Blog

Identifying diagnostic biomarkers for Electroacupuncture Treatment of

Introduction

Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory arthritis, which can cause progressive destruction of joint cartilage.¹ RA can manifest at any age, with its peak incidence typically observed in individuals aged 30–60. As a challenging chronic condition, RA significantly impairs patients’ quality of life and imposes substantial societal and economic burdens. With a prevalence of approximately 0.3% to 1%, RA is often associated with various chronic diseases, further exacerbating healthcare demands and caregiving responsibilities.²

Currently, radical treatment for RA is limited. The therapeutic management of RA predominantly involves non-steroidal anti-inflammatory drugs (NSAIDs), conventional biological disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and other pharmacological interventions. These approaches aim to mitigate inflammation, retard disease progression, and optimize patients’ quality of life.³ However, the side effects of these drugs are controversial. Acupuncture has been practiced in Asia for over two millennia as a complementary and alternative therapeutic modality.⁴ Clinical studies have shown that electroacupuncture (EA) significantly relieved pain and joint swelling in RA patients and improved their quality of life without significant adverse effects.^5–7 Preclinical studies have also shown that EA can significantly improve the levels of pro-inflammatory factors in the peripheral blood of RA patients to improve the internal environment for the development and progression of RA.^8,9 Identifying the targeted genes underlying the therapeutic effects of EA in alleviating RA can provide critical insights for further mechanistic investigations¹⁰ and facilitate the development of standardized treatment protocols.¹¹ However, the exact target genes of EA for RA, especially in peripheral blood, remained unidentified.

With the development of gene microarray and bioinformatics technologies, more and more studies were focused on exploring the mechanisms of RA occurrence and key genes at the transcriptomic level.^12,13 In the context of precision medicine and personalized health care, Traditional Chinese Medicine (TCM) has received increasing attention for providing personalized medical services based on TCM theories. Several studies have utilized bioinformatics analysis to identify hub targets involved in the pathogenesis of RA and validated the regulatory effects of Chinese herbal medicine on these hub targets through animal experiments. Furthermore, network pharmacology approaches were employed to elucidate the bioactive components responsible for the therapeutic efficacy.^14,15 These findings provided valuable references for identifying key targets underlying EA-mediated RA alleviation. Current studies primarily aimed to elucidate how EA alleviates RA by modulating phenotype-specific genes,^16,17 yet there remained a paucity of research employing bioinformatics technologies to systematically identify EA-targeted genes for RA treatment. Given the limited availability of gene targets for EA in RA, this study aimed to fill this gap by identifying the diagnostic markers for EA treatment in RA using bioinformatics tools and machine learning algorithms.

This research retrieved mRNA expression datasets related to RA from the GEO database. The differentially expressed genes (DEGs) of RA in peripheral blood compared to normal samples and the DEGs altered by EA were obtained by differential analysis, respectively, and 26 DEGs associated with EA for RA were obtained by taking the intersection. Two diagnostic-related genes were identified by three machine learning methods, and the diagnostic efficacy of the two genes was evaluated by constructing diagnostic models. Furthermore, we determined the regulatory effects of EA on two diagnostic-related genes using qPCR.

Materials and Methods

Dataset Collection

The RA relative microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/ and Table 1). Transcriptome data for GSE15573 and GSE59526 were obtained from peripheral blood. GSE15573 contained 15 normal samples and 18 RA samples, and GSE59526 contained 8 RA samples and 7 samples treated with EA. Transcriptome data for GSE17755, GSE205962, and GSE93272 were obtained from peripheral blood. GSE17755 contained 53 normal samples with 112 RA samples and GSE205962 contained 4 normal samples with 16 RA samples. To compare differences in the regulation of RA peripheral blood target genes by EA and drugs, blood samples associated with disease-modifying antirheumatic drugs (DMARDs) were downloaded from a dataset (GSE93272) containing 43 normal samples, 115 RA samples, 40 samples treated with infliximab (IFX), 37 samples treated with methotrexate (MTX), and 40 samples treated with tocilizumab (TCZ). The GSE15573 dataset was normalized using the “normalize quantiles” function in BeadStudio Software. The GSE59526 and GSE93272 datasets were normalized using the MAS 5.0 algorithm in GeneSpring Software. The GSE17755 dataset was normalized by global ratio median normalization. The GSE205962 dataset was analyzed using the RMA method with Affymetrix default analysis settings, applying global scaling as the normalization method. According to item 1 and 2 of Article 32 of the Measures for Ethical Review of Life Science and Medical Research Involving Human Subjects (dated February 18, 2023, China), this part of the bioinformatics analysis in this study was exempt from ethical approval.

Table 1 The Details of Gene Expression Datasets

Identification of Differentially Expressed Genes (DEGs) Related to EA in RA

The filtering threshold was as follows: P-value < 0.05 and |log2-fold change| ≥ 0.1. DEGs related to RA were identified by comparing normal people with RA patients. DEGs related to EA treatment were identified by comparing RA patients with those who received EA treatment. By taking the intersection of DEGs related to RA and DEGs related to EA treatment, we obtained DEGs related to EA in RA.

Identification of Diagnostic Biomarkers for RA Patients

Diagnostic biomarkers were identified using three distinct machine learning algorithms. Specifically, the least absolute shrinkage and selection operator (LASSO) algorithm was implemented using the “glmnet” package to identify potential biomarkers, with parameters set at alpha = 1, nlambda = 100, and λmin determined as the optimal λ. LASSO effectively reduces subset size and serves as a biased estimator for handling complex collinearity. It is also efficient in selecting a limited set of predictive features. The advantages of the random forest algorithm include minimal tuning of hyperparameters and handling non-linear relationships. It also has the capability to predict continuous variables with a high degree of accuracy, sensitivity, and specificity,¹⁸ as demonstrated in this study using the “randomForest” package with nTree = 500 as the specified parameters. The top ten genes exhibiting mean decrease Gini (MDG) were identified as potential biomarkers. The support vector machine recursive feature elimination (SVM-RFE) technique is utilized to prevent overfitting and is a commonly used discriminant method for regression, classification, and pattern recognition analyses. It can improve the discriminative ability of biomarkers in classification and regression tasks, while effectively removing irrelevant features. This method was implemented using the “e1071” package, and the performance was evaluated based on the average misjudgment rates obtained from 10‐fold cross‐validations. The strategic integration of these three machine learning algorithms enhanced the confidence in selected biomarkers through complementary feature selection paradigms.

Establishment and Evaluation of Nomogram

The Nomogram model was developed using the “rms” package to generate calibration curves and clinical decision curves, facilitating the evaluation of clinical utility and discriminative performance of the model in the context of RA. Additionally, the “pROC” package was utilized to compute the area under the receiver operating characteristic (ROC) curve along with 95% confidence intervals (CI).

Animals

Eighteen specific pathogen free (SPF) male Sprague-Dawley (SD) rats aged 8 weeks weighing 160–200 g were procured from Shanghai B&K Laboratory Animals Co., Ltd. and accommodated in the Experimental Animal Center of Shanghai University of Traditional Chinese Medicine. The rats were provided with free access to food and water within a 12-hour light-dark cycle. All animal handling protocols adhered to the guidelines set forth by the National Research Council’s Guide for the Care and Use of Laboratory Animals and were sanctioned by the Experimental Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (PZSHUTCM2401080014).

Model Establishment

Eighteen rats were divided into three groups using random assignment (n = 6 per group): (1) Control group, (2) CFA group and (3) CFA + EA group. In the CFA and CFA + EA groups, the CFA model was prepared according to previous research. Rats were anesthetized with 2–3% isoflurane (RWD Life Science Company, Shenzhen, Guangdong, China) and 100 μL CFA suspension was injected into the right hindpaw of the rats, while saline was administered to the control group.¹⁹ Successful model induction was evidenced by the development of ipsilateral paw edema and mechanical allodynia in rats post-modeling.

Evaluation of Pain-Response Behavior

The paw withdrawal threshold (PWT) was assessed using an electronic von Frey anesthesiometer (IITC 2391, USA) following the methodology described by Vivancos.²⁰ This test was conducted to observe the progression of mechanical allodynia in CFA-induced rats and to evaluate the analgesic efficacy of EA. Rats underwent testing on day 0 before the model was created, as well as on days 1, 3, and 7 following EA. Before each evaluation, the rats were acclimated in Plexiglas enclosures for a period of 30 minutes. The pressure was applied to the midplantar area of the hindpaw using a polypropylene tip connected to an electronic von Frey device. The threshold for response was automatically measured when the hindpaw reacted to the pressure. The mean value of three consecutive measurements of the PWT was calculated for each paw after recording it thrice with a 5-minute interval between each measurement.

EA Treatment

Stainless steel needles (0.25 × 40 mm, Huatuo) were inserted into the Kunlun (BL60) and Zusanli (ST36) acupoints on the right side to a depth of about 5 mm. A 2 Hz, 1 mA electrical signal was administered on the needles daily for 30 minutes using a stimulation device (Model G6805-2A; Shanghai Huayi Co., Shanghai, China). The treatment with EA started on the first day after the surgery and continued for 7 days. Following the final PWT assessment, the rats were anesthetized with isoflurane (5%) and blood samples were collected from the abdominal aorta into ethylenediaminetetraacetic acid (EDTA) tubes. Subsequently, the rats were euthanized via cervical dislocation, and their peripheral blood was gathered for further biological investigations.

Real-Time Fluorescence Quantitative PCR

The results of our bioinformatics analysis were confirmed by qPCR validation of peripheral blood samples from all rats. The primers utilized have been documented in Table 2. Total RNA was isolated with a total RNA extraction solution following the manufacturer’s protocol (Servicebio, Wuhan, China). Three individual reactions were conducted for every sample, with the average and standard deviation computed for each data point. The 2^−ΔΔCT method was employed to quantify mRNA expression levels of diagnostic biomarkers, with GAPDH serving as the internal reference.

Table 2 Specific Primer Sequences Used in qPCR

Statistical Analysis

The experimental data was statistically analyzed based on the GraphPad Prism software and presented as the mean ± standard deviation (SD). Statistical analysis of the control, CFA, and CFA + EA groups was performed using One-way ANOVA followed by Bonferroni post hoc tests applied for qPCR analysis, while behavioral analysis was conducted using two-way ANOVA with Bonferroni post hoc testing. A P-value of less than 0.05 was considered statistically significant for all analyses.

Results

Screening of DEGs Related to EA in RA

The differential expression analysis revealed 2428 DEGs related to RA, with 1671 downregulated and 757 upregulated genes (Figure 1A and B). Similarly, a total of 486 DEGs related to EA treatment were identified, with 228 downregulated and 258 upregulated genes (Figure 1C and D). By taking the intersection of two groups of DEGs, a total of 26 DEGs related to EA in RA were identified (Figure 1E).

Figure 1 Identification of DEGs related to EA in RA. The volcano plot (A) and heatmap (B) for DEGs related to RA. The volcano plot (C) and heatmap (D) for DEGs related to EA treatment. (E) Venn diagram of the intersection of DEGs related to RA and DEGs related to EA treatment.

Determination of the Diagnostic Biomarkers

As shown in Figure 2A and B, the LASSO regression algorithm identified ten potential candidate biomarkers. Then, the random forest algorithm determined the top ten candidate genes ranked by MeanDecreaseGini (Figure 2C and D). As for SVM-RFE, when the number of features was 9, the accuracy was maximized (Figure 2E), and the error was minimized (Figure 2F). After combining the results of three algorithms, two diagnostic biomarkers were identified: VEGFB and ARHGAP17 (Figure 2G).

Figure 2 Identification of diagnostic biomarkers. The lambda values (A) and minimum (B) of diagnostic biomarkers were identified by LASSO. (C) Potential diagnostic biomarkers selection via Random Forest. (D) MeanDecreaseGini showed the rank of genes in accordance with their relative importance. (E) Accuracy and (F) error of 10-fold cross-validation in SVM-RFE algorithms, respectively. (G) The intersection of diagnostic biomarkers screened by three machine algorithms.

