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Abstract Introduction Clinical practice guidelines are essential tools for standardizing medical practices and improving healthcare quality. However, current guideline implementation is unsatisfactory. Barriers to guideline implementation include external environmental factors (e.g., medical personnel, medical institutions, local policies) and intrinsic characteristics (e.g., context, format, language etc.), with the latter being addressable by optimizing the guidelines themselves. This study aims to develop an appraisal tool to promote effective guideline implementation. Existing guideline implementability appraisal tools lack a clear theoretical basis, evidence of reliability and validity, and/or empirically-based guidance for effective implementation, all of which will be addressed in this study. Methods and analysis The research is divided into four phases: (1) Generating a theoretical framework for guideline implementability (i.e., scoping review and concept analysis method); (2) Conducting a factorial experiment (i.e., guideline users simulate the use of different guideline versions to examine the relationship between constructs in the framework and implementability), and removing constructs with weak relationships to form the final implementability theoretical framework; (3) Generating dimensions and items for the guideline implementability appraisal tool based on the constructs in the theoretical framework, conducting comprehensive reliability and validity testing, usability testing, and iterative optimization according to the COSMIN guidelines; (4) Integrating the validated tool with the STAR guideline rating system for guideline appraisal and feedback to promote guideline implementability. Strengths and limitations (1) Our research will follow a standardized and rigorous process for developing measurement scales, ensuring that the resulting evaluation scale for the implementability of CPGs is theoretically grounded, internally consistent between theory and practice, and reliable and valid. (2) The theoretical framework developed in our study will strengthen the validity and rationality of constructs in the real world. (3) In the confirmatory factor analysis, this study will determine the dimensions and items’ weight through factor loadings, allowing for the quantification of the implementability of CPGs and providing users of the guidelines with objective evaluative results. In addition, the clinical practice guideline implementability evaluation tool developed in this study can assist guideline developers in enhancing implementability before, during, and after guideline formulation.

Mutation of the MAPK7 gene was related to human scoliosis. Mapk7 regulated the development of limb bones and skulls in mice. However, the role of MAPK7 in vertebral development is still unclear. In this study, we constructed Col2a1-cre; Mapk7f/f transgenic mouse model to delete Mapk7 in cartilage, which displayed kyphosis and osteopenia. Mechanistically, Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes, which impaired chondrocyte hypertrophy and attenuated vertebral ossification. In vivo, systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency. Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development, which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.

Abstract Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially the limited regulation of PD-L1 expression. Herein, we show that low expression of AP-2α is correlated with high expression of PD-L1 in high-grade glioma tissues. AP-2α binds directly to the promoter of the CD274 gene, not only inhibits the transcriptional activity of PD-L1 but enhances endocytosis and degradation of PD-L1 proteins. Overexpression of AP-2α in gliomas enhances CD8+ T cell-mediated proliferation, effector cytokine secretion, and cytotoxicity in vitro. Tfap2a could increase the cytotoxic effect of Cd8+ T cells in CT26, B16F10, and GL261 tumor-immune models, improve anti-tumor immunity, and promote the efficacy of anti-PD-1 therapy. Finally, the EZH2/H3K27Me3/DNMT1 complex mediates the methylation modification of AP-2α gene and maintains low expression of AP-2α in gliomas. 5-Aza-dC (Decitabine) treatment combines with anti-PD-1 immunotherapy to efficiently suppress the progression of GL261 gliomas. Overall, these data support a mechanism of epigenetic modification of AP-2α that contributes to tumor immune evasion, and reactivation of AP-2α synergizes with anti-PD-1 antibodies to increase antitumor efficacy, which may be a broadly applicable strategy in solid tumors.

Summary: Background: This study aims to evaluate primary care providers' adherence to the standard of measuring blood pressure for people aged 35 or above during their initial visit, as per Chinese guidelines, and to identify factors affecting their practices. Methods: We developed 11 standardized patients (SP) cases as tracer conditions to evaluate primary care, and deployed trained SPs for unannounced visits to randomly selected providers in seven provinces of China. The SPs used a checklist based on guidelines to record whether and how blood pressure was measured. Data were analyzed descriptively and regression analysis was performed to examine the association between outcomes and factors such as provider, patient, facility, and clinical case characteristics. Findings: The SPs conducted 1201 visits and found that less than one-third of USPs ≥35 had their blood pressure measured. Only 26.9% of migraine and 15.4% of diabetes cases received blood pressure measurements. Additionally, these measurements did not follow the proper guidelines and recommended steps. On average, 55.6% of the steps were followed with few providers considering influencing factors before measurement and only 6.0% of patients received both-arm measurements. The use of wrist sphygmomanometers was associated with poor blood pressure measurement. Interpretation: In China, primary care hypertension screening practices fall short of guidelines, with infrequent initiation of blood pressure measurements and inadequate adherence to proper measurement steps. To address this, priority should be placed on adopting, implementing, and upholding guidelines for hypertension screening and measurement. Funding: National Natural Science Foundation of China, Swiss Agency for Development and Cooperation, Doctoral Fund Project of Inner Mongolia Medical University, China Postdoctoral Science Foundation.

IntroductionMelanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear.MethodsWe established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR.ResultsGPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity.DiscussionGPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.

