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Accumulating interest has emerged in exploring the toxicity profiles of the combination strategy of radiotherapy (RT) and immune checkpoint inhibitors (ICIs). Much remains unknown regarding safety and the potential increased risk of toxicity of a combined treatment. ICI prolongs survival but can induce immune-related adverse events as well. To increase awareness of adverse effect and support immediate and successful management, we go over the literature on the safety of RT combined immunotherapy strategy. Representative evidence relevant to RT combined with ICI in the brain, lung, head and neck, and pelvic malignance was reviewed respectively. Given radiation doses and fractionation, the irradiated volume, the timing of RT, and ICI would significantly affect the safety and efficiency of ICI+RT combination therapy, and no consensus had been reached about how to arrange RT delivery in the combined contexture, we went over the available literature and tried to address these challenges including the timing of RT, optimal dose and fractionations, RT target and target volume, and potential biomarkers to predict toxicity. We found even though RT+ICI combination therapy might augment toxicities, the majority of patients experienced grade 4 or 5 AE are relatively rare and no significant difference could be found between combination group and monotherapy group. Sometimes the acute toxicity with ICI is much less predictable and often life threatening and in some can give rise to permanent effects. Clinicians across disciplines should be aware of these uncommon lethal complications induced by ICI+RT. Early recognition is the key to successful treatment, reversibility of organ dysfunction, and in some cases even prevention of fatal outcome. If recognized early, managed properly, and no fatal AE occurs, the development of irAE indicates a good prognosis. It should be noted that nothing is known about potential late effects because very few studies have 5-year follow-up. The nature of irAE is the attack of activated immune cells on normal tissues. The nature of RT-induced AE is the DNA damage on normal tissue, which is related with the dose delivered and volume irradiated and the tolerance of surrounding normal tissues. The immune-modulating effect of SBRT may augment the damage on normal tissues. To maximize the antitumor immune response, 8-12 Gy/fraction is preferred when conducting RT. The available clinical evidence suggest RT of this dose/fractionated strategy combined with ICI have a tolerable AE profile, which need further validation by more clinical trials in the future. The combination strategy of RT with anti-PD1/PDL1 anti-body is supposed to be concurrent or RT followed by anti-PD1/PDL1 antibody. Although RT and ipilimumab combination sequence is controversial, ipilimumab prior to or concurrent with RT might be proper, which need more clinical validation. Under the concept of immunological dose painting, SBRT work as a trigger of immune response. It has been observed that SBRT of partially radiated tumors combined with ICI could induce similar tumor control compared with total tumor irradiation. The side effects of RT may be mitigated potentially due to the reduction of irradiated volume. The antitumor efficiency and safety profile of immunological RT dose painting+ICI deserve further investigation. Clinical predictive factors for irAE risk remain unclear, and more investigation deserves to be conducted about the irAE prediction.

BACKGROUND: Sleep staging is an important part of sleep research. Traditional automatic sleep staging based on machine learning requires extensive feature extraction and selection. OBJECTIVE: This paper proposed a deep learning algorithm without feature extraction based on one-dimensional convolutional neural network and long short-term memory. METHODS: The algorithm can automatically divide sleep into 5 phases including awake period, non-rapid eye movement sleep period (N1 [Formula: see text] N3) and rapid eye movement using the electroencephalogram signals. The raw signal was processed by the wavelet transform. Then, the processed signal was directly input into the deep learning algorithm to obtain the staging result. RESULTS: The accuracy of staging is 93.47% using the Fpz-Cz electroencephalogram signal. When using the Fpz-Cz and electroencephalogram signal, the algorithm can obtain the highest accuracy of 94.15%. CONCLUSION: These results show that this algorithm is suitable for different physiological signals and can realize end-to-end automatic sleep staging without any manual feature extraction.