Diagnostic Efficacy of Diagnostic Biomarkers

Based on the expression of two genes, a diagnostic nomogram was constructed for RA to assess its diagnostic specificity and sensitivity (Figure 3A). ROC curves were generated to evaluate the diagnostic utility of individual genes and the nomogram. Figure 3B illustrated that VEGFB (0.819) and ARHGAP17 (0.978) had AUC values exceeding 0.75. In addition, the nomogram model (AUC = 0.981) based on two genes showed better diagnostic performance than two genes alone (Figure 3C). Based on the calibration curve analysis in Figure 3D, the nomogram model demonstrated comparable accuracy to the true positivity rate. The clinical decision curves revealed that the Nomogram model developed with two genes had a high predictive ability for RA, as the model curve outperformed the two threshold curves for benefits (Figure 3E).

Figure 3 Construction of the nomogram model and efficacy assessment. (A) The nomogram of diagnostic biomarkers for risk prediction of RA. (B) The ROC curves of each diagnostic biomarker. (C) The ROC curve of the nomogram model. (D) The calibration curve of nomogram model prediction in RA. (E) DCA results to evaluate the clinical value of the nomogram model.

Identification and Verification of Diagnostic Biomarkers

The diagnostic effectiveness of two genes for RA was validated on peripheral blood samples from three external datasets with RA. The AUC values of VEGFB and ARHGAP17 were 0.692 and 0.815 in GSE17755 (Figure 4A), respectively, and the diagnostic model showed promising efficacy in RA (AUC = 0.817) (Figure 4D). Besides, the AUC values of VEGFB and ARHGAP17 genes were 0.721 and 0.767 in GSE93272 (Figure 4B), respectively, and the diagnostic model showed good efficacy in RA (AUC = 0.794) (Figure 4E). The AUC values of VEGFB and ARHGAP17 genes were 0.922 and 0.945 in GSE205962 (Figure 4C), respectively, and the diagnostic model showed good efficacy in RA (AUC = 1.000) (Figure 4F).

Figure 4 The ROC curves of each diagnostic biomarker and the nomogram model in GSE17755 (A and D), GSE93272 (B and E) and GSE205962 (C and F).

In addition, the diagnostic biomarkers showed differential expression in the training and validation cohorts. The expression levels of ARHGAP17 and VEGFB in the peripheral blood of patients with RA were significantly decreased in GSE15573 (Figure 5A and B), GSE17755 (Figure 5C and D), GSE93272 (Figure 5E and F), and GSE205962 (Figure 5G and H) compared to healthy individuals. Besides, EA can increase the levels of VEGFB and ARHGAP17 in the peripheral blood of RA patients (Figure 6A and B), with comparable effectiveness to DMARDs such as IFX (Figure 6C and D), MTX (Figure 6E and F), and TCZ (Figure 6G and H).

Figure 5 Expression levels of ARHGAP17 and VEGFB in the GSE15573 (A and B), GSE17755 (C and D), GSE93272 (E and F), and GSE205962 (G and H). *p < 0.05, **p < 0.01, ***p < 0.001, compared to the Control group.

Figure 6 Comparison of ARHGAP17 and VEGFB expression levels following treatment with EA (A and B), IFX (C and D), MTX (E and F), and TCZ (G and H). *p < 0.05, **p < 0.01, ***p < 0.001, compared to the RA group.

EA Demonstrated Analgesic Effects in CFA-Induced Mechanical Allodynia

Measurement of PWT in the ipsilateral hindpaws of rats showed hyperalgesia induced by CFA and antihyperalgesic effects of EA. As shown in Figure 7, the baseline values of PWT prior to injection of CFA did not exhibit significant differences across groups. Following the administration of CFA, the PWT of the CFA group and the CFA+EA group exhibited a significant decrease in comparison to the control group and the hyperalgesia endured for a minimum duration of one week. After receiving EA therapy, the rats in the CFA+EA group demonstrated a significant improvement in PWT starting from the first day as compared to the CFA group, indicating that EA significantly alleviated mechanical allodynia in CFA rats.

Figure 7 The effects of EA on mechanical allodynia induced by CFA. ***p < 0.001 compared to the control group; ^##p < 0.01, compared to the CFA group.

The qPCR analysis showed a significant reduction in ARHGAP17 and VEGFB mRNA expression levels in the peripheral blood of the CFA group compared to the control group. Conversely, EA can significantly increase the expression of ARHGAP17 and VEGFB in the peripheral blood of CFA rats (Figure 8A and B).

Figure 8 The effect of EA on regulating the diagnostic biomarkers. The mRNA expression of ARHGAP17 (A) and VEGFB (B) were analyzed by qPCR. ***p < 0.001 compared to the control group; ^###p < 0.001 compared to the CFA group.

Discussion

This study identified 26 genes associated with the therapeutic effects of EA on RA. Machine learning algorithms were employed to identify two genes, ARHGAP17 and VEGFB, as potential diagnostic biomarkers, and their diagnostic efficacy was subsequently validated through the construction of a Nomogram model. Meanwhile, we demonstrated through various validation datasets that both diagnostic markers were significantly decreased in RA patients and exhibited excellent diagnostic performance. Furthermore, we found that these two biomarkers could effectively reflect the therapeutic effects of DMARDs and EA on RA, serving as prognostic indicators for evaluating treatment efficacy in RA. To further validate these findings, we established a CFA model, which revealed that the transcription levels of ARHGAP17 and VEGFB were significantly reduced in the peripheral blood of CFA-treated rats. Notably, EA therapy reversed this reduction, suggesting its potential therapeutic benefits for RA.

Rho guanosine triphosphatases (GTPases) function as molecular switches and have been implicated in the dysregulation associated with the pathogenesis of RA.²¹ The enzymatic activity of Rho GTPases is stringently regulated by Rho GTPase-activating proteins (GAPs), which play a crucial role in modulating signaling accuracy and preventing aberrant activation. ARHGAP17 (Rho GTPase Activating Protein 17), also known as RICH1, belongs to the GTPase-activating proteins (GAP) family, widely expressed in human tissues, and functions as a negative regulator of GTPases. Current research on ARHGAP17 has primarily focused on its role in cancer,²² while the potential involvement of ARHGAP17 in the effects of EA remained unexplored. Notably, the Rho GTPase (RAC1) is involved in the progression of various pain conditions,^23–25 and EA has been shown to alleviate pain by suppressing RAC1 expression.²⁶ To date, no studies have established the diagnostic or therapeutic value of ARHGAP17 in RA. Interestingly, existing evidence indicated that ARHGAP17 may suppress RAC1 expression and reduce cellular apoptosis.²² Our study demonstrated that EA can reverse the decreased expression of ARHGAP17 in the peripheral blood of CFA rats, suggesting that EA may exert its anti-inflammatory and analgesic effects by promoting ARHGAP17 expression, thereby inhibiting the activation of the Rho GTPase and mitigating the progression of RA.

Vascular endothelial growth factors (VEGFs) are the crucial molecule that promotes angiogenesis, which is a characteristic pathological feature of RA.²⁷ Notably, a previous study has demonstrated that serum VEGF levels in RA patients correlated positively with disease severity,²⁸ suggesting that VEGF may serve as a valuable molecular biomarker for evaluating the severity of RA. However, emerging evidence suggested that VEGF not only promoted inflammation and angiogenesis but also facilitated subchondral bone regeneration in arthritic joints.²⁹ A preliminary study found that promoting VEGF expression within the joint can enhance lymphatic drainage, thereby reducing the severity of RA.³⁰ As one of the subtypes of VEGF, VEGFB can be regulated by vagus nerve electrical stimulation, suppressing inflammatory responses through activation of the PI3K/AKT-FoxO3A-VEGF-A/B signaling cascade.³¹ This study revealed that EA can upregulate VEGFB expression in the peripheral blood of RA patients and CFA rats. This finding appeared contradictory to previous research demonstrating that EA suppressed VEGF mRNA expression in synovial tissue of adjuvant arthritis rats.³² We hypothesized that the inconsistent results may be due to differences in the regulation of VEGF subtypes by EA.

This study was not the first to apply bioinformatics analysis to identify potential biomarkers involved in EA treatment for RA. However, compared with previous research,³² it incorporated a broader range of machine learning algorithms and validated the findings across multiple validation datasets. The present study has the following limitations: Firstly, the datasets employed in this study contained a relatively limited number of EA treatment cases. Additionally, we did not evaluate biomarker diagnostic efficacy across diverse demographic subgroups or perform batch-effect correction on the dataset. Secondly, due to experimental limitations, this study did not expand on the diagnostic efficacy of biomarkers in clinical RA patients or the regulatory effects of EA on these biomarkers. Current animal models exhibited limited capacity to fully recapitulate the complex pathogenesis of RA, thereby constraining accurate assessment of diagnostic biomarker performance and EA therapeutic efficacy across disease subtypes. Therefore, further clinical experiments are needed to extend the application of biomarkers.

Conclusion

The present study identified two potential diagnostic biomarkers for RA using bioinformatics and machine learning approaches, and revealed that EA modulated the expression of these genes in peripheral blood. These findings not only provided new potential biomarkers for RA diagnosis but also offered novel therapeutic targets for EA-based treatment in RA management. However, further clinical trials are necessary to validate the diagnostic efficacy of biomarkers for different populations and the regulatory effects of EA on these biomarkers.

Abbreviations

CFA, Complete Freund’s Adjuvant; DEGs, Differentially expressed genes; DMARDs, disease-modifying antirheumatic drugs; EA, Electroacupuncture; GEO, Gene Expression Omnibus; IFX, Infliximab; LASSO, Least absolute shrinkage and selection operator; MDG, Mean decrease Gini; MTX, Methotrexate; NSAIDs, Non-steroidal anti-inflammatory drugs; PWT, Paw withdrawal threshold; RA, Rheumatoid arthritis; ROC, Receiver operating characteristic; SVM-RFE, Support vector machine recursive feature elimination; TCM, Traditional Chinese Medicine; TCZ, Tocilizumab.

Data Sharing Statement

The datasets analyzed for this study can be found in the GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc = GSE15573, GSE59526, GSE17755, GSE205962, and GSE93272).

Funding

This research was fund by Shanghai Chinese Medicine Three-Year Action Plan Project (ZY(2021-2023)-0202, ZY(2021-2023)-0502).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Xie Y, Fan KW, Guan SX, Hu Y, Gao Y, Zhou WJ. LECT2: a pleiotropic and promising hepatokine, from bench to bedside. J Cell Mol Med. 2022;26(13):3598–3607. doi:10.1111/jcmm.17407

2. Wan R, Fan Y, Zhao A, et al. Comparison of efficacy of acupuncture-related therapy in the treatment of rheumatoid arthritis: a network meta-analysis of randomized controlled trials. Front Immunol. 2022;13:829409. doi:10.3389/fimmu.2022.829409

3. Shang J, Xu J, Zhang Z, Tian L, He Y. The efficacy and safety of acupuncture-related therapy in the treatment of rheumatoid arthritis: a protocol for systematic review and network meta-analysis. Medicine. 2021;100(32):e26859. doi:10.1097/md.0000000000026859

4. Zhang Q, Tan Y, Wen X, Li F. Involvement of Neuropeptide Y within paraventricular nucleus in electroacupuncture inhibiting sympathetic activities in hypertensive rats. Int J Hypertens. 2022;2022:9990854. doi:10.1155/2022/9990854

5. Seca S, Kirch S, Cabrita AS, Greten HJ. Evaluation of the effect of acupuncture on hand pain, functional deficits and health-related quality of life in patients with rheumatoid arthritis–A study protocol for a multicenter, double-blind, randomized clinical trial. J Integr Med. 2016;14(3):219–227. doi:10.1016/s2095-4964(16)60254-6

6. Seca S, Patrício M, Kirch S, Franconi G, Cabrita AS, Greten HJ. Effectiveness of acupuncture on pain, functional disability, and quality of life in rheumatoid arthritis of the hand: results of a double-blind randomized clinical trial. J Altern Complementary Med. 2019;25(1):86–97. doi:10.1089/acm.2018.0297

7. Lee H, Lee JY, Kim YJ, et al. Acupuncture for symptom management of rheumatoid arthritis: a pilot study. Clin Rheumatol. 2008;27(5):641–645. doi:10.1007/s10067-007-0819-3

8. Ouyang BS, Gao J, Che JL, et al. Effect of electro-acupuncture on tumor necrosis factor-α and vascular endothelial growth factor in peripheral blood and joint synovia of patients with rheumatoid arthritis. Chin J Integr Med. 2011;17(7):505–509. doi:10.1007/s11655-011-0783-2

9. Zeng C, Bai X, Qin H, Wang H, Rong X, Yan J. Effect of adjuvant therapy with electroacupuncture on bone turnover markers and interleukin 17 in patients with rheumatoid arthritis. J Tradit Chin Med. 2019;39(4):582–586.

