1.Clinical characteristics and correlation between laboratory indicators and prognosis of children with severe Mycoplasma pneumoniae pneumonia
Yanyan CHAI ; Fang DENG ; Yuanyuan XU ; Yao SHENG ; Yaping LIANG ; Wenjia TONG ; Danqun JIN
Chinese Journal of Nosocomiology 2025;35(20):3124-3127
OBJECTIVE To analyze the clinical characteristics and the correlation between laboratory indicators and prognosis of severe Mycoplasma pneumoniae pneumonia(SMPP)in children.METHODS A total of 85 children with SMPP admitted to Anhui Provincial Children's Hospital from Nov.2021 to May 2024 were selected as the study subjects.Based on clinical typing at admission,they were divided into a high-risk group(n=59)and a low-risk group(n=26).The clinical manifestations,laboratory indicators and outcomes at 28 days of treatment were compared between the two groups.RESULTS The duration of fever and cough before admission in the high-risk group was(7.17±1.09)days and(6.79±1.25)days,respectively,which was longer than that in the low-risk group(P<0.05).There were no statistically significant differences in pulmonary auscultation(wheezing rales,moist rales)and extrapulmonary complications between the two groups.The levels of C-reactive protein(CRP),serum amyloid A(SAA),platelets(PLT),fibrinogen(FIB),D-dimer(DD)and N-terminal pro-brain natriuretic peptide(NT-proBNP)in the high-risk group were(11.62±1.45)mg/L,(226.88±36.83)mg/L,(3 18.57±39.82)×109/L,(4.28±0.74)g/L,(0.81±0.12)μg/ml and(2 295.48±413.75)pg/ml,respectively,all of which were higher than those in the low-risk group(P<0.05).Within 28 days after treatment of children in both groups,one patient in the high-risk group died.CONCLUSIONS Compared with children with SMPP in the low-risk group,those in the high-risk group have a higher risk of prognostic mor-tality,suggesting a correlation between the children's blood CRP,SAA,PLT,FIB,DD and NT-proBNP levels and the prognosis of children with SMPP.
2.Expert consensus on the diagnosis and treatment of cemental tear.
Ye LIANG ; Hongrui LIU ; Chengjia XIE ; Yang YU ; Jinlong SHAO ; Chunxu LV ; Wenyan KANG ; Fuhua YAN ; Yaping PAN ; Faming CHEN ; Yan XU ; Zuomin WANG ; Yao SUN ; Ang LI ; Lili CHEN ; Qingxian LUAN ; Chuanjiang ZHAO ; Zhengguo CAO ; Yi LIU ; Jiang SUN ; Zhongchen SONG ; Lei ZHAO ; Li LIN ; Peihui DING ; Weilian SUN ; Jun WANG ; Jiang LIN ; Guangxun ZHU ; Qi ZHANG ; Lijun LUO ; Jiayin DENG ; Yihuai PAN ; Jin ZHAO ; Aimei SONG ; Hongmei GUO ; Jin ZHANG ; Pingping CUI ; Song GE ; Rui ZHANG ; Xiuyun REN ; Shengbin HUANG ; Xi WEI ; Lihong QIU ; Jing DENG ; Keqing PAN ; Dandan MA ; Hongyu ZHAO ; Dong CHEN ; Liangjun ZHONG ; Gang DING ; Wu CHEN ; Quanchen XU ; Xiaoyu SUN ; Lingqian DU ; Ling LI ; Yijia WANG ; Xiaoyuan LI ; Qiang CHEN ; Hui WANG ; Zheng ZHANG ; Mengmeng LIU ; Chengfei ZHANG ; Xuedong ZHOU ; Shaohua GE
International Journal of Oral Science 2025;17(1):61-61
Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans
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Dental Cementum/injuries*
;
Consensus
;
Diagnosis, Differential
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Cone-Beam Computed Tomography
;
Tooth Fractures/therapy*
3.Inhibition of cap-dependent endonuclease in influenza virus with ADC189: a pre-clinical analysis and phase I trial.