Intracavitary and/or interstitial brachytherapy is an integral component of the management of patients with central pelvic-recurrent cervical cancer after primary hysterectomy, and is typically delivered using conventional applicators. We investigated the efficacy and safety of three-dimensional (3D)-printed, customizable applicators for those patients.Twenty-six patients were treated with combination external beam radiotherapy and brachytherapy. Patients with lesions ≤1 and1 cm before brachytherapy were treated with intracavitary and interstitial brachytherapy, respectively. Dosimetric plans were compared between the vaginal cylinder and 3D-printed applicator for the first 9 patients. Outcomes and treatment-related complications were also investigated.The median tumor size before brachytherapy was 0.81 cm. Intracavitary, interstitial, and combined interstitial-intracavitary brachytherapy were performed in 22 (85%), 3 (11%), and 1 (4%) of the patients, respectively. The clinical target volume (CTV) coverage goal was achieved with all 3D-printed plans but failed with three single-channel cylinder plans (33.3%). Owing to 3D-printed transvaginal applicator guidance, there was no need to adjust the needle position after implantation. The mean CTV dose for all patients was 71 ± 8.2 Gy; all met the dose constraints to the organs at risk, but 1 (4%) had a rectal DHigh-quality intracavitary and/or interstitial brachytherapy can be achieved using a 3D-printed applicator and yields favorable outcomes with acceptable toxicity.

Qian Xu,1– 3 Xiaorong Hou,1,2 Tingchao Xiao,3 Wenlong Zhao1,2 1College of Medical Informatics, Chongqing Medical University, Chongqing, People’s Republic of China; 2Medical Data Science Academy, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Medical Informatics Library, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wenlong Zhao, College of Medical Informatics Chongqing Medical University, Chongqing, People’s Republic of China, Tel +86 23 6571 4682, Email cqzhaowl@163.comBackground: With the dramatic growth in smartphones, mobile health applications (apps) in the field of healthcare or medicine, which are characterized by strong operability, flexibility and interactivity, provide a supplementary approach to medical learning. The aims of this study were to awaken medical students to pay more attention to the learning function of mobile health app and gain deeper insight into our understanding of the factors influencing medical students’ mobile health apps continuance intention for enhancing practical utilization.Methods: A cross-sectional survey was conducted with a self-designed questionnaire administered to medical students at Chongqing Medical University. Data were collected from 450 participants from March to April 2019. SPSS V.25 was used for the descriptive statistical analysis of the results. Smart PLS 3.2.7 was used to construct a structural equation modelling framework to estimate the influencing factors of medical students’ continuance intention to use mobile health apps.Results: The external characteristics of mobile health apps had a positive influence on perceived ease of use (β = 0.378, P < 0.001). Perceived ease of use had a positive impact on perceived usefulness (β = 0.573, P < 0.001). Perceived ease of use (β = 0.195, P = 0.011), perceived usefulness (β = 0.450, P < 0.001) and subjective norms (β = 0.255, P < 0.001) had a positive impact on attitude towards using mobile health apps. Additionally, perceived usefulness (β = 0.202, P < 0.001) and attitude (β = 0.730, P < 0.001) had a remarkable influence on continuance intention. Furthermore, the mediating effect of attitude between perceived usefulness and continuance intention was significant (β = 0.329, P < 0.001).Conclusion: Both perceived usefulness and attitude have a significant effect on medical students’ mobile health apps continuance intention. So, we suggest apps providers and developers evoking and maintaining users’ interest in mobile health apps and perfecting apps’ features from various aspect. Also, more attention should be paid on social relationship to introduce medical students to familiarize mobile health apps and strengthen adhesiveness of medical students.Keywords: mobile apps, medical students, structural equation modelling, continuance intention