10. Zhang RB, Dong LC, Shen Y, et al. Electroacupuncture alleviates ulcerative colitis by targeting CXCL1: evidence from the transcriptome and validation. Front Immunol. 2023;14:1187574. doi:10.3389/fimmu.2023.1187574

11. Wie HS, Kim SN. Therapeutic components of acupuncture stimulation based on characteristics of sensory nerve and nervous signaling pathway. J Integr Med. 2025;23(2):106–112. doi:10.1016/j.joim.2025.02.002

12. Zhou S, Lu H, Xiong M. Identifying immune cell infiltration and effective diagnostic biomarkers in rheumatoid arthritis by bioinformatics analysis. Front Immunol. 2021;12:726747. doi:10.3389/fimmu.2021.726747

13. Cheng Q, Chen X, Wu H, Du Y. Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis. J Transl Med. 2021;19(1):18. doi:10.1186/s12967-020-02689-y

14. Li L, Zhou D, Liu Q, et al. Network analysis indicating the pharmacological mechanism of Yunpi-Qufeng-Chushi-prescription in prophylactic treatment of rheumatoid arthritis. BMC Complement Med Therap. 2021;21(1):142. doi:10.1186/s12906-021-03311-4

15. Hui P, Zhou S, Cao C, Zhao W, Zeng L, Rong X. The elucidation of the anti-inflammatory mechanism of EMO in rheumatoid arthritis through an integrative approach combining bioinformatics and experimental verification. Front Pharmacol. 2023;14:1195567. doi:10.3389/fphar.2023.1195567

16. Khadour FA, Khadour YA, Xu T. Electroacupuncture delays the progression of juvenile collagen-induced arthritis via regulation NLRP3/ NF-κB signaling pathway -mediated pyroptosis and its influence on autophagy. Clin Rheumatol. 2025;44(4):1713–1728. doi:10.1007/s10067-025-07354-7

17. Dong SY, Zhou Y, Wang XC, Du ZH, Ye TS. Electroacupuncture attenuates bone erosion and promotes macrophage polarization in a mouse model of collagen-induced arthritis. Acupunct Med. 2025;9645284251331991. doi:10.1177/09645284251331991

18. Ellis K, Kerr J, Godbole S, Lanckriet G, Wing D, Marshall S. A random forest classifier for the prediction of energy expenditure and type of physical activity from wrist and Hip accelerometers. Physiol Meas. 2014;35(11):2191–2203. doi:10.1088/0967-3334/35/11/2191

19. Alolga RN, Opoku-Damoah Y, Alagpulinsa DA, et al. Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylopic acid in a bioinspired lipoprotein nanoformulation. Biomaterials. 2021;268:120482. doi:10.1016/j.biomaterials.2020.120482

20. Vivancos GG, Verri WA, Cunha TM, et al. An electronic pressure-meter nociception paw test for rats. Braz J Med Biol Res. 2004;37(3):391–399. doi:10.1590/s0100-879×2004000300017

21. Zeng R, Zhuo Z, Luo Y, Sha W, Chen H. Rho GTPase signaling in rheumatic diseases. iScience. 2022;25(1):103620. doi:10.1016/j.isci.2021.103620

22. Wang L, Yang X, Wan L, Wang S, Pan J, Liu Y. ARHGAP17 inhibits pathological cyclic strain-induced apoptosis in human periodontal ligament fibroblasts via Rac1/Cdc42. Clin Exp Pharmacol Physiol. 2020;47(9):1591–1599. doi:10.1111/1440-1681.13336

23. Wan Y, Zhou J, Zhang P, Lin X, Li H. Inhibition of spinal Rac1 attenuates chronic inflammatory pain by regulating the activation of astrocytes. Cell Signalling. 2024;114:110972. doi:10.1016/j.cellsig.2023.110972

24. Chen Z, Zhang S, Nie B, et al. Distinct roles of srGAP3-Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel. J Physiol. 2020;598(12):2415–2430. doi:10.1113/jp279525

25. Xu L, Yang L, Wu Y, et al. Rac1/PAK1 signaling contributes to bone cancer pain by regulation dendritic spine remodeling in rats. Mol Pain. 2023;19:17448069231161031. doi:10.1177/17448069231161031

26. Wu Q, Cai C, Ying X, et al. Electroacupuncture inhibits dendritic spine remodeling through the srGAP3-Rac1 signaling pathway in rats with SNL. Bio Res. 2023;56(1):26. doi:10.1186/s40659-023-00439-0

27. MacDonald IJ, Liu SC, Su CM, Wang YH, Tsai CH, Tang CH. Implications of angiogenesis involvement in arthritis. Int J Mol Sci. 2018;19(7):2012. doi:10.3390/ijms19072012

28. Kim JW, Kong JS, Lee S, et al. Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis. Exp Mol Med. 2020;52(5):843–853. doi:10.1038/s12276-020-0443-8

29. Rong M, Liu D, Xu X, et al. A superparamagnetic composite hydrogel scaffold as in vivo dynamic monitorable theranostic platform for osteoarthritis regeneration. Adv Mater. 2024;36(35):e2405641. doi:10.1002/adma.202405641

30. Luo B, Wu Y, Liu SL, et al. Vagus nerve stimulation optimized cardiomyocyte phenotype, sarcomere organization and energy metabolism in infarcted heart through FoxO3A-VEGF signaling. Cell Death Dis. 2020;11(11):971. doi:10.1038/s41419-020-03142-0

31. Zhu J, Su C, Chen Y, Hao X, Jiang J. Electroacupuncture on ST36 and GB39 acupoints inhibits synovial angiogenesis via downregulating HIF-1α/VEGF expression in a rat model of adjuvant arthritis. Evid Based Complement Alternat Med. 2019;2019:5741931. doi:10.1155/2019/5741931

32. Shen C, Gu B, Tang M, et al. Biomarkers identification of early rheumatoid arthritis via bioinformatics approach and experimental verification. Ann Clin Lab Sci. 2024;54(5):661–670.

Continue Reading

July 5, 2025

Space burial goes wrong: Capsule with remains of 166 people and cannabis seeds crashes into Pacific ocean |

A space capsule carrying the ashes of 166 people, along with a collection of cannabis seeds, was lost after crashing into the Pacific Ocean during reentry. The capsule, part of a mission called “Mission Possible” by German aerospace start-up The Exploration Company (TEC), launched on June 23, 2025. Its cargo, arranged through Texas-based space burial firm Celestis, successfully completed two orbits around Earth before communication was lost. While the mission aimed to be Celestis’s first to return from orbit, a reentry anomaly led to the capsule’s destruction and the scattering of its contents at sea.

Space burial mission ends in loss after promising start

The Nyx capsule, designed and launched by The Exploration Company, initially performed well. It powered its payloads in orbit, stabilized after launch separation, and briefly re-established communication during reentry. However, the company lost contact just minutes before splashdown. TEC confirmed the capsule crashed into the Pacific Ocean, with no materials recovered. This was Celestis’s first attempt at a return-from-orbit space burial, carrying remains of 166 individuals entrusted by families around the world. The mission also carried cannabis seeds as part of the Martian Grow project, a citizen science initiative aimed at exploring the potential of farming cannabis on Mars. TEC has only launched one other capsule prior to Nyx, and while they hailed several technical milestones, they acknowledged the risks involved and expressed a commitment to relaunching in the future.

Families mourn while celestis promises support

Celestis co-founder Charles M. Chafer expressed disappointment and offered condolences to the families involved. He acknowledged the bravery of those who chose to participate in a first-of-its-kind return mission and emphasized the symbolic value of having their loved ones orbit Earth before their final resting place in the Pacific Ocean. Despite the tragic outcome, he noted that many milestones — launch, orbit, and controlled reentry — had been achieved. The company has reached out to affected families to offer support and discuss possible next steps. In his words, while no technical feat can replace the personal meaning behind such missions, “we remain committed to serving with transparency, compassion, and care.”

Continue Reading

July 5, 2025
Space capsule carrying ashes of 166 people meets bizarre end – MSN
1. Space capsule carrying ashes of 166 people meets bizarre end MSN
2. Video Emerges of Legendary Boxer’s ICE Arrest The Daily Beast
3. “We Lost Bodies and Weed in Space”: Human Remains and Cannabis Crash Into Ocean After Shocking Mission Failure Rude Baguette
4. Space burial company loses 166 human remains in failed mission Boing Boing
5. 160 People Wanted to Be Buried in Space. Their Capsule Slammed Into the Ocean Instead. Popular Mechanics
Continue Reading
July 5, 2025
Oasis comeback gig in Cardiff was dream come true for fans

Paul Burnell

BBC News Manchester

PA Media

Fans said they could die happy now the band have played again

It was rock’s most eagerly awaited comeback tour and some of the more than 70,000 fans crammed into Cardiff to see Oasis said they were not disappointed.

Feuding Mancunian siblings Noel and Liam Gallager walked on to stage for the first time together since 2009 and the crowd went wild.

Lifelong fan Kevin Varley, 42, from Manchester, said: “It was brilliant – it was a real moment in time.

Mr Varley, whose first gig was at Maine Road, the former home of Manchester City, in 1995, said: “I’ve seen them 10 times and this was up there with the best.”

He added: “I took my lad, who is six, and he thought it was great I hope in years to come he will really appreciate it even more.

“It was everything I hoped it would be.”

Mr Varley, who spent £250 each for his tickets said: “If I could go again tonight I would do.”

He added; “I’m thinking of trying to get tickets for the gig at Heaton Park [in Manchester] as it is not far from my house.”

PA Media

Noel Gallagher has not enjoyed the best of relationships with his brother

Speaking after the concert, Steve from Hertfordshire, who last saw them perform in 2006, said they had lived up to his expectations – but admitted to having had quite a few beers before the show.

Asked for his favourite part, he said: “The beginning, the middle, and also the end.”

“All of it was fantastic,” he said, adding: “We had a really good time, we’ve come all the way from Hertfordshire to see them in Wales.”

Morgan, 20 and from Wales, said: “It made my life, honestly, I could get hit by a car and die, and I’d have a smile on my face.”

Describing himself as an Oasis fan from birth, with his father encouraging him to get into them, he said: “It was unreal, being in that stadium, I’m still shaking, being here tonight is something else.”

PA Media

More than 70,000 fans joined in the massive singalong

The band split acrimoniously in 2009 after a backstage altercation following a gig in Paris that began with Liam throwing a plum at his older brother’s head.

In the intervening years, they engaged in a long war of words in the press, on stage and social media.

Liam repeatedly called Noel a “massive potato” on Twitter and, more seriously, accused him of skipping the One Love concert for victims of the Manchester Arena bombing.

Noel responded by saying Liam was a “village idiot” who “needs to see a psychiatrist”.