Jing WEI ; Yaping DENG ; Xiaoyun ZHU ; Xin XIAO ; Yang YANG ; Chunlei TANG ; Jian CHEN
Frontiers of Medicine 2025;19(2):347-358
ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans
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Antiviral Agents/therapeutic use*
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Animals
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Male
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Adult
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Mice
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Female
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Endonucleases/antagonists & inhibitors*
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Influenza, Human/drug therapy*
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Young Adult
;
Dibenzothiepins/pharmacology*
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Oseltamivir/pharmacology*
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Middle Aged
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Triazines/pharmacology*
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Thiepins/pharmacology*
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Influenza B virus/drug effects*
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Influenza A Virus, H1N1 Subtype/drug effects*
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Pyridines/pharmacology*
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Morpholines
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Pyridones
4.Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury (version 2025)
Aijun XU ; Shuixia LI ; Bo CHEN ; Mengyuan YE ; Lejiao LANG ; Ning NING ; Lin ZHANG ; Changqing LIU ; Zhonglan CHEN ; Weihu MA ; Weishi LI ; Xiaoning WANG ; Dongmei BIAN ; Jiancheng ZENG ; Xin WANG ; Yuan GAO ; Yaping CHEN ; Jiali CHEN ; Yun HAN ; Xiuting LI ; Yang ZHOU ; Xiaojing SU ; Qiong ZHANG ; Tianwen HUANG ; Ping ZHANG ; Hua LIN ; Xingling XIAO ; Ruifeng XU ; Fanghui DONG ; Bing HAN ; Luo FAN ; Yanling PEI ; Suyun LI ; Xiaoju TAN ; Rongchen GUO ; Yefang ZOU ; Xiaoyun HAN ; Junqin DING ; Yi WANG ; Shuhua DENG ; Jinli GUO ; Yinhua LIANG ; Yuan CEN ; Xiaoqin LIU ; Junru CHEN ; Haiyang YU ; Lunlan LI ; Ying REN ; Yunxia LI ; Jianli LU ; Ying YING ; Lan WEI ; Yin WANG ; Qinhong XU ; Yanqin ZHANG ; Yang LYU ; Shijun ZHANG ; Sui WENJIE ; Sanlian HU ; Shuhong YANG ; Guoqing LI ; Jingjing AN ; Baorong HE ; Leling FENG
Chinese Journal of Trauma 2025;41(6):530-541
Paraplegia caused by spinal cord injury is a serious neurological complication, for which surgery is currently the main treatment method. Due to different surgical approaches, patients are usually expected to maintain a passive prone position for a long time or switch between the supine and prone positions. Affected by multiple factors such as neurogenic sensory disorders, pathological changes in muscle tone and operative duration, the risk of intraoperative acquired pressure injury (IAPI) is significantly increased. Current clinical prevention strategies for IAPI in these patients predominantly focus on localized pressure relief during positioning, lacking systematic, standardized comprehensive prevention protocols or evidence-based guidelines. To address it, Department of Nursing, Orthopedics Branch, China International Exchange and Promotive Association for Medical and Health Care, Spinal Trauma Professional Committee, Orthopedics Branch, Chinese Medical Doctor Association, Nursing Group of Spine and Spinal Cord Professional Committee of Chinese Association of Rehabilitation Medicine organized experts in relevant fields to formulate Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury ( version 2025), based on evidence-based medical evidence and latest research results and clinical practice at home and abroad. Eleven recommendations were put forward from the aspects of preoperative risk assessment, intraoperative prevention strategies, postoperative handover and monitoring, and supportive mechanisms for IAPI prevention, aiming to standardize the prevention measures and management strategies of IAPI in paraplegic patients with spinal cord injury and accelerate the recovery of patients and improve the therapeutic effect.
5.Clinical characteristics and correlation between laboratory indicators and prognosis of children with severe Mycoplasma pneumoniae pneumonia
Yanyan CHAI ; Fang DENG ; Yuanyuan XU ; Yao SHENG ; Yaping LIANG ; Wenjia TONG ; Danqun JIN
Chinese Journal of Nosocomiology 2025;35(20):3124-3127
OBJECTIVE To analyze the clinical characteristics and the correlation between laboratory indicators and prognosis of severe Mycoplasma pneumoniae pneumonia(SMPP)in children.METHODS A total of 85 children with SMPP admitted to Anhui Provincial Children's Hospital from Nov.2021 to May 2024 were selected as the study subjects.Based on clinical typing at admission,they were divided into a high-risk group(n=59)and a low-risk group(n=26).The clinical manifestations,laboratory indicators and outcomes at 28 days of treatment were compared between the two groups.RESULTS The duration of fever and cough before admission in the high-risk group was(7.17±1.09)days and(6.79±1.25)days,respectively,which was longer than that in the low-risk group(P<0.05).There were no statistically significant differences in pulmonary auscultation(wheezing rales,moist rales)and extrapulmonary complications between the two groups.The levels of C-reactive protein(CRP),serum amyloid A(SAA),platelets(PLT),fibrinogen(FIB),D-dimer(DD)and N-terminal pro-brain natriuretic peptide(NT-proBNP)in the high-risk group were(11.62±1.45)mg/L,(226.88±36.83)mg/L,(3 18.57±39.82)×109/L,(4.28±0.74)g/L,(0.81±0.12)μg/ml and(2 295.48±413.75)pg/ml,respectively,all of which were higher than those in the low-risk group(P<0.05).Within 28 days after treatment of children in both groups,one patient in the high-risk group died.CONCLUSIONS Compared with children with SMPP in the low-risk group,those in the high-risk group have a higher risk of prognostic mor-tality,suggesting a correlation between the children's blood CRP,SAA,PLT,FIB,DD and NT-proBNP levels and the prognosis of children with SMPP.
