protein Folding Shape Code (PFSC) was derived for completely covering folding space in alphabetic description. Sequentially, a database was created to collect all possible folding shapes of local folding variations for all permutation of five amino acids. Successively, Protein Folding Variation Matrix (PFVM) assembled all possible local folding variations along sequence for a protein, which possesses several prominent features. First, it showed the fluctuation with certain folding patterns along sequence which revealed how the protein folding was related the order of amino acids in sequence. Second, all folding variations for an entire protein can be simultaneously apprehended at a glance within PFVM. Third, all conformations can be determined by local folding variations from PFVM, so total number of conformations is no longer ambiguous for any protein. Finally, the most possible folding conformation and its 3D structure can be acquired according PFVM for protein structure prediction. Therefore, the protein structure fingerprint approach provides a significant means for investigation of protein folding problem.

Discovery and reduction of tryptophan oxidation-induced IgG1 fragmentation in a polysorbate 80-dependent manner.

The fragmentation of therapeutic antibodies, particularly in the complementarity determining region (CDR), is considered a critical quality attribute. However, our understanding of CDR fragmentation remains limited. Here, we report the mechanism behind CDR fragmentation of a therapeutic IgG1 formulation, which is prone to fragmentation in heavy-chain CDR during storage, and screened excipients to control fragmentation based on the mechanism. In the degraded samples, fragments were generated from the cleavage around Tyr102, and a high level of oxidation was observed. Trp100 correlated most strongly with fragments among all the oxidized sites in multiple batches of mAb1 drug products. Oxidant-induced selective upregulation of mAb1 Trp100 oxidation level increased fragment level. This trend was rescued by the addition of Trp, indicating that Trp100 oxidation induced mAb1 fragmentation. A minor change in the mAb1 structure explored the potential mechanism of the regulatory relationship between Trp100 oxidation and fragmentation. Moreover, there was no obvious Trp100 oxidation or fragments in the mAb1 formulation without polysorbate 80 (PS80). Accordingly, substitution of PS80 with new surfactants, a combination of antioxidants, or EDTA with PS80, maintained mAb1 stability. This study demonstrated that mAb1 CDR fragmentation results from Trp100 oxidation and provides new excipients to resolve mAb fragmentation during formulation development.

How does WeChat's active engagement with health information contribute to psychological well-being through social capital?

This study aims to examine how the users' engagement with health information benefits their well-being and to demonstrate the underlying mechanism of the relationships through bonding and bridging social capital. An online survey was conducted with 522 WeChat users in China. Structural equation modeling using the maximum likelihood of estimation was employed to test the study's hypothesized model. Bootstrapping methods were used to examine mediation effects. The results revealed that users' liking, sharing, and commenting behaviors were positively related to the bonding and bridging capital accumulated on WeChat. These two forms of social capital were also positively associated with users' psychological well-being, though bridging capital exerted more power in our research model. Moreover, both bonding and bridging capital mediated the relationship between WeChat affordances and psychological well-being. The findings shed new light on directions for leveraging mobile social media as an alternative means to bring about improvements in well-being in mobile-phone-saturated China. This is likely to be the first study that examines the mediating roles of bonding and bridging social capital on the relationship between users' health information engagement and users' psychological well-being. By providing robust findings by adopting the variable-centered approach in a health context, the findings of this study are promising for the extension and theoretical development of mobile social media research in the context of health information engagement.

A Novel CD73 Inhibitor SHR170008 Suppresses Adenosine in Tumor and Enhances Anti-Tumor Activity with PD-1 Blockade in a Mouse Model of Breast Cancer.

INTRODUCTION: CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cells, and promote anti-PD-1 mAb therapy-induced immune escape. Consequently, developing a CD73 inhibitor as monotherapy and a potential beneficial combination partner with immune-checkpoint inhibitors needs investigation. METHODS: CD73 inhibitors were evaluated in vitro with soluble and membrane-bound CD73 enzymes, as well as its PD biomarker responses in human peripheral blood mononuclear cells (PBMC) by flow cytometry and ELISA. The binding modes of the molecules were analyzed via molecular modeling. The anti-tumor activity and synergistic effect of SHR170008 in combination with anti-PD-1 mAb were evaluated in a syngeneic mouse breast cancer model. RESULTS: SHR170008 was discovered during the initial structural modifications on the link between the ribose and the α-phosphate of AMPCP, which significantly improved the stability of the compound confirmed by the metabolite identification study. Further modifications on the adenine base of AMPCP improved the potency due to forming stronger interactions with CD73 protein. It exhibited potent inhibitory activities on soluble and endogenous membrane-bound CD73 enzymes, and induced IFNγ production, reversed AMP-suppressed CD25+ and CD8+/CD25+ expression, and enhanced granzyme B production on CD8+ T cells in human PBMC. SHR170008 showed dose-dependent anti-tumor efficacy with suppression of adenosine in the tumors in EMT6 mouse breast tumor model. The increase of adenosine in tumor tissue by anti-PD-1 mAb alone was suppressed by SHR170008 in the combination groups. Simultaneous inhibition of CD73 and PD-1 neutralization synergistically enhanced antitumor immunity and biomarkers in response, and exposures of SHR170008 were correlated with the efficacy readouts. CONCLUSION: Our findings suggest that CD73 may serve as an immune checkpoint by generating adenosine, which suppresses the antitumor activity of anti-PD-1 mAb, and inhibition of CD73 may be a potential beneficial combination partner with immune-checkpoint inhibitors to improve their therapeutic outcomes in general.

First Impression Formation Based on Valenced Self-Disclosure in Social Media Profiles.

This study aims to understand how the valence of self-disclosure (operationalized as the dominantly positive vs. balanced vs. dominantly negative social media posts of a future collaborator) influences first impression formation on social media. We also focus on trustworthiness as a mediator and perceived homophily as a moderator to specify the underlying mechanisms through which self-disclosure valence affects first impression formation. The results from an online experiment (N = 204) suggest that self-disclosure valence has a significant effect on perceived trustworthiness and likability when individuals evaluate an unknown future collaborator using the social media profile. Trustworthiness mediates the effect of self-disclosure valence on likability when the individuals feel that they are dissimilar or even slightly similar to strangers. At that time, individuals tend to seek cues from both self-disclosure valence and perceived homophily to form the trustworthiness perception, and the influence of self-disclosure depends on the level of perceived homophily.