Continue Reading

July 5, 2025
“At home, I never felt included, I always felt on the outside”: Deaf peoples’ perspectives on how inadequate access to childhood communication influences mental health outcomes | BMC Public Health
Kusters A, Meulder MD, O’Brien D. Innovations in deaf studies : The role of deaf scholars. Oxford University Press; 2017. https://www.researchgate.net/publication/316878714_Innovations_in_Deaf_Studies_The_Role_of_Deaf_Scholars.
World Federation of The Deaf. Our Work 2016 [cited 2024 February]. Available from: https://wfdeaf.org/our-work/.
Department of Health and Aged Care. About ear health 2021 [cited 2024 June]. Available from: https://www.health.gov.au/topics/ear-health/about.
Australian Bureau of Statistics. Language used at home (LANP) Census of population and housing 2021 [cited 2024 February]. Available from: https://www.abs.gov.au/census/guide-census-data/census-dictionary/2021/variables-topic/cultural-diversity/language-used-home-lanp.
Wroblewska-Seniuk KE, Dabrowski P, Szyfter W, Mazela J. Universal newborn hearing screening: methods and results, obstacles, and benefits. Pediatr Res. 2017;81(3):415–22.

PubMed

Google Scholar
Baker-Shenk CL, Padden C. American sign language: A look at its history, structure, and community. TJ Pub Incorporated. 1979. https://www.amazon.com/American-Language-History-Structure-Community/dp/0932666019.
Higgins M, Lieberman AM. Deaf students as a linguistic and cultural minority: shifting perspectives and implications for teaching and learning. PubMed Central. 2016;196(1):9–18.

Google Scholar
O’Donnell MB, Falk EB, Lieberman MD. Social in, social out: How the brain responds to social language with more social language. Commun Monogr. 2015;82(1):31–63.

PubMed
PubMed Central

Google Scholar
Humphries T, Mathur G, Napoli DJ, Padden C, Rathmann C. Deaf children need rich language input from the start: Support in advising parents. Children. 2022;9(11):1609.

PubMed
PubMed Central

Google Scholar
Hall ML, Hall WC, Caselli NK. Deaf children need language, not (just) speech. First Lang. 2019;39(4):367–95.

Google Scholar
Chomsky N. Knowledge of language: Its nature, origin, and use. New York; 1986. https://www.amazon.com/Knowledge-Language-Nature-Origin-Convergence/dp/0030055520.
Willems RM, Varley R. Neural insights into the relation between language and communication. Frontiers in Human Neuroscience. 2010;4(203).
Mayberry RI, Lock E. Age constraints on first versus second language acquisition: Evidence for linguistic plasticity and epigenesis. Brain Lang. 2003;87(3):369–84.

PubMed

Google Scholar
Humphries T, Kushalnagar P, Mathur G, Napoli DJ, Padden C, Rathmann C, et al. Language choices for deaf infants: Advice for parents regarding sign languages. Clin Pediatr. 2016;55(6):513–7.

Google Scholar
Cohen NJ. The impact of language development on the psychosocial and emotional development of young children. In: Tremblay RE, Boivin M, Peters RD, editors. Encyclopedia on Early Childhood Development [Internet]. Montreal, Quebec: CEECD / SKC-ECD; 2010.
Glickman N, Crump C, Hamerdinger S. Language deprivation is a game changer for the clinical specialty of deaf mental health. JADARA. 2020;54(1):54.

Google Scholar
Hall WC. What you don’t know can hurt you: The risk of language deprivation by impairing sign language development in deaf children. Matern Child Health. 2017;21:961–5.

Google Scholar
Hall WC, Levin LL, Anderson ML. Language deprivation syndrome: A possible neurodevelopmental disorder with sociocultural origins. Soc Psychiatry Psychiatr Epidemiol. 2017;52(6):761–76.

PubMed
PubMed Central

Google Scholar
Gulati S. Language deprivation syndrome. In: Glickman NS, Hall WC, editors. Language Deprivation and Deaf Mental Health. New York and London: Routledge Tayor & Francis Group; 2019. p. 24–46.

Google Scholar
Johnston T, Schembri A. Australian sign language (Auslan): An introduction to sign language linguistics. Cambridge University Press; 2007. https://www.researchgate.net/publication/32893365_Australian_Sign_Language_Auslan_An_Introduction_to_Sign_Language_Linguistics.
Murray J, Hall WC, Snoddon K. The importance of signed languages for deaf children and their families. The Hearing Journal. 2020;73(3):30–2.

Google Scholar
Haualand H, Allen C. Deaf people and human rights. World Federation of the Deaf and Swedish National Association of the Deaf; 2009. https://inee.org/resources/deaf-people-and-human-rights.
Howell T, Sung V, Smith L, Dettman S. Australian families of deaf and hard of hearing children: Are they using sign?. Int J Pediatr Otorhinolaryngol. 2024;179. https://pubmed.ncbi.nlm.nih.gov/38579404/.
Mitchell RE, Karchmer MA. Chasing the mythical ten percent: Parental hearing status of deaf and hard of hearing students in the United States. Sign Language Studies. 2004;4(2):138–63.

Google Scholar
Humphries T, Kushalnagar P, Mathur G, Napoli DJ, Rathmann C, Smith S. Support for parents of deaf children: Common questions and informed, evidence-based answers. Int J Pediatr Otorhinolaryngol. 2019;118:134–42.

PubMed

Google Scholar
Dougherty E. Studying Language Acquisition in Deaf Children: The Brink; 2019 [updated March 6, 2017; cited 2024 February]. Available from: https://www.bu.edu/articles/2017/asl-language-acquisition/.
Dall M, Fellinger J, Holzinger D. The link between social communication and mental health from childhood to young adulthood: A systematic review. Front Psych. 2022;13:1–18.

Google Scholar
Parke EM, Becker ML, Graves SJ, Baily AR, Paul MG, Freeman AJ, et al. Social cognition in children with ADHD. J Atten Disord. 2021;25(4):519–29.

PubMed

Google Scholar
James TG, McKee MM, Sullivan MK, Ashton G, Hardy SJ, Santiago Y, et al. Community-engaged needs assessment of deaf American sign language users in Florida, 2018. Public Health Rep. 2022;137(4):730–8.

PubMed

Google Scholar
Gilmour J, Hill B, Place M, Skuse DH. Social communication deficits in conduct disorder: a clinical and community survey. J Child Psychol Psychiatry. 2004;45(5):967–78.

CAS
PubMed

Google Scholar
The diagnostic and statistical manual of mental disorders. DSM–5. 5th, editor: American Psychiatric Association; 2013. https://www.psychiatry.org/psychiatrists/practice/dsm.
Guthrie S, Leslie P. “We didn’t realise how much we needed you”. Speech and language therapy provision in adult mental health settings. Advances in Mental Health. 2023;22(2):212–28.
Zangrilli A, Conneely M, McCabe R, Catalfio F, Priebe S. Categorizing what patients with psychosis say in clinical interactions: The development of a framework informed by theory of mind, metacognition and cognitive behavioral theory. J Ment Health. 2022;31(5):673–82.

PubMed

Google Scholar
Walsh I, Regan J, Sowman R, Parsons B, McKay P. A needs analysis for the provision of a speech and language therapy service to adults with mental health disorders. Irish Journal of Psychological Medicine. 2007;24(3):89–93.

PubMed

Google Scholar
World Health Organization. Mental Health [Internet]: World Health Organization; 2024 [cited 2024 June]. Available from: https://www.who.int/health-topics/mental-health#tab=tab_1.
Fellinger J, Holzinger D, Pollard R. Mental health of deaf people. The Lancet. 2012;379(9820):1037–44.

Google Scholar
Moore MS, Levitan L. For hearing people only: 4th edition. Deaf Life Press; 2016. https://www.amazon.com/Hearing-People-Only-4th/dp/B07433KLTK.
Australian Bureau of Statistics. National Health Survey: first results, Australia 2017–18 [Canberra, A.C.T.]: Australian Bureau of Statistics; 2018 [cited 2024 February]. Available from: https://research.ebsco.com/linkprocessor/plink?id=6b04c912-58b3-356a-a321-b5f0e623e466.
Australian Bureau of Statistics. Disability, ageing and carers, Australia: summary of findings, 2018 Canberra, ACT: Australian Bureau of Statistics; 2019 [cited 2024 February]. Available from: https://research.ebsco.com/linkprocessor/plink?id=591e5870-55a8-3a6b-a4b6-192800f78d4a.
Conama JB. Situating the socio-economic position of Irish deaf community in the equality framework. Equality, Diversity and Inclusion. 2013;32(2):173–94.

Google Scholar
Kushalnagar P, Bruce S, Sutton T, Leigh IW. Retrospective basic parent-child communication difficulties and risk of depression in deaf adults. J Dev Phys Disabil. 2017;29:25–34.

PubMed

Google Scholar
Anderson ML, Craig KSW, Hall WC, Ziedonis DM. A pilot study of deaf trauma survivors’ experiences: Early traumas unique to being deaf in a hearing world. J Child Adolesc Trauma. 2016;9(4):353–8.

PubMed

Google Scholar
Marschark M, Knoors H. Educating deaf children: Language, cognition, and learning. Deaf Educ Int. 2012;14(3):136–60.

Google Scholar
O’Connell N. “Opportunity Blocked”: Deaf people, employment and the sociology of audism. Humanit Soc. 2022;46(2):336–58.

Google Scholar
Lott VG, Easterbrooks SR, Heller KW, O’Rourke CM. Work attitudes of students who are deaf and their potential employers. JADARA. 2019;34(2):31–55.

Google Scholar
Punch R. Employment and adults who are deaf or hard of hearing. Am Ann Deaf. 2016;161(3):384–97.

PubMed

Google Scholar
Napier J, Kidd MR. English literacy as a barrier to health care information for deaf people who use Auslan. Aust Fam Physician. 2013;42(12):896–9.

PubMed

Google Scholar
Barnett SL, Matthews KA, Sutter EJ, DeWindt LA, Pransky JA, O’Hearn AM, et al. Collaboration with deaf communities to conduct accessible health surveillance. Am J Prev Med. 2017;52(3):250–4.

Google Scholar
Liamputtong P. Handbook of research methods in health social sciences. Singapore: Springer; 2019.

Google Scholar
Ferndale D, Watson B, Munro L. Creating deaf-friendly spaces for research: Innovating online qualitative enquiries. Qual Res Psychol. 2015;12(3):246–57.

Google Scholar
Uwe F. Triangulation in data collection. Sage Publications; 2018. 527–44 p. https://chooser.crossref.org/?doi=10.4135%2F9781526416070.n34.
Liamputtong P. Researching the vulnerable : A guide to sensitive research methods: Sage Publication; 2007. https://methods.sagepub.com/book/mono/researching-the-vulnerable/toc.
Manohar N, MacMillan F, Steiner GZ, Arora A. Recruitment of research participants. In: Liamputtong P, editor. Handbook of research methods in health social sciences. 2018. p. 71–98. https://www.researchgate.net/publication/323554760_Recruitment_of_Research_Participants.
Kushalnagar RS, Vogler C. Teleconference accessibility and guidelines for deaf and hard of hearing users. In: Machinery AfC, editor. Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; Virtual Event, Greece2020. p. 1–6. https://par.nsf.gov/servlets/purl/10209492.
Jacobson D, Mustafa N. Social identity map: A reflexivity tool for practicing explicit positionality in critical qualitative research. Int J Qual Methods. 2019;18. https://journals.sagepub.com/doi/full/10.1177/1609406919870075.
Manohar N, Liamputtong P, Bhole S, Arora A. Researcher positionality in cross-cultural and sensitive research. In: Liamputtong P, editor. Handbook of Research Methods in Health Social Sciences. Singapore: Springer; 2017. p. 1601–16.

Google Scholar
Temple B. Qualitative research and translation dilemmas. Qual Res. 2004;4(2):161–78. https://www.researchgate.net/publication/249731128_Qualitative_Research_and_Translation_Dilemmas.

Google Scholar
Anderson ML, Riker T, Gagne K, Hakulin S, Higgins T, Meehan J, et al. Deaf qualitative health research: Leveraging technology to conduct linguistically and sociopolitically appropriate methods of inquiry. Qualitative health research. 2018;28(11). https://pubmed.ncbi.nlm.nih.gov/29890891/.
Cawthon SW, Garberoglio CL. Evidence-based practices in deaf education: A call to center research and evaluation on the experiences of deaf people. Rev Res Educ. 2021;45(1):346–71.