Objective The study aimed to evaluate site‐specific recurrent patterns via competing risks analysis and hazard function to provide evidence for adjuvant treatment and follow‐up for early staged endometrial cancer (EC). Methods A total of 858 patients with International Federation of Gynecology and Obstetrics stage I–II EC who received adjuvant radiotherapy at our institution (2000–2017) were included. The radiotherapy modality comprised external beam radiotherapy (EBRT) with or without vaginal brachytherapy (VBT) or VBT alone. Competing risks analysis and hazard rate function were employed to evaluate the recurrence rate according to the ESMO–ESGO–ESTRO risk classification. Results The 5‐year overall survival rates of the low‐risk (LR), intermediate‐risk (IR), high–intermediate risk (HIR), and high‐risk (HR) groups were 96.1%, 95%, 93%, and 89.7%, respectively (p = 0.018). Sixty‐eight patients developed recurrence. The 5‐year incidence of distant recurrence was the highest in the HR group (14.87%), followed by the HIR (7.71%), IR (5.27%), and LR (1.26%) groups (Gray's test, p, The recurrence pattern of endometrial cancer is affected by risk groups and adjuvant treatment. The time‐varying competing risk analysis and hazard function modeling were established. The site‐specific recurrence patterns differed across the risk classification and adjuvant radiotherapy modality. More intense and targeted follow‐up schedules should be administrated to the high‐risk group.

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.

Zhikai Liu,1 Fangjie Liu,2,&ast; Wanqi Chen,1,&ast; Yinjie Tao,1 Xia Liu,1 Fuquan Zhang,1 Jing Shen,1 Hui Guan,1 Hongnan Zhen,1 Shaobin Wang,3 Qi Chen,3 Yu Chen,3 Xiaorong Hou1 1Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 3MedMind Technology Co., Ltd., Beijing, 100055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaorong Hou Tel +86 138 1196 3013Email hxr_pumch@163.comObjective: Delineation of clinical target volume (CTV) and organs at risk (OARs) is important for radiotherapy but is time-consuming. We trained and evaluated a U-ResNet model to provide fast and consistent auto-segmentation.Methods: We collected 160 patients’ CT scans with breast cancer who underwent breast-conserving surgery (BCS) and were treated with radiotherapy. CTV and OARs were delineated manually and were used for model training. The dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) were used to assess the performance of our model. CTV and OARs were randomly selected as ground truth (GT) masks, and artificial intelligence (AI) masks were generated by the proposed model. Two clinicians randomly compared CTV score differences of the contour. The consistency between two clinicians was tested. Time cost for auto-delineation was evaluated.Results: The mean DSC values of the proposed method were 0.94, 0.95, 0.94, 0.96, 0.96 and 0.93 for breast CTV, contralateral breast, heart, right lung, left lung and spinal cord, respectively. The mean 95HD values were 4.31mm, 3.59mm, 4.86mm, 3.18mm, 2.79mm and 4.37mm for the above structures, respectively. The average CTV scores for AI and GT were 2.89 versus 2.92 when evaluated by oncologist A (P=0.612), and 2.75 versus 2.83 by oncologist B (P=0.213), with no statistically significant differences. The consistency between two clinicians was poor (kappa=0.282). The time for auto-segmentation of CTV and OARs was 10.03 s.Conclusion: Our proposed model (U-ResNet) can improve the efficiency and accuracy of delineation compared with U-Net, performing equally well with the segmentation generated by oncologists.Keywords: clinical target volume, organ at risk, auto-segmentation, breast cancer radiotherapy, clinical evaluation

Background The application of information technology in the medical industry is growing. The traditional face-to-face doctor–patient interaction has turned into an online doctor–patient interaction, particularly in the case of an epidemic outbreak. Online doctor–patient communication has become increasingly common. Text communication can no longer meet people’s new communication needs. The appearance of emoji compensates for the challenges in online doctor–patient interactions to convey nontext information, such as facial emoji, gestures and voice tones. Objective This study aimed to explore the impact of using emoji during online doctor–patient communication on users’ perception of the medical community by considering the moderating effect of demographics. Methods An online questionnaire survey was conducted amongst 520 people from December 2021 to January 2022 by random sampling. The frequency, emoji use style and the users’ previous consultation experience score were used as the main independent variables in this study. The perceived effect of the user was adopted as the dependent variable. Wilcoxon signed-rank test and multiple regression analysis were used for data analysis. Result For the use frequency and style of emoji mentioned in this study, a significant difference exists between the preference of users who use emoji for a single time and those who use the same emoji continuously (P , with the former showing a better performance than the latter. A significant difference exists between users who use open-style emoji and users who use neutral-style emoji (P ). The emoji perception effect of open style was better than that of neutral style. Users’ preference for emoji use is not affected regardless of whether they are platform users a platform is used (P > 0.05). Men and individuals under 30 are easily influenced by the use of emoji and the characteristics of emoji use. People (users) with educational attainment not higher than high school education tend to have preferences for the frequency of emoji use. Conclusion The characteristics of emoji use affected the perceived effect of online communication with doctors. Single use of emoji and relatively open style of emoji had a positive impact on the degree of acceptance of doctors’ information. Men and people under the age of 30 showed more expressive preferences for facial features than women and people over the age of 30. Therefore, doctors should properly use emoji for patients with different characteristics to help strengthen the communication between doctors and patients. Moreover, the online medical community should design diversified emoji for patients with different characteristics to provide personalized services.