6.Establishment and verification of nomogram model for predicting implant-assisted bone grafting after posterior teeth alveolar ridge preservation
Jiaqi DENG ; Ze YANG ; Yi LIU ; Ruoyan CAO ; Yaping PAN
Chinese Journal of Stomatology 2025;60(5):464-473
Objective:Constructing a risk prediction model to assess the impact of various factors on the need for auxiliary bone grafting with implant placement following alveolar ridge preservation (ARP) in posterior teeth.Methods:According to the sample size calculation formula, the sample size was calculated using the pmsampsize package of R 4.1.3 software, based on inclusion and exclusion criteria, a total of 110 posterior teeth in 98 patients who underwent ARP at the Department of Periodontology, School and Hospital of Stomatology, China Medical University, from January 2018 to May 2024 were conducted. Teeth were randomly divided into modeling group and validation group with 7∶3 ratio according to the random number table. The modeling group was divided into direct implantation group and auxiliary bone grafting group on the basis of whether auxiliary bone grafting was performed 6 months after ARP. Univariate and multivariate analyses were conducted to identify factors influencing auxiliary bone grafting with implant placement following ARP. Nomogram was constructed using R software. Receiver operator characteristic (ROC) curve and calibration curve were drawn to evaluate model differentiation and consistency. The decision curve analysis (DCA) was used to assess the clinical application value of the model.Results:Age ( OR=1.06, P=0.001), maximum attachment loss (AL) ( OR=1.75, P<0.001), reason of tooth extraction ( OR=12.73, P<0.001), smoking [<10 cigarettes/d ( OR=7.59, P<0.001);≥10 cigarettes/d ( OR=28.12, P<0.001)] and stage of periodontitis [stage Ⅱ ( OR=2.57, P=0.430); stage Ⅲ ( OR=21.00, P=0.007); stage Ⅳ ( OR=76.50, P<0.001)] influenced the necessity for auxiliary bone grafting with implant placement after ARP. After multivariate analysis of the above influencing factors, it was found that smoking [<10 cigarettes/d ( OR=7.02, P=0.009);≥10 cigarettes/d ( OR=10.27, P=0.026)] was an independent risk factor for the need of auxiliary bone grafting with implant placement after ARP. The area under the ROC curve for internal verification was 0.90 (95 %CI: 0.84-0.97), and the H-L goodness of fit test results were χ 2=4.79, P=0.780, indicating a good agreement. The area under the externally verified ROC curve was 0.97 (95 %CI: 0.92-1.00), suggesting that the fitting effect was slightly lower than that of the modeling group, and the predicted value of the model was slightly lower than the true value, which might underestimate the risk of additional surgery in patients. Results:of H-L goodness of fit test were χ 2=5.03, P=0.754. The DCA curve showed that when the probability of high-risk threshold was between 0.06 and 0.93, the clinical application value of the prediction model was higher. Conclusions:Age, smoking, reason of tooth extraction, stage of periodontitis, and maximum AL of the affected teeth were related to the necessity for auxiliary bone grafting with implant placement 6 months after ARP. Smoking was an independent risk factor for auxiliary bone grafting surgery. The constructed nomogram model had good discrimination and consistency.