Google Scholar
Harris R, Holmes HM, Mertens DM. Research ethics in sign language communities. Sign Language Studies. 2009;9(2):104–31.

Google Scholar
Rowlands J. Interviewee transcript review as a tool to improve data quality and participant confidence in sensitive research. International Journal of Qualitative Methods. 2021;20.
Braun V, Clarke V. Toward good practice in thematic analysis: Avoiding common problems and be(com)ing a knowing researcher. International Journal of Transgender Health. 2022;24(1):1–6.

PubMed
PubMed Central

Google Scholar
Allsop DB, Chelladurai JM, Kimball ER, Marks LD, Hendricks JJ. Qualitative methods with Nvivo software: A practical guide for analyzing qualitative data. Psych. 2022;4(2):142–59.

Google Scholar
Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: Conceptual issues and research evidence. Psychol Bull. 2003;129(5):674–97.

PubMed
PubMed Central

Google Scholar
Lund EM. Examining the potential applicability of the minority stress model for explaining suicidality in individuals with disabilities. Rehabil Psychol. 2021;66(2):183–91.

PubMed

Google Scholar
Botha M, Frost DM. Extending the minority stress model to understand mental health problems experienced by the autistic population. Society and Mental Health. 2018;10(1):20–34.

Google Scholar
Berry JW. Stress perspectives on acculturation. In: Sam DL, Berry JW, editors. The Cambridge handbook of acculturation psychology. 12006. p. 43–56.
Braun V, Clarke V. A critical review of the reporting of reflexive thematic analysis in Health Promotion International. Health Promotion International. 2024;39(3). https://pubmed.ncbi.nlm.nih.gov/38805676/.
Mortelmans D. Doing qualitative data analysis with NVivo: Springer Nature; 2025.
Bauman H-DL. Audism: Exploring the metaphysics of oppression. Journal of deaf studies and deaf education. 2004;9(2):239–46.
Wilson JAB, Atcherson SR. Audism and its implications for audiology. Perspectives of the ASHA Special Interest Groups. 2017;2:18–28.

Google Scholar
Aparicio M, Peigneux P, Charlier B, Balériaux D, Kavec M, Leybaert J. The neural basis of speech perception through lipreading and manual cues: Evidence from deaf native users of cued speech. Front Psychol. 2017;8(426):1–23.

Google Scholar
Dirth TP, Adamsb GA. Decolonial theory and disability studies: On the modernity/coloniality of ability. J Soc Polit Psychol. 2019;7(1):260–89.

Google Scholar
Engberg-Pedersen E. Space in Danish sign language: The semantics and morphosyntax of the use of space in a visual language: Signum Press; 1993. https://www.cambridge.org/core/journals/nordic-journal-of-linguistics/article/abs/elisabeth-engbergpedersen-space-in-danish-sign-language-the-semantics-and-morphosyntax-of-the-use-of-space-in-a-visual-language-international-studies-on-sign-language-research-and-communication-of-the-deaf-vol-19-hamburg-signum-verlag-1993-406-pp/773C6C3D6DFA88C2C3F4CCAD85AECF9D.
Kusters A, Green M, Moriarty E, Snoddon K. Sign language ideologies: Practices and politics. Sign language ideologies in practice. 2020:3–22. https://www.researchgate.net/publication/344263685_Sign_language_ideologies_Practices_and_politics.
Meek DR. Dinner table syndrome: A phenomenological study of deaf individuals’ experiences with inaccessible communication. Qualitative Report. 2020;25(6):1676–94.

Google Scholar
Listman JD, Kurz KB. Lived experience: Deaf professionals’ stories of resilience and risks. The Journal of Deaf Studies and Deaf Education. 2020;25(2):239–49.

PubMed

Google Scholar
Glickman N. Do you hear voices? Problems in assessment of mental status in deaf persons with severe language deprivation. The Journal of Deaf Studies and Deaf Education. 2007;12(2):127–47.

PubMed

Google Scholar
Solomon A. Far from the tree: Parents, children, and the search for identity. Am J Med Genet A. 2014;164A(9):2412–3.

Google Scholar
Berry M. Being deaf in mainstream education in the United Kingdom: Some implications for their health. Universal Journal of Psychology. 2017;5(3):129–39.

Google Scholar
Herbert M, Pires A. Bilingualism and code-blending among deaf ASL-English bilinguals. In: Guijarro-Fuentes P, Suárez-Gómez C, editors. New Trends in Language Acquisition Within the Generative Perspective Studies in Theoretical Psycholinguistics. 49. Dordrecht: Springer; 2020. p. 99–139.
Mauldin L, Fannon T. They told me my name: Developing a deaf identity. Symb Interact. 2021;44(2):339–66.

Google Scholar
Zeshan U, Panda S. Two languages at hand: Code-switching in bilingual deaf signers. In: Zeshan U, Webster J, editors. Sign Multilingualism. Berlin: Boston: De Gruyter Mouton; 2020. p. 81–126.

Google Scholar
Marschark M, Hauser PC. How deaf children learn: What parents and teachers need to know. USA: Oxford University Press; 2012.

Google Scholar
Holcomb TK, Smith DH. Deaf eyes on interpreting: Gallaudet University Press; 2018. https://gupress.gallaudet.edu/Books/D/Deaf-Eyes-on-Interpreting.
Jemina N, Skinner R, Young A, Oram R. Mediating identities: Sign language interpreter perceptions on trust and representation. Journal of Applied Linguistics and Professional Practice. 2017;14(1):75–95.

Google Scholar
O’Brien D, Hodge G, Gulamani S, Rowley K, Adam R, Emery S, et al. Deaf academics’ perceptions of “trust” in relationships with signed language interpreters. Translation & Interpreting: The International Journal of Translation and Interpreting Research. 2023;15(2):25–42.

Google Scholar
Sheppard K, Badger T. The lived experience of depression among culturally Deaf adults. J Psychiatr Ment Health Nurs. 2010;17(9):783–9.

CAS
PubMed

Google Scholar
Pinquart M, Pfeiffer JP. Bullying in students with and without hearing loss. Deaf Educ Int. 2015;17(2):101–10.

Google Scholar
Weiner MT, Day SJ, Galvan D. Deaf and hard of hearing students’ perspectives on bullying and school climate. Am Ann Deaf. 2013;158(3):334–43.

PubMed

Google Scholar
Fellinger J, Holzinger D, Sattel H, Laucht M, Goldberg D. Correlates of mental health disorders among children with hearing impairments. Dev Med Child Neurol. 2009;51(8):635–41.

PubMed

Google Scholar
Bouldin E, Patel SR, Tey CS, White M, Alfonso KP, Govil N. Bullying and children who are deaf or hard-of-hearing: A Scoping review. The Laryngoscope. United States: Wiley-Blackwell; 2021. p. 1884–92.
Jalkhi AG, Rowley J. ‘There is no barrier when it comes to your deafness’: participatory research exploring the views of deaf and hard-of-hearing students being educated in a resource provision. Eur J Spec Needs Educ. 2024:1–17. https://www.researchgate.net/publication/381950138_’There_is_no_barrier_when_it_comes_to_your_deafness’_participatory_research_exploring_the_views_of_deaf_and_hard-of-hearing_students_being_educated_in_a_resource_provision.
Edmondson S, Howe J. Exploring the social inclusion of deaf young people in mainstream schools, using their lived experience. Educ Psychol Pract. 2019;35(2):216–28.

Google Scholar
Olsson S, Dag M, Kullberg C. Deaf and hard-of-hearing adolescents’ experiences of inclusion and exclusion in mainstream and special schools in Sweden. Eur J Spec Needs Educ. 2018;33(4):495–509.

Google Scholar
Power D, Hyde M. The characteristics and extent of participation of deaf and hard-of-hearing students in regular classes in Australian schools. J Deaf Stud Deaf Educ. 2002;7(4):302–11.

PubMed

Google Scholar
Humphries T, Kushalnagar P, Mathur G, Napoli DJ, Padden C, Rathmann C, et al. Language acquisition for deaf children: Reducing the harms of zero tolerance to the use of alternative approaches. Harm Reduct J. 2012;9(16). https://harmreductionjournal.biomedcentral.com/articles/10.1186/1477-7517-9-16.
Caselli N, Pyers J, Lieberman AM. Deaf children of hearing parents have age-level vocabulary growth when exposed to American sign language by 6 months of age. J Pediatr. 2021;232:229–36.

PubMed
PubMed Central

Google Scholar
Nordhagen GG. Ål folk college brings together deaf people from all corners of the world [Internet] Norway: FriFagbevegelse; 2022 [cited 2024 March]. Available from: https://frifagbevegelse.no/ntlmagasinet/al-folkehogskole-samler-dove-fra-alle-verdenshjorner-6.469.921918.1ec744a630?fbclid=IwY2xjawE6fsNleHRuA2FlbQIxMAABHZIZzT2UQUX3xSZD_q0spfV6vNMtsU5J-DI0F5ckax8PEybLxIctLjXvaw_aem_eJ0G9guUFTVM61r0QNnU4w.
Szarkowski A, Moeller MP, Gale E, Smith T, Birdsey BC, Moodie STF, et al. Family-centered early intervention deaf/hard of hearing (FCEI-DHH): Cultural & global implications. The Journal of Deaf Studies and Deaf Education. 2024;29(1):127–39.

Google Scholar
Hoskin J, Herman R, Woll B. Deaf language specialists: Delivering language therapy in signed languages. The Journal of Deaf Studies and Deaf Education. 2023;28(1):40–52.

Google Scholar
The Hands and Voices Off to a Great Start. The Hands & Voices Family Support Activities Guide [Internet]: Hands and Voices; 2024 [cited 2024 March]. Available from: https://handsandvoices.org/great-start/fam-support-guide/index.html.
Hauser PC, O’Hearn A, McKee M, Steider A, Thew D. Deaf epistemology: Deafhood and deafness. Am Ann Deaf. 2010;154(5):486–92.

PubMed

Google Scholar
Johnston T. W(h)ither the deaf community? Population, genetics, and the future of Australian sign language. Sign Language Studies. 2006;6(2):137–73.

Google Scholar
Zamborlin C. Going beyond pragmatic failures: Dissonance in intercultural communication. Intercult Pragmat. 2007;4(1):21–50.

Google Scholar
Schwartz S, Zamboanga B, Wang W, Olthuis J. Measuring identity from an Eriksonian perspective: Two sides of the same coin? J Pers Assess. 2009;91(2):143–54.

PubMed

Google Scholar
Molinsky A. Cross-cultural code-switching: The psychological challenges of adapting behavior in foreign cultural interactions. Acad Manag Rev. 2007;32(2):622–40.

Google Scholar
Gardner-Chloros P. Contact and code-switching. In: Hickey R, editor. The Handbook of Language Contact. John Wiley & Sons Ltd; 2020. p. 181-99. https://onlinelibrary.wiley.com/doi/10.1002/9781119485094.ch9.
Hauser PC. An analysis of codeswitching. In: Metzger M, editor. Bilingualism and Identity in Deaf Communities. Washington, DC: Gallaudet University Press; 2000. p. 43–78.

Google Scholar
Hall MA, Dugan E, Zheng B, Mishra AK. Trust in physicians and medical institutions: what is it, can it be measured, and does it matter? Milbank Q. 2001;79(4):613–39.

CAS
PubMed
PubMed Central

Google Scholar
Jaiswal J, Halkitis PN. Towards a more inclusive and dynamic understanding of medical mistrust informed by science. Behav Med. 2019;45(2):79–85.