Introduction As direct-to-consumer teleconsultation (hereafter referred to as ‘teleconsultation’) has gained popularity, an increasing number of patients have been leaving online reviews of their teleconsultation experiences. These reviews can help guide patients in identifying doctors for teleconsultation. However, few studies have examined the validity of online reviews in assessing the quality of teleconsultation against a gold standard. Therefore, we aim to use unannounced standardised patients (USPs) to validate online reviews in assessing both the technical and patient-centred quality of teleconsultations. We hypothesise that online review results will be more consistent with the patient-centred quality, rather than the technical quality, as assessed by the USPs.Methods and analysis In this cross-sectional study, USPs representing 11 common primary care conditions will randomly visit 253 physicians via the three largest teleconsultation platforms in China. Each physician will receive a text-based and a voice/video-based USP visit, resulting in a total of 506 USP visits. The USP will complete a quality checklist to assess the proportion of clinical practice guideline-recommended items during teleconsultation. After each visit, the USP will also complete the Patient Perception of Patient-Centeredness Rating. The USP-assessed results will be compared with online review results using the intraclass correlation coefficient (ICC). If ICC >0.4 (p

Abstract Background Long bones of limbs are formed through endochondral bone formation, which depends on the coordinated development of growth plates. Our previous studies have demonstrated that dysfunction of mitogen-activated protein kinase 7 (MAPK7) can cause skeletal dysplasia. However, little is known about the role of MAPK7 in the regulation of proliferation and differentiation of chondrocytes during growth plate development. Results Ablation of MAPK7 expression in chondrocytes led to growth restriction, short limbs and bone mass loss in postnatal mice. Histological studies revealed that MAPK7 deficiency increased the apoptosis and decreased the proliferation of chondrocytes in the center of the proliferative layer, where the most highly hypoxic chondrocytes are located. Accordingly, hypertrophic differentiation markers were downregulated in the central hypertrophic layer, beneath the site where abnormal apoptosis was observed. Simultaneously, we demonstrated that hypoxic adaptation and hypoxia-induced activation of hypoxia-inducible factor 1 subunit α (HIF1α) were impaired when MAPK7 could not be activated normally in primary chondrocytes. Concomitantly, vascular invasion into epiphyseal cartilage was inhibited when Mapk7 was deleted. Conclusions We demonstrated that MAPK7 is necessary for maintaining proliferation, survival, and differentiation of chondrocytes during postnatal growth plate development, possibly through modulating HIF1α signaling for adaptation to hypoxia. These results indicate that MAPK7 signaling might be a target for treatment of chondrodysplasia.

Increasing evidence shows that polycystic ovary syndrome (PCOS) patients are particularly vulnerable to anxiety/depression-like behaviors. This study sought to determine the prevalence of anxiety/depression-like behaviors among women with PCOS and to identify factors associated with these behaviors. This study was a secondary analysis of three studies performed on Chinese women who were aged 18 to 40 and diagnosed with PCOS according to the modified Rotterdam criteria. We obtained 802 useable responses for the self-rating anxiety scale and 798 responses for the self-rating depression scale. The prevalence of anxiety-like and depression-like behaviors among women with PCOS was 26.1% (209/802) and 52.0% (415/798), respectively. Anxiety-like behaviors were associated with age, body image-related factors (including body mass index and waist-to-hip ratio), and hyperandrogenism-related factors (including free androgen index and hirsutism). Depression-like behaviors were associated with age, body image-related factors, hyperandrogenism-related factors, and metabolic factors (including fasting insulin, fasting plasma glucose, and homeostatic model assessment of insulin resistance). Body image-related factors and hyperandrogenism-related factors were related to both anxiety-like behaviors and depression-like behaviors in both infertile and fertile PCOS patients.

Background Clinical treatment of target organ damage in hypertension is mainly based on systemic hypotension supplemented by topical medication, but the treatment is unsatisfactory due to different or even mutually exclusive responses of tissues to the drugs. The relationship between calcium-sensing receptors (CaSR) and hypertension has been investigated, however, studies on their role and mechanisms in hypertensive retinal disease are still lacking. Objective To investigate the expression level of CaSR in hypertensive retina and its relationship with myocardial remodeling and retinal vascular changes in hypertension. Methods Ten 8-week-old healthy wistar-kyoto rats (WKY) were selected as the WKY group, and 20 homologous spontaneous hypertensive rats (SHR) of the same age were randomly divided into SHR group and inhibitor (SHR+NPS2143) group from May to December 2021. During a 16-week intervention, the SHR+NPS2143 group received intraperitoneal injection of CaSR inhibitor NPS2143, while WKY and SHR groups were intraperitoneally injected with the equal volume of normal saline. At baseline and the end of intervention, blood pressure was measured by non-invasive blood pressure monitor in all rats, and from each group, five rats were selected and executed, and myocardial and retinal tissues were taken out for testing. Masson's Trichrome staining was used to measure the collagen deposition in the myocardium. H & E staining was used to detect the pathological changes in retinal tissues. The distribution and expression of CaSR and vascular endothelial growth factor A (VEGFA) in retinal tissues were detected using immunohistochemical staining and qRT-PCR. Results SHR group had significantly higher levels of systolic blood pressure (SBP) , diastolic blood pressure (DBP) and mean arterial pressure (MAP) than WKY group either at baseline or the end of intervention (P