Multi-feature, Chinese-Western medicine-integrated prediction model for diabetic peripheral neuropathy based on machine learning and SHAP.

BACKGROUND: Clinical studies have shown that diabetic peripheral neuropathy (DPN) has been on the rise, with most patients presenting with severe and progressive symptoms. Currently, most of the available prediction models for DPN are derived from general clinical information and laboratory indicators. Several Traditional Chinese medicine (TCM) indicators have been utilised to construct prediction models. In this study, we established a novel machine learning-based multi-featured Chinese-Western medicine-integrated prediction model for DPN using clinical features of TCM. MATERIALS AND METHODS: The clinical data of 1581 patients with Type 2 diabetes mellitus (T2DM) treated at the Department of Endocrinology of the First Affiliated Hospital of Anhui University of Chinese Medicine were collected. The data (including general information, laboratory parameters and TCM features) of 1142 patients with T2DM were selected after data cleaning. After baseline description analysis of the variables, the data were divided into training and validation sets. Four prediction models were established and their performance was evaluated using validation sets. Meanwhile, the accuracy, precision, recall, F1 score and area under the curve (AUC) of ROC were calculated using ten-fold cross-validation to further assess the performance of the models. An explanatory analysis of the results of the DPN prediction model was carried out using the SHAP framework based on machine learning-based prediction models. RESULTS: Of the 1142 patients with T2DM, 681 had a comorbidity of DPN, while 461 did not. There was a significant difference between the two groups in terms of age, cause of disease, systolic pressure, HbA1c, ALT, RBC, Cr, BUN, red blood cells in the urine, glucose in the urine, and protein in the urine (p < 0.05). T2DM patients with a comorbidity of DPN exhibited diverse TCM symptoms, including limb numbness, limb pain, hypodynamia, thirst with desire for drinks, dry mouth and throat, blurred vision, gloomy complexion, and unsmooth pulse, with statistically significant differences (p < 0.05). Our results showed that the proposed multi-featured Chinese-Western medicine-integrated prediction model was superior to conventional models without characteristic TCM indicators. The model showed the best performance (accuracy = 0.8109, precision = 0.8029, recall = 0.9060, F1 score = 0.8511, and AUC = 0.9002). SHAP analysis revealed that the dominant risk factors that caused DPN were TCM symptoms (limb numbness, thirst with desire for drinks, blurred vision), age, cause of disease, and glycosylated haemoglobin. These risk factors were exerted positive effects on the DPN prediction models. CONCLUSIONS: A multi-feature, Chinese-Western medicine-integrated prediction model for DPN was established and validated. The model improves early-stage identification of high-risk groups for DPN in the diagnosis and treatment of T2DM, while also providing informative support for the intelligent management of chronic conditions such as diabetes.

Treatment of Traditional Chinese Medicine for Diabetic Peripheral Neuropathy Based on Mitochondrial Quality Control： A Review / 中国实验方剂学杂志

Diabetic peripheral neuropathy（DPN） is a neurodegenerative disease of diabetes mellitus involving peripheral nervous system damage， which is characterized by axonal degenerative necrosis， Schwann cell apoptosis and demyelination of nerve myelin sheath as the main pathological features， this disease is highly prevalent and is a major cause of disability in diabetic patients. Currently， the pathogenesis of DPN may be related to oxidative stress， inflammatory response， metabolic abnormality， and microcirculation disorder. The treatment of DPN in modern medicine mainly starts from controlling blood glucose， nourishing nerves and improving microcirculation， which can only alleviate the clinical symptoms of patients， and it is difficult to fundamentally improve the pathological damage of peripheral nerves. Mitochondrial quality control refers to the physiological mechanisms that can maintain the morphology and functional homeostasis of mitochondria， including mitochondrial biogenesis， mitochondrial dynamics， mitochondrial oxidative stress and mitochondrial autophagy， and abnormal changes of which may cause damage to peripheral nerves. After reviewing the literature， it was found that traditional Chinese medicine（TCM） can improve the low level of mitochondrial biogenesis in DPN， maintain the balance of mitochondrial dynamics， inhibit mitochondrial oxidative stress and mitochondrial autophagy， and delay apoptosis of Schwann cells and neural axon damage， which has obvious effects on the treatment of DPN. With the deepening of research， mitochondrial quality control may become one of the potential targets for the research of new anti-DPN drugs， therefore， this paper summarized the research progress of TCM in treating DPN based on four aspects of mitochondrial quality control， with the aim of providing a theoretical research basis for the discovery of new drugs.

[Systematic review and Meta-analysis of efficacy and safety of Shuxuetong Injection in treatment of diabetic peripheral neuropathy].