PubMed

Google Scholar
Kaplunov E. Mistrust between deaf patients and hearing staff in healthcare settings. Empedocles: European Journal for the Philosophy of Communication. 2023;14(1):21–42.
Hellström L, Thornberg R, Espelage DL. Definitions of bullying. In: Smith PK, Norman JOH, editors. The Wiley Blackwell handbook of bullying: A comprehensive and international review of research and intervention. 1: John Wiley & Sons Ltd; 2021. p. 2–21. https://www.researchgate.net/publication/351365405_Definitions_of_bullying.
Gaynor C, Watson S. Evaluating DFID’s policy on tackling social exclusion: Baseline, framework and indicators. 2007. https://assets.publishing.service.gov.uk/media/5a751239ed915d5c544654fc/wp22-social-exclusion.pdf.
Williams KD, Carter-Sowell AR. Margalization through social ostracism: Effects of being ignored and excluded. In: Butera F, Levine JM, editors. Coping with Minority Status: Responses to Exclusion and Inclusion: Cambridge University Press; 2008. p. 104–21. https://www.cambridge.org/core/books/abs/coping-with-minority-status/marginalization-through-social-ostracism-effects-of-being-ignored-and-excluded/F7EE772BE45E332DE501BE528B8E748F.

Continue Reading

Introduction

The prevalence of dementia is increasing worldwide, with projections estimating that the number of individuals affected will reach 150 million by 2050.^1,2 Alzheimer’s disease (AD) and other major forms of dementia are progressive neurodegenerative disorders that affect the entire body, ultimately leading to death from complications and associated conditions.^3,4 Patients with Vascular dementia (VD) often succumb to cerebrovascular disease or myocardial infarction; however, VD itself can result in pathologies such as aspiration pneumonia, which can also be fatal.⁵

As awareness grows regarding dementia as a terminal condition, it has become a focus of palliative care in many countries.^6,7 Consequently, AD and other dementias rank among the leading causes of death in European countries and the United States (US). Notably, AD is the most common form of dementia, accounting for approximately 60% of all cases, with a reported death rate of 13% in France, 12% in the United Kingdom, and 7% in the US.⁸

Although the prevalence of dementia increases with age, Japan, despite having one of the longest life expectancies globally, reports a lower ranking of dementia as a cause of death compared to that in other countries. The reported mortality rate for AD and other dementias in Japan is 1.6% for both, significantly lower than rates observed in Western countries.⁹ Conversely, “senility” ranked as the third leading cause of death in Japan’s 2018 mortality statistics, accounting for 8% of deaths. This discrepancy has sparked debate over whether deaths caused by dementia are being inaccurately documented as senility on death certificates.^10,11

The idea that dementia should be recognized as a cause of death was proposed by Molsa et al⁵ in 1986 and is now well established in many countries. However, even in the US, where dementia ranks higher as a cause of death than in Japan, the underreporting of dementia-related mortality remains a contentious issue.¹² Research has estimated that the actual death rate due to dementia in the US is approximately 14%, whereas only approximately 5% is officially recorded.¹³ Japanese death statistics are compiled based on death certificates issued by physicians. The first author, a psychiatrist with extensive experience in internal medicine, observed that in psychiatric hospitals, where many patients with dementia are admitted, the cause of death listed on death certificates was often recorded as another condition, even when the patient had died of dementia. Although the proportion of deaths occurring in hospitals in Japan has been gradually decreasing, it still accounts for nearly 70% of all deaths. According to a 2020 survey by the Ministry of Health, Labour and Welfare (MHLW), a total of 75,900 individuals with dementia were hospitalized in Japan, including 50,600 with AD and 25,300 with other dementias. Of these, 39,200 patients with AD and 18,800 with other dementias were admitted to psychiatric hospitals, resulting in a total of 58,000 patients with dementia hospitalized in such facilities.¹⁴ According to statistics from the MHLW, 76% (58,000) of all hospitalized Japanese patients with dementia are admitted to psychiatric hospitals. Japan has approximately 1.58 million hospital beds, of which approximately 20%, or 323,000 beds, are designated for psychiatric care. Of these, 244,000 beds are in psychiatric hospitals, and 79,000 are in general hospitals.¹⁵ The majority of inpatient psychiatric care is provided in psychiatric hospitals. In recent years, there has been an increasing trend of patients with dementia being admitted to psychiatric hospitals and remaining there until death.^16,17

We hypothesized that the low proportion of deaths attributed to dementia in Japanese mortality statistics may be due to the omission of AD and other dementias in the direct cause of death section on death certificates. To explore this, we aimed to investigate whether dementia was accurately recorded as the main diagnosis or direct cause of death on death certificates, focusing on psychiatric hospitals with a high number of inpatients with dementia. This analysis utilized both death certificates and medical records.

Methods

Participants

We examined the death certificates of patients who died in 11 psychiatric hospitals in the northern Kanto region of Japan between fiscal years (FY) 2010 and 2020. During this period, 942 deaths were recorded, with death certificates available for all cases and medical records accessible for 653 cases. Therefore, the 653 cases with both death certificates and medical records were selected for the present study (Figure 1).

Figure 1 Consort flow diagram of study patients.

All data used in this study were anonymized during the collection process to ensure individuals’ confidentiality and informed consent was obtained from participants in the form of opt-out on the website. The study was approved by the Ethical Review Committee of Jichi Medical University (approval number: 23–139). The study protocol adhered to the Declaration of Helsinki guidelines.

Survey Items

The investigation of death certificates and medical records was conducted by Sato, a Board Certified Member of the Japanese Society of Internal Medicine. In cases where uncertainties arose during the review of medical records, particularly in determining the direct cause of death, the final determination was made in consultation with Shioda, who had worked as a general physician for many years.

From the total of 653 death certificates (male: 393; female: 260), we extracted the following information: age at death, sex, column I of the death certificate (Disease or condition directly leading to death), and column II of the death certificate (Other significant conditions contributing to death but not related to the disease or condition causing it). The direct cause of death was defined as the disease listed at the bottom of column I, in accordance with the methods prescribed by the World Health Organization (WHO) and the MHLW for identifying causes of death. The names of the direct causes of death were classified using the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), which is the standard classification system used in official death statistics in Japan.

We analyzed 653 medical records (male: 393; female: 260) of patients for whom records were available, focusing on the disease that led to admission, the presence of AD as a comorbidity, and the categorization of dementia as a cause of hospital admission (AD or other dementias). Additionally, we examined whether dementia was accurately documented in column I of the death certificate when AD or any other dementia was identified as the cause of death. The medical records were further reviewed to determine whether dementia had progressed to become a direct cause of death. In this study, death due to dementia was defined using two criteria:¹ the patient’s condition prior to death met the National Hospice and Palliative Care Organization (NHPCO) definition of hospice care induction criteria (Table 1); and² the patient died from a condition attributable to dementia, such as pneumonia, asphyxia resulting from impaired swallowing, urinary tract infections and kidney failure due to dysuria, or infections related to pressure ulcers and other recurring conditions. Cases in which patients with dementia died from apparent malignant diseases, heart diseases, or cerebrovascular diseases were excluded.

Table 1 Hospice Criteria for Dementia

Analysis

We categorized the mental disorders causing hospitalization into the following groups: AD (F00), other dementias (F0 excluding F00), mood disorder spectrum (F3), schizophrenia disorder spectrum (F4), and other mental disorders. The age at death was compared across these categories.

Based on the death certificates, we classified the direct causes of death for the 653 cases using the ICD-10 codes. The number of deaths for men, women, and the overall death rates were identified by ICD codes.

The medical records of 148 patients hospitalized for AD were reviewed to determine the appropriate direct cause of death. For each ICD code, we calculated the difference between the number of deaths recorded on the death certificate and the number of deaths corrected based on the medical record review.

The medical records of 124 patients hospitalized for other dementias were reviewed to determine the appropriate direct cause of death. For each ICD code, the difference between the number of deaths recorded on the death certificate and the number of deaths corrected through medical record review was calculated.

The medical records of 13 patients with comorbid AD who were admitted for other mental disorders were reviewed to determine the appropriate direct cause of death and the mental disorder leading to hospitalization. Discrepancies between the number of deaths recorded on death certificates and the corrected number of deaths based on medical record investigations were identified.

We examined whether there were differences in the number of deaths attributed to AD between death certificates and the corrected number of deaths. The proportions of AD deaths, as recorded on death certificates and as determined by medical record review, were compared overall and by sex. Ratios were analyzed using the chi-squared (χ²) test. Additionally, the χ² test was used to determine whether there were significant differences in AD mortality by sex.

We investigated whether there were differences in the number of deaths attributed to all dementias between death certificates and the corrected number of deaths. The proportion of dementia-related deaths, as recorded on death certificates and as determined by medical record review, were compared overall and by sex. Ratios were analyzed using the χ² test. Additionally, the χ² test was used to assess whether there were significant differences in dementia-related mortality by sex.

A P-value of <0.05 was considered statistically significant. All statistical analyses were conducted using IBM SPSS statistics for Windows, version 26.

Results

A total of 942 death certificates were identified for patients who died between FY 2010 and FY 2020 in 11 psychiatric hospitals. Of these, 393 were male, and 260 were female, resulting in a total of 653 patients for which both death certificates and medical records were verified (Figure 1).

Mental Disorders Causing Hospitalization and Associated Age of Death

We categorized mental disorders causing hospitalization into AD (F00), other dementias (F0 excluding F00), mood disorder spectrum (F3), schizophrenia disorder spectrum (F4), and other psychiatric disorders. The age at death was analyzed for each disorder.

The most common mental disorder was schizophrenia (293 cases), followed by AD (148 cases) and other dementias (124 cases) (Table 2). The average age at death for patients with AD and other dementias was over 80 years. In contrast, the average age at death for patients with other conditions was approximately 70 years (Table 2).

Table 2 Mental Disorders Causing Hospitalization and Associated Age of Death

Causes of Death Based on Death Certificates (by ICD Code)

The results derived from death certificates showed that the leading cause of death was classified under ICD-10 code J, with pneumonia and aspiration pneumonia accounting for 40.3% (263 cases) of all deaths. The second most common cause was ICD-10 code I, representing heart failure and other diseases of the circulatory system, which accounted for 17.6% (115 cases) of deaths. Neoplasms, categorized under ICD-10 code C, were the third most common cause, comprising 12.6% (82 cases) of total deaths. AD accounted for 5.2% (34 cases) of total deaths, while other dementias combined accounted for 6.9% (45 cases).

Furthermore, 6.6% (43 cases) were classified as others (code R), including 5.4% (35 cases) attributed to senility (Table 3).

Table 3 Causes of Death Based on Death Certificates (by ICD Code)

Changes in Direct Cause of Death Before and After Medical Record Confirmation for Patients Admitted with AD

We examined whether patients admitted with AD were accurately reported as having died from AD. Among 148 cases of patients hospitalized with AD, only 34 death certificates listed AD as the direct cause of death. However, after reviewing the medical records and identifying cases that met the definition of death due to dementia, it was determined that AD should have been listed as the direct cause of death in 116 of the 148 cases.

A review of medical records where AD was already listed as the direct cause of death on the death certificate confirmed that all these cases met the criteria for dementia-related death, supporting the accuracy of AD as the direct cause of death. For other cases, the direct cause of death was revised as follows: in 43 out of 47 cases of pneumonia and all nine cases of aspiration pneumonia, the direct cause of death was corrected to AD; all 11 cases classified as senility were corrected to AD; 6 out of 9 cases of heart failure were corrected to AD; all 3 cases of renal failure and 3 of urinary tract infections were corrected to AD; one case of infectious and parasitic diseases and one case of diseases of the skin and subcutaneous tissue were corrected to AD; 2 cases classified under external causes of morbidity and mortality were corrected to AD; one case initially labeled as dementia was corrected to AD, as the diagnosis in the medical record specified AD (Table 4).

Table 4 Changes in Direct Cause of Death Before and After Medical Record Confirmation for Patients Admitted with AD

Changes in Cause of Death Before and After Medical Record Confirmation for Patients Admitted with Dementias Other Than AD

The study included 124 patients admitted with dementias other than AD (other dementias). Among these, the primary cause of death listed on the death certificate was dementia in only 10 cases, accounting for less than one-tenth of the total. After reviewing the medical records and identifying cases that met the definition of death due to dementia, it was determined that dementia should have been listed as the direct cause of death in an additional 64 of the 124 cases.