7.Establishment and verification of nomogram model for predicting implant-assisted bone grafting after posterior teeth alveolar ridge preservation
Jiaqi DENG ; Ze YANG ; Yi LIU ; Ruoyan CAO ; Yaping PAN
Chinese Journal of Stomatology 2025;60(5):464-473
Objective:Constructing a risk prediction model to assess the impact of various factors on the need for auxiliary bone grafting with implant placement following alveolar ridge preservation (ARP) in posterior teeth.Methods:According to the sample size calculation formula, the sample size was calculated using the pmsampsize package of R 4.1.3 software, based on inclusion and exclusion criteria, a total of 110 posterior teeth in 98 patients who underwent ARP at the Department of Periodontology, School and Hospital of Stomatology, China Medical University, from January 2018 to May 2024 were conducted. Teeth were randomly divided into modeling group and validation group with 7∶3 ratio according to the random number table. The modeling group was divided into direct implantation group and auxiliary bone grafting group on the basis of whether auxiliary bone grafting was performed 6 months after ARP. Univariate and multivariate analyses were conducted to identify factors influencing auxiliary bone grafting with implant placement following ARP. Nomogram was constructed using R software. Receiver operator characteristic (ROC) curve and calibration curve were drawn to evaluate model differentiation and consistency. The decision curve analysis (DCA) was used to assess the clinical application value of the model.Results:Age ( OR=1.06, P=0.001), maximum attachment loss (AL) ( OR=1.75, P<0.001), reason of tooth extraction ( OR=12.73, P<0.001), smoking [<10 cigarettes/d ( OR=7.59, P<0.001);≥10 cigarettes/d ( OR=28.12, P<0.001)] and stage of periodontitis [stage Ⅱ ( OR=2.57, P=0.430); stage Ⅲ ( OR=21.00, P=0.007); stage Ⅳ ( OR=76.50, P<0.001)] influenced the necessity for auxiliary bone grafting with implant placement after ARP. After multivariate analysis of the above influencing factors, it was found that smoking [<10 cigarettes/d ( OR=7.02, P=0.009);≥10 cigarettes/d ( OR=10.27, P=0.026)] was an independent risk factor for the need of auxiliary bone grafting with implant placement after ARP. The area under the ROC curve for internal verification was 0.90 (95 %CI: 0.84-0.97), and the H-L goodness of fit test results were χ 2=4.79, P=0.780, indicating a good agreement. The area under the externally verified ROC curve was 0.97 (95 %CI: 0.92-1.00), suggesting that the fitting effect was slightly lower than that of the modeling group, and the predicted value of the model was slightly lower than the true value, which might underestimate the risk of additional surgery in patients. Results:of H-L goodness of fit test were χ 2=5.03, P=0.754. The DCA curve showed that when the probability of high-risk threshold was between 0.06 and 0.93, the clinical application value of the prediction model was higher. Conclusions:Age, smoking, reason of tooth extraction, stage of periodontitis, and maximum AL of the affected teeth were related to the necessity for auxiliary bone grafting with implant placement 6 months after ARP. Smoking was an independent risk factor for auxiliary bone grafting surgery. The constructed nomogram model had good discrimination and consistency.
8.Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury (version 2025)
Aijun XU ; Shuixia LI ; Bo CHEN ; Mengyuan YE ; Lejiao LANG ; Ning NING ; Lin ZHANG ; Changqing LIU ; Zhonglan CHEN ; Weihu MA ; Weishi LI ; Xiaoning WANG ; Dongmei BIAN ; Jiancheng ZENG ; Xin WANG ; Yuan GAO ; Yaping CHEN ; Jiali CHEN ; Yun HAN ; Xiuting LI ; Yang ZHOU ; Xiaojing SU ; Qiong ZHANG ; Tianwen HUANG ; Ping ZHANG ; Hua LIN ; Xingling XIAO ; Ruifeng XU ; Fanghui DONG ; Bing HAN ; Luo FAN ; Yanling PEI ; Suyun LI ; Xiaoju TAN ; Rongchen GUO ; Yefang ZOU ; Xiaoyun HAN ; Junqin DING ; Yi WANG ; Shuhua DENG ; Jinli GUO ; Yinhua LIANG ; Yuan CEN ; Xiaoqin LIU ; Junru CHEN ; Haiyang YU ; Lunlan LI ; Ying REN ; Yunxia LI ; Jianli LU ; Ying YING ; Lan WEI ; Yin WANG ; Qinhong XU ; Yanqin ZHANG ; Yang LYU ; Shijun ZHANG ; Sui WENJIE ; Sanlian HU ; Shuhong YANG ; Guoqing LI ; Jingjing AN ; Baorong HE ; Leling FENG
Chinese Journal of Trauma 2025;41(6):530-541
Paraplegia caused by spinal cord injury is a serious neurological complication, for which surgery is currently the main treatment method. Due to different surgical approaches, patients are usually expected to maintain a passive prone position for a long time or switch between the supine and prone positions. Affected by multiple factors such as neurogenic sensory disorders, pathological changes in muscle tone and operative duration, the risk of intraoperative acquired pressure injury (IAPI) is significantly increased. Current clinical prevention strategies for IAPI in these patients predominantly focus on localized pressure relief during positioning, lacking systematic, standardized comprehensive prevention protocols or evidence-based guidelines. To address it, Department of Nursing, Orthopedics Branch, China International Exchange and Promotive Association for Medical and Health Care, Spinal Trauma Professional Committee, Orthopedics Branch, Chinese Medical Doctor Association, Nursing Group of Spine and Spinal Cord Professional Committee of Chinese Association of Rehabilitation Medicine organized experts in relevant fields to formulate Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury ( version 2025), based on evidence-based medical evidence and latest research results and clinical practice at home and abroad. Eleven recommendations were put forward from the aspects of preoperative risk assessment, intraoperative prevention strategies, postoperative handover and monitoring, and supportive mechanisms for IAPI prevention, aiming to standardize the prevention measures and management strategies of IAPI in paraplegic patients with spinal cord injury and accelerate the recovery of patients and improve the therapeutic effect.