Objective To explore the effect of age at diagnosis as a continuous variable on survival and treatment choice of patients with early-stage endometrial carcinoma (EC). Materials and methods We retrospectively analyzed data from patients with early-stage EC from January 1999 to December 2015 in multiple institutions in China. All patients received primary hysterectomy/bilateral salpingo-oophorectomy and adjuvant radiotherapy for EC confirmed pathology of stage I and II disease (FIGO 2009 staging). All patients were divided into low-risk, intermediate-risk, high-intermediate-risk and high-risk groups according to ESMO-ESGO-ESTRO risk classification. Results The median follow-up time was 57months, and the 5-year cancer-specific survival (CSS) was 95.7%. Age as a continuous variable was an independent prognostic factor for CSS. With an increase in age, the hazard ratio (HR) for CSS increases gradually. Other independent prognostic factors included myometrial invasion (MI), grade, and chemotherapy. In the stratified analysis of age, the HRs of age on CSS in patients >70y were 5.516, 5.015, 4.469, 4.618, 5.334, and 5.821 after adjusting for cancer characteristics, local treatment, chemotherapy and treatment-related late toxicity. In patients 66-70-year-old, the HRs were 2.509, 2.074, 2.101, 2.091, 2.157 and 1.621 after adjusting for the above covariates. In patients ≤65y, there was no significant difference in the HR of age on CSS after adjustment. Conclusion Age as a continuous variable is an independent prognostic factor and 65 year-old may be the best cut-off point for CSS in patients with early-stage EC in the Asian population. Quality of life should be given greater weight in the choice of therapeutic schedule for those patients >70 y.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS. The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants. A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS. This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.

Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

Purpose Radiation therapy (RT) affects tumor-infiltrating immune cells, cooperatively driving tumor growth inhibition. However, there is still no absolute consensus on whether the homing ability of dendritic cells (DCs) is affected by direct x-ray irradiation. Most importantly, the underlying mechanisms are poorly understood. Methods and Materials Using noninvasive imaging, we systematically examined the dose effect of RT on the in vivo homing and distribution of bone marrow–derived DCs and elucidated the detailed mechanisms underlying these events. After exposure to 2, 5, 10, 15, and 20 Gy, DCs were analyzed for maturation, in vivo homing ability, and T cell priming. Results At ranges of 2 to 20 Gy, irradiation did not cause direct cellular apoptosis or necrosis, but it induced mitochondrial damage in DCs independent of dose. In addition, upregulation of CD40, CD80, CD86, CXCR4, and CCR7 were detected on irradiated DCs. Secretion of IL-1β and IL-12p70 remained unchanged, whereas decreased secretion of IL-6 and promotion of tumor necrosis factor α secretion were observed. In particular, the homing ability of both the local residual and blood circulating DCs to lymphoid tissues was significantly higher in groups that received ≥5 Gy radiation than in the group that received 2 Gy. Furthermore, improved homing ability was associated with rearrangement of the cytoskeleton, which was regulated by reactive oxygen species accumulation through the RhoA/ROCK1 signaling pathway. Finally, more robust T cell activation was observed in mice inoculated with 20 Gy–treated DCs than in those inoculated with 2 Gy–irradiated DCs, and T cell activation also correlated with reactive oxygen species production. Conclusions An RT dose ≥5 Gy has distinct advantages over 2 Gy in facilitating DC homing to lymph nodes and cross-priming T cells.