A review of medical records where dementia was already listed as the direct cause of death on the death certificate confirmed that all these cases met the criteria for dementia-related death, supporting the accuracy of dementia as the direct cause of death. For other cases, the direct cause of death was revised as follows: in 31 out of 46 cases of pneumonia and all 11 cases of aspiration pneumonia, the direct cause of death was corrected to dementia; all 9 cases initially classified as senility were corrected to dementia; 8 of 15 cases of heart failure were corrected to dementia; one case categorized under ICD-10 code R (multi-organ failure) was corrected to dementia; a case of urinary tract infections was corrected to dementia; 2 cases of infectious and parasitic diseases were corrected to dementia; one case classified under external causes of morbidity and mortality was corrected to dementia; 5 cases diagnosed with other dementias at the time of admission were reclassified as AD, and their cause of death was corrected to AD (Table 5).

Table 5 Changes in Cause of Death Before and After Medical Record Confirmation for Patients Admitted with Dementias Other Than AD

Causes of Death in Cases of Comorbid AD and Hospitalization for Other Mental Disorders

The same investigations were conducted for cases where the primary reason for hospitalization was a mental disorder other than AD or other dementias but where AD was present as a complication. Among these, 11 patients were admitted with schizophrenia and 2 with bipolar disorder, both complicated by AD. For the 11 patients with schizophrenia, the direct causes of death listed on death certificates were as follows: pneumonia (five cases), aspiration pneumonia (two cases), senility (two cases), and heart failure (two cases). After a medical record review, all 11 cases were corrected to AD as the direct cause of death. For the two patients with bipolar disorder, the direct causes of death listed on death certificates were pneumonia and aspiration pneumonia. Both cases were also corrected to AD as the direct cause of death.

Appropriate AD Death Rate in Psychiatric Hospital Inpatients

The results showed that AD was the direct cause of death in 116 patients hospitalized with AD, 5 patients hospitalized with other dementias, and 13 patients hospitalized with other mental disorders. The proportion of AD-related deaths reported on death certificates and the corrected number of AD-related deaths after medical record confirmation were compared overall and by sex. In total, 134 of the 653 cases (20.5%) were determined to have AD as the direct cause of death, a significant increase from the 34 cases initially identified from death certificates alone (P<0.01). Similarly, by sex: among male patients, 20 of 393 cases (5.1%) were recorded as AD-related deaths before medical record confirmation, while 78 cases (19.8%) were identified after confirmation (P<0.01). Among female patients, 14 of 260 cases (5.4%) were recorded as AD-related deaths before medical record confirmation, while 56 cases (21.5%) were identified after confirmation, also showing a significant difference (P<0.01). The mortality rate due to AD after medical record review was significantly higher in men than in women (P=0.035) (Table 6).

Table 6 Difference in the Number of Patients Considered to Have AD as the Cause of Death

Appropriate Dementia-Related Death Rates in Psychiatric Hospital Inpatients

After reviewing the medical records of 653 patients, 203 (134 with AD and 69 with other dementias) were identified as having dementia as the direct cause of death, representing 31.1% of all deaths. This rate was significantly higher than the rate identified before the medical record review (P<0.01).

When examining dementia-related deaths by sex: among males, 122 out of 393 patients (31%) were determined to have dementia as the direct cause of death, a significant increase compared to the rate before the medical record review (P<0.01). Among females, 81 out of 260 (31.1%) patients were determined to have dementia as the direct cause of death, also showing a significant increase (P<0.01) (Table 7). The mortality rate due to all dementias after the medical record review showed no significant difference between males and females (P=0.975).

Table 7 Difference in the Number of Patients Considered to Have Dementia (Including AD) as the Cause of Death

Discussion

A survey of the causes of death based on death certificates, categorized by ICD code, revealed that respiratory diseases accounted for approximately 40% of all deaths, followed by cardiovascular diseases at 17.6%, with half of these cases listed as heart failure.

The underlying cause of death, which forms the foundation for mortality statistics, is determined according to WHO guidelines. Under these guidelines, the illness or injury listed at the bottom of column I on the death certificate is considered the direct cause of death. However, the WHO specifies that terminal conditions, such as heart failure or respiratory failure, are not appropriate as direct causes of death.⁸

Additionally, 6.6% of deaths were categorized under the ICD-10 R code, which were found to be inappropriate as direct causes of death, with senility alone accounting for 5.4% of these cases. This indicates that inappropriate causes, such as heart failure and senility, were frequently listed as the direct cause of death. These findings highlight that death certificates in Japanese psychiatric hospitals are often not completed in accordance with proper standards.

Patients admitted with AD or other dementias accounted for 42% of the total, but only approximately 7% of the total deaths. Among patients admitted with AD, only 25% had AD listed as the cause of death on their death certificate. Respiratory diseases were the most common cause of death, accounting for approximately 40%, with most cases involving pneumonia, including aspiration pneumonia. This finding aligns with those of previous studies.^18–21 However, in 91% of the cases where pneumonia and aspiration pneumonia were listed as the cause of death, it was believed that the progression of AD led to impaired swallowing and other functional declines, ultimately resulting in pneumonia.

Clinically, determining whether complications or the underlying disease is the true cause of death is often challenging. This determination also depends on the country’s rules for selecting the underlying cause of death. For example, in Canada and the United Kingdom^22,23 the rule is that if a patient with dementia dies of aspiration pneumonia, dementia is considered the cause of death. While similar rules have been adopted in Japan, they are not widely recognized in clinical practice.

This discrepancy is also evident in the US, where dementia is reported on death certificates for only a quarter of dementia-related deaths despite being a leading cause of death. A US cohort study reported a significant increase in mortality associated with the incidence and progression of AD, suggesting that AD contributes to more deaths than are officially recorded.^24,25

In contrast, countries such as France and Italy report higher rates of dementia as the underlying cause of death. In Italy, dementia is listed in approximately 12–19% of cases, while in France, it is listed in approximately 26–33% of cases. These differences highlight how the tendency to underreport dementia as a cause of death may vary by country.²⁶

In this study, approximately 7% of patients hospitalized for AD had “senility” listed as the cause of death. Unlike in other countries, senility is a leading cause of death as per Japan’s mortality statistics. Originally, senility was defined as “symptoms, signs, and abnormal clinical or detection findings that are not classified elsewhere”, making it a condition with an unclear diagnosis. In Japan, it is generally considered acceptable to record “senility” as the cause of death on death certificates, particularly in settings such as nursing homes and home-based palliative care.²⁷

In contrast, in Europe and the United States, listing only terms such as “senility” or “natural causes” is typically regarded as insufficient for determining the underlying cause of death. This practice may also complicate postmortem investigations or insurance procedures; hence, physicians are strongly encouraged to specify a definitive medical diagnosis.²⁸

In Japan, the rate of deaths attributed to senility has quadrupled, rising from 2.6% in 2000 to 10.3% in 2020. In contrast, the rate is only 0.8% in France and 0.2% in the US, highlighting a significant international discrepancy.²⁹ In many cases, listing senility as the primary cause of death is inappropriate, particularly when dementia is the underlying condition that leads to a gradual decline and eventual death. Nevertheless, in this study, there were cases where only senility was recorded as the primary cause of death.

Hayashi et al reported that 90% of death certificates listing senility as the cause of death did not mention any other causes, and this percentage has been increasing over time.²⁹ This raises an important question: was senility truly the sole cause of death, or were there underlying diseases that went unlisted? Based on our investigation, it is likely the latter, indicating a need for a better understanding of dementia, clearer definitions of senility, and greater public awareness about the proper completion of death certificates.

Additionally, the results of the medical record survey revealed six cases where heart failure was described as a terminal condition without detailed examination. The underlying cause of death, which serves as the basis for mortality statistics, is determined by the guidelines set by the WHO. According to these rules, if the condition listed in the bottom line of column I is likely to have caused all the other conditions listed above, it is considered the underlying cause of death. However, if an inappropriate condition is listed in column II as the cause of death, it may be inaccurately classified as such. Furthermore, the WHO guidelines advise against listing terminal conditions, such as cardiac failure or respiratory failure, as the cause of death.

In this study, 124 patients with non-AD dementia were found to have psychiatric disorders that led to their hospitalization. Among the patients whose death certificates listed pneumonia and aspiration pneumonia as the cause of death, 74% may have developed pneumonia and aspiration pneumonia due to the deterioration of swallowing and other functions caused by the progression of dementia. Additionally, as seen in AD cases, there were nine instances where only senility was listed as the cause of death on the death certificate. Many cases also featured a diagnosis of dementia without further classification. In such instances, AD was often considered the underlying cause of death. These findings suggest that a significant number of cases may have had AD as the actual cause of death.

The results of the medical record survey indicated that in cases where AD was diagnosed alongside other psychiatric disorders, the cause of death was frequently misattributed, with some instances where it should have been recognized as resulting from AD. Notably, a significant number of patients with schizophrenia were identified with complications related to AD.

The risk of developing dementia among patients with ataxia is reported to be approximately twice as high as that in the general population.³⁰ Specifically, it is hypothesized that patients with schizophrenia who develop AD may experience heightened susceptibility to schizophrenia-like symptoms due to the progressive decline in cognitive function.³¹

In diagnosing dementia, cognitive dysfunction observed in patients with schizophrenia during the early stages of their illness can complicate the timely diagnosis of dementia. This delay can hinder accurate estimation of the co-occurrence rates of schizophrenia and AD.³² Comprehensive patient interviews and detailed examination findings are essential for differentiating schizophrenia from dementia. However, distinguishing schizophrenia from dementia based solely on clinical symptoms remains challenging.^33,34 This diagnostic difficulty may lead to underdiagnosis or misdiagnosis of both conditions, as the perceived benefit of differentiating between them might be minimal.

There was a significant increase in deaths attributed to AD across both sexes before and after the medical record survey. This rise can largely be attributed to complications of AD, such as pneumonia, being documented as the immediate cause of death, while AD, as the underlying condition, was often omitted from the records.

Overall, in this study, the appropriate cause of death was identified by analyzing the diseases and medical conditions listed in patients’ medical records and comparing them to the information documented on death certificates. This analysis revealed a significant increase in the reported mortality rate of AD and overall dementia. The findings suggest that while physicians often diagnose AD and dementia, there is insufficient recognition of dementia as a direct cause of death, leading to incomplete or inaccurate death certificates. Given that Japan’s death statistics are based on these certificates, the actual number of dementia-related deaths in Japan is likely substantially higher than that officially reported.

Prior to the survey, 34 out of 653 deaths (5.2%) were attributed to AD, whereas post-survey, this number increased to 134 out of 653 (20.5%), representing nearly a fourfold rise. These findings imply that while the official number of deaths due to AD in Japan is approximately 25,000, the actual figure could be closer to 100,000. Similarly, deaths attributed to total dementia increased from 45 out of 653 (6.9%) before the survey to 203 out of 653 (31.1%) after the survey, approximately 4.5 times higher. These results suggest that the actual number of dementia-related deaths in Japan might be approximately 220,000, surpassing the approximately 190,000 deaths reported due to senility and potentially making dementia the third leading cause of death in the country.

These findings indicate that the number of deaths due to dementia, including AD, is significantly underreported on death certificates. As approximately 30% of the deaths in psychiatric hospitals analyzed in this study were attributed to dementia, it is imperative for medical personnel involved in psychiatric care to be well-informed about dementia, including AD. Furthermore, death certificates serve as foundational data for death statistics and are critical for national healthcare administration and policy decision-making. Therefore, even psychiatrists must possess adequate knowledge on how to accurately complete death certificates.

Additionally, in this study, heart failure was often not diagnosed following a thorough examination immediately prior to death, and some death certificates listed heart failure as a terminal condition for convenience. Villar et al reported that 56.8% of death certificates listed respiratory or cardiac arrest as the direct cause of death prior to educational interventions, whereas none listed these causes following such education.³⁵ This emphasizes the importance of proper training on accurate death certificate entries in Japan.