9.Interaction between implants and natural teeth in patients with severe periodontitis:a retrospective study
Ze YANG ; Yu DENG ; Lei MIAO ; Junge LI ; Chen LI ; Yaping PAN
Chinese Journal of Stomatology 2024;59(4):336-343
Objective:To evaluate the clinical outcomes after implant restoration in the posterior region of severe periodontitis patients and to investigate the factors of natural tooth affecting the implant from the perspective of improving natural periodontal health, which may provide a reference for clinical practice.Methods:Fifty-three patients with severe periodontitis who visited the Department of Periodontology at the Affiliated Stomatological Hospital of China Medical University from June 2014 to June 2023 and completed posterior implant treatment with single crown were included, among which were 16 males and 37 females, aged (52.2±8.0) years old, with a total of 136 implants, 135 adjacent natural teeth in the edentulous area. We retrospectively compared the changes of probing depth (PD), bleeding on probing (BOP) and tooth mobility (TM) before and after implant placement. Besides, we explored the effects of the natural periodontal status on PD, BOP and marginal bone loss (MBL) of the implant at the last follow-up examination by univariate analysis and multivariate analysis.Results:Fifty-three patients were followed up for (44.5±14.1) months in average, with longest interval of (8.3±2.7) months. The PD of adjacent natural teeth in the edentulous area improved from 4.3 (3.6, 4.6) mm before implantation to 3.6 (3.2, 4.0) mm in the last review ( P<0.01), while the proportion of BOP (+) improved from 69.6% (94/135) before implantation to 46.7% (63/135) in the last review ( P<0.01). The proportion of teeth with mobility≥Ⅱ decreased from 15.6% (21/135) to 5.9% (8/135) ( P<0.01). The percentage of natural teeth with PD≥4 mm in the same segment improved from 21.0% (13.3%, 26.0%) before implantation to 18.0% (12.0%, 25.0%) in the last review ( P<0.05). The BOP (+)% improved from 29.0% (24.0%, 35.0%) before implantation to 23.0% (18.0%, 31.0%) in the last review ( P<0.05), and the number of teeth with mobility≥Ⅱ decreased from 0.0 (0.0, 1.0) to 0.0 (0.0, 0.8) ( P<0.05). The functional tooth unit score of full natural teeth increased from 8.0 (6.0, 10.0) points before implantation to 12.0 (12.0, 12.0) points in the last review ( P<0.01). PD≥4 mm % increased from 11.0% (6.0%, 25.0%) before implantation to 13.0% (3.0%, 21.0%) in the last review ( P<0.05) and there was no significant differences in BOP (+)% [(17.0±9.7) % vs (14.6±7.2) %, P>0.05]. The number of teeth with mobility≥Ⅱ decreased from 1.0 (0.0, 1.8) to 0.0 (0.0, 0.8) ( P<0.05). Conclusions:Under the premise of regular supportive care, implant restorative treatment in the posterior region of severe periodontitis patients is helpful to improve the PD, BOP and TM of remaining natural teeth. Besides, the stages and grades of periodontitis at initial diagnosis can affect the PD and BOP of implants.
10.Research advances on the application of negative pressure wound therapy in free flap transplantation surgery
Chinese Journal of Burns 2024;40(9):885-890
Negative pressure wound therapy (NPWT) is a therapy that utilizes continuous vacuum negative pressure to manage wounds, and it is commonly employed in treating various wounds. The local application of NPWT technology is helpful in removing wound exudate, decreasing bacterial infection, and stimulating the formation of blood vessels and granulation tissue, thus providing a good base for free flap transplantation. However, there is controversy over whether NPWT should be performed after free flap transplantation. Researches showed that NPWT combined with free flap transplantation could promote wound healing and reduce complications. Additionally, applying NPWT in the wounds of flap donor areas can decrease wound tension, promote wound healing, and improve pigmentation. This paper aims to review literature related to the clinical use of NPWT in free flap transplantation, providing a theoretical basis for their combined application.

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