This study has some limitations. The result lacks broader applicability. It was conducted exclusively in the northern Kanto region of Japan, which may limit the applicability of its findings to other regions, as the practices for completing death certificates could vary geographically. Additionally, the study focused exclusively on psychiatric diseases, without including a death certificate survey in general hospitals or home care settings. Therefore, generalizing these findings to estimate the national mortality rate of dementia, including AD, across Japan may not be appropriate. Furthermore, It has been suggested that individuals with mental disorders receive less frequent medical evaluations.³⁶ Since the patients in this study were also hospitalized in psychiatric facilities, it is possible that serious conditions such as cancer and myocardial infarction were insufficiently investigated. Consequently, the potential for an elevated mortality rate for dementia, including Alzheimer’s disease, in the medical record survey cannot be ruled out.

Although not relevant to the present study, we found that patients hospitalized with schizophrenia spectrum disorders, mood disorder spectrum disorders, and other mental disorders had shorter life expectancies than did those with AD or other dementias. Patients with schizophrenia have reduced life expectancies. Kiviniemi et al reported that patients with schizophrenia have a 4.45-fold higher risk of death than that in the general population,³⁷ and Owens et al noted that these patients have a life expectancy approximately 20% shorter than that of the general population.³⁸ In the present study, the age at death for patients with schizophrenia was approximately 10 years younger than for those with dementia.

In recent years, individuals with various mental disorders reportedly have significantly shorter life expectancies than do those without mental illness. Patients with organic mental illnesses, including dementia, experience reduced life expectancy, but the extent of reduction is reported to be smaller than that for other psychiatric disorders. Consequently, the age at death for patients with AD and other dementias is higher than for those with other psychiatric disorders.³⁹ The results of our study align with these previous findings.

Conclusion

We investigated whether dementia was accurately recorded as the main diagnosis or direct cause of death on death certificates, focusing on psychiatric hospitals with a high number of inpatients with dementia. Dementia including AD was not accurately recorded on death certificates and the actual mortality rate for dementia including AD was estimated to be higher than currently reported. These findings underscore the critical need to increase awareness about dementia as a cause of death and to educate the public and healthcare professionals on accurately documenting it on death certificates.To further validate the findings of this study, it is necessary to expand the scope of the research to include general hospitals and nursing care facilities in future investigations and to examine the actual conditions more comprehensively.

Acknowledgments

This work was supported by Ministry of Education, Culture, Sports, Science and Technology Japan Society for the Promotion of Science Grant Number JP20K23203. We would like to thank Editage for English language editing and all the participants for their cooperation.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.

References

1. Nichols E, Steinmetz JD, Vollset SE. GBD. 2019 dementia forecasting collaborators. estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the global burden of disease study 2019. Lancet Public Health. 2022;7(2):e105–e125. doi:10.1016/S2468-2667(21)00249-8

2. Prince M, Wimo A, Guerchet M, et al. World Alzheimer Report 2015: The Global Impact of Dementia. London, UK: Alzheimer’s Disease International; 2015.

3. Crowell V, Reyes A, Zhou SQ, et al. Disease severity and mortality in Alzheimer’s disease: an analysis using the U.S. National Alzheimer’s coordinating center uniform data set. BMC Neurol. 2023;23(1):302. doi:10.1186/s12883-023-03353-w

4. Todd S, Barr S, Passmore AP. Cause of death in Alzheimer’s disease: a cohort study. QJM. 2013;106(8):747–753. doi:10.1093/qjmed/hct103

5. Mölsä PK, Marttila RJ, Rinne UK. Survival and cause of death in Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand. 1986;74(2):103–107. doi:10.1111/j.1600-0404.1986.tb04634.x

6. Parker D, Lewis J, Gourlay K. Palliative care and dementia. Dement Aust. 2017. Available from https://palliativecare.org.au/wp-content/uploads/dlm_uploads/2018/05/Dementia-Aus-Palliative-Care-Discussion-Paper-36pp-R5.pdf. Accessed February 2023.

7. The National Hospice Organization Standards and Accreditation Committee Medical Guidelines Task Force. Medical guidelines for determining prognosis in selected non-cancer diseases. Hosp J. 1996;11(2):47–63. doi:10.1080/0742-969X.1996.11882820

8. World Health Organization (WHO). Global health estimates: leading causes of death. Available from: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death. Accessed December 2023.

9. Statistics of Japan. Available from: https://www.e-stat.go.jp/en/stat-search/files?page=1&layout=datalist&toukei=00450011&tstat=000001028897&cycle=7&year=20220&month=0&tclass1=000001053058&tclass2=000001053061&tclass3=000001053065. Accessed December, 2023.

10. Hayashi R, Imanaga T, Marui E, et al. Senility deaths in aged societies: the case of Japan. Glob Health Med. 2024;6(1):40–48. doi:10.35772/ghm.2023.01127

11. Imanaga T, Toyama T. Survey on the diagnosis of senility as the cause of death in home medical care. Jpn Prim Care Assoc. 2018;41(4):169–175.

12. Taylor C, Greenlund S, McGuire L, et al. Deaths from Alzheimer’s disease—United States, 1999-2014. MMWR Morb Mortal Wkly Rep. 2017;66(20):521–526. doi:10.15585/mmwr.mm6620a1

13. Stokes AC, Weiss J, Lundberg DJ, et al. Estimates of the association of dementia with US mortality levels using linked survey and mortality records. JAMA Neurol. 2020;77(12):1543–1550. doi:10.1001/jamaneurol.2020.2831

14. Ministry of health, labour and welfare. Available from: https://www.mhlw.go.jp/toukei/saikin/hw/kanja/20/index.html. Accessed December 2023.

15. Ministry of Health, Labour and Welfare. Handbook of Health and Welfare Statistics 2023. Available from: https://www.mhlw.go.jp/english/database/db-hh/2-2.html. Accessed December, 2023.

16. Okayama T, Usuda K, Okazaki E, et al. Number of long-term inpatients in Japanese psychiatric care beds: trend analysis from the patient survey and the 630 survey. BMC Psychiatry. 2020;20(1):522. doi:10.1186/s12888-020-02927-z

17. Toba K. Japan’s new framework on dementia care. Innov Aging. 2021;5(Suppl 1):383. doi:10.1093/geroni/igab046.1487

18. Brunnstrom HR, Englund EM. Cause of death in patients with dementia disorders. Eur J Neurol. 2009;16(4):488–492. doi:10.1111/j.1468-1331.2008.02503.x

19. Burns A, Jacoby R, Luthert P, et al. Cause of death in Alzheimer’s disease. Age Ageing. 1990;19(5):341–344. doi:10.1093/ageing/19.5.341

20. Ives DG, Samuel P, Psaty BM, et al. Agreement between nosologist and cardiovascular health study review of deaths: implications of coding differences. J Am Geriatr Soc. 2009;57(1):133–139. doi:10.1111/j.1532-5415.2008.02056.x

21. Romero JP, Benito-Leon J, Louis ED, et al. Underreporting of dementia deaths on death certificates: a systematic review of population-based cohort studies. J Alzheimers Dis. 2014;41(1):213–226. doi:10.3233/JAD-132765

22. UK Government. Guidance for doctors completing medical certificates of cause of death in England and Wales (accessible version). Available from: https://www.gov.uk/government/publications/guidance-notes-for-completing-a-medical-certificate-of-cause-of-death/guidance-for-doctors-completing-medical-certificates-of-cause-of-death-in-england-and-wales-accessible-version. Accessed December, 2023.

23. Statistics Canada. Canadian Vital Statistics Death Database: Data Dictionary and User Guide 2013; 2017.

24. Ganguli M, Rodriguez EG. Reporting of dementia on death certificates: a community study. J Am Geriatr Soc. 1999;47(7):842–849. doi:10.1111/j.1532-5415.1999.tb03842.x

25. James BD, Leurgans SE, Hebert LE, et al. Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014;82(12):1045–1050. doi:10.1212/WNL.0000000000000240

26. Désesquelles A, Demuru E, Salvatore MA, et al. Mortality from Alzheimer’s disease, Parkinson’s disease, and dementias in France and Italy: a comparison using the multiple cause-of-death approach. J Aging Health. 2014;26(2):283–315. doi:10.1177/0898264313514443

27. Ministry of Health. Labour and welfare. manual to fill in a death certificate: Available from: https://www.mhlw.go.jp/toukei/manual/dl/manual_r03.pdf. Accessed December, 2024.

28. Centers for Disease Control and Prevention. Physicians’ handbook on medical certification of death. Available from: https://www.cdc.gov/nchs/data/misc/hb_cod.pdf. Accessed December, 2024.

29. Hayashi R, Beppu M, Ishii F, et al. Statistical analysis of senility death in Japan. J Popul Probl. 2023;78(1):1–18.

30. Lin CE, Chung CH, Chen LF, et al. Increased risk of dementia in patients with schizophrenia: a population-based cohort study in Taiwan. Eur Psychiatry. 2018;53:7–16. doi:10.1016/j.eurpsy.2018.05.005

31. Harrison PJ. The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain. 1999;122(4):593–624.

32. Radhakrishnan R, Butler R, Head L. Dementia in schizophrenia. Adv Psychiatr Treat. 2012;18(2):144–153. doi:10.1192/apt.bp.110.008268

33. Tsuang MT, Stone WS, Faraone SV. Toward reformulating the diagnosis of schizophrenia. Am J Psychiatry. 2001;158(5):670–676.

34. McKeith IG, Cummings J. Behavioural changes in dementia with Lewy bodies. Lancet Neurol. 2005;4(1):19–27.

35. Villar J, Pérez-Méndez L. Evaluating an educational intervention to improve the accuracy of death certification among trainees from various specialties. BMC Health Serv Res. 2007;7(1):183. doi:10.1186/1472-6963-7-183

36. Goldman ML, Mangurian C, Corbeil T, et al. Medical comorbid diagnoses among adult psychiatric inpatients. Gen Hosp Psychiatry. 2020;66:16–23.

37. Kiviniemi M, Suvisaari J, Pirkola S, et al. Regional differences in five-year mortality after a first episode of schizophrenia in Finland. Psychiatr Serv. 2010;61(3):272–279. doi:10.1176/ps.2010.61.3.272

38. Owens DG, Cunningham EC, Johnstone EC. Treatment and management of schizophrenia. In: Gelder M, editor. New Oxford Textbook of Psychiatry. 2nd ed ed. Oxford, UK: Oxford University Press; 2012.

39. Peritogiannis V, Ninou A, Samakouri M. Mortality in schizophrenia-spectrum disorders: recent advances in understanding and management. Healthcare. 2022;10(2366):2366. doi:10.3390/healthcare10122366

Blog

Introduction

Materials and Methods

Dataset Collection

Identification of Differentially Expressed Genes (DEGs) Related to EA in RA

Identification of Diagnostic Biomarkers for RA Patients

Establishment and Evaluation of Nomogram

Animals

Model Establishment

Evaluation of Pain-Response Behavior

EA Treatment

Real-Time Fluorescence Quantitative PCR

Statistical Analysis

Results

Screening of DEGs Related to EA in RA

Determination of the Diagnostic Biomarkers

Diagnostic Efficacy of Diagnostic Biomarkers

Identification and Verification of Diagnostic Biomarkers

EA Demonstrated Analgesic Effects in CFA-Induced Mechanical Allodynia

Discussion

Conclusion

Abbreviations

Data Sharing Statement

Funding

Disclosure

References

Space burial mission ends in loss after promising start

Families mourn while celestis promises support

Interstellar Comet 3I/ATLAS Speeds Toward Sun at 68 km/s, Offers Rare Study Opportunity

‘Plug support gaps’

Introduction

Methods

Participants

Survey Items

Analysis

Results

Mental Disorders Causing Hospitalization and Associated Age of Death

Causes of Death Based on Death Certificates (by ICD Code)

Changes in Direct Cause of Death Before and After Medical Record Confirmation for Patients Admitted with AD

Changes in Cause of Death Before and After Medical Record Confirmation for Patients Admitted with Dementias Other Than AD

Causes of Death in Cases of Comorbid AD and Hospitalization for Other Mental Disorders

Appropriate AD Death Rate in Psychiatric Hospital Inpatients

Appropriate Dementia-Related Death Rates in Psychiatric Hospital Inpatients

Discussion

Conclusion

Acknowledgments

Author Contributions

Disclosure

References