The present study evaluated the efficacy and safety of Shuxuetong Injection in the treatment of diabetic peripheral neuropathy(DPN). PubMed, Cochrane Library, EMbase, CNKI, VIP, SinoMed, and Wanfang were searched for randomized controlled trials(RCTs) of Shuxuetong Injection in the treatment of DPN from database inception to July 18, 2021. Literature screening was carried out according to the inclusion and exclusion criteria, and the required information was extracted. Cochrane risk-of-bias tool was used to evaluate the quality of the included trials, and RevMan 5.3 was used for Meta-analysis. Finally, six articles were included, involving 507 patients. The overall quality of included RCTs was not high. As revealed by Meta-analysis results, in terms of DPN score, one trial showed a significant difference in the experimental group before and after treatment, and the symptom of the experimental group was significantly improved compared with that in the control group after treatment. After treatment, a significant difference in DPN scores of the experimental group and the control group was observed(P<0.05), and the symptom improvement of the experimental group was significantly better than that of the control group. In terms of sensory nerve conduction velocity(SCV), the experimental group was superior to the control group in improving conduction velocities(MD_(median SCV)=4.45, 95%CI[2.79, 6.10], P<0.000 01; MD_(peroneal SCV)=6.70, 95%CI[5.64, 7.75], P<0.000 01; MD_(posterior tibial SCV)=4.03, 95%CI[0.56, 7.49], P=0.02). In terms of motor nerve conduction velocity(MCV), compared with the conditions before treatment, the conduction velocities of median nerve, peroneal nerve, and posterior tibial nerve in both groups increased after treatment(P<0.01). The experimental group was superior to the control group in improving MCV after treatment(P<0.05). In terms of average blood glucose change, there is no statistical significance of the improvement of average blood glucose between experimental group and the control group(MD=-0.15, 95%CI[-0.82, 0.51], P=0.65). In terms of overall response rate, the curative effect of the experimental group in the treatment of DPN was superior to that of the control group(RR=1.23, 95%CI[1.11, 1.37], P=0.000 1). In terms of adverse events, no obvious adverse events were reported in the included RCTs. In light of existing data and indexes, the clinical efficacy of Shuxuetong Injection combined with western medicine in the treatment of DPN may be superior to that of conventional western medicine. It can improve the clinical symptoms, SCV, MCV, and average blood glucose of DPN, with good safety. However, existing clinical trials are few and the quality is low. It is recommended to further verify the above conclusions with internationally recognized outcome indicators.

Effect of Modified Huangqi Biejiatang Combined with Auricular Acupressure on Diabetic Peripheral Neuropathy of Qi-Yin Deficiency Syndrome and Serum MyD88/IκB Signaling Pathway / 中国实验方剂学杂志

Objective:To observe the effects of modified Huangqi Biejiatang combined with auricular acupressure on diabetic peripheral neuropathy （DPN） due to Qi and Yin deficiency and serum myeloid differentiation factor 88/inhibitor of nuclear factor-<italic>κ</italic>B （MyD88/I<italic>κ</italic>B） signaling pathway. Method:One hundred and forty cases were randomly divided into an observation group （<italic>n</italic>=70） and a control group （<italic>n</italic>=70）. In addition to routine treatments like dietary intervention and the regulation of fasting blood glucose （FBG） and blood pressure， the modified Huangqi Biejiatang combined with auricular acupressure was further provided in the observation group， while mecobalamine was administered in the control group. After four-week intervention， the toronto clinical scoring system （TCSS） score， traditional Chinese medicine （TCM） syndrome score， the conduction velocities of motor and sensory nerves （median nerve， common peroneal nerve， tibial nerve， and ulnar nerve）， glucose metabolism indexes ［fasting plasma glucose （FPG）， 2 h postprandial blood glucose （2 h PG）， and hemoglobin A1c （HbA1c）］， intestinal genera （<italic>Clostridium</italic>， <italic>Prauserella</italic>， <italic>Bacteroides</italic>， and <italic>Faecalibacterium</italic>）， as well as the serum MyD88， I<italic>κ</italic>B<italic>α</italic>， and phosphorylated I<italic>κ</italic>B<italic>α </italic>（p-I<italic>κ</italic>B<italic>α</italic>） levels in the MyD88/I<italic>κ</italic>B signaling pathway before and after treatment were observed in the two groups， for comparing their clinical efficacy and safety. Result:The total effective rate of the observation group was 85.3% （58/68）， which was higher than 48.5% （32/66） of the control group （<italic>χ</italic>²=6.143， <italic>P</italic><0.05）. The comparison with the control group revealed that the scores of TCSS and TCM syndrome， the levels of FPG， 2 h PG， HbA1c， MyD88， and p-I<italic>κ</italic>B<italic>α</italic>， as well as the abundances of <italic>Clostridium</italic> and <italic>Prauserella</italic> in the observation group were decreased （<italic>P</italic><0.05）， while the conduction velocities of motor and sensory nerves （median nerve， common peroneal nerve， tibial nerve， and ulnar nerve） were significantly accelerated （<italic>P</italic><0.05）. Besides， the abundances of <italic>Bacteroides</italic> and <italic>Faecalibacterium</italic> and I<italic>κ</italic>B<italic>α</italic> level were significantly elevated （<italic>P</italic><0.05）. The incidence of adverse reactions in the observation group was 1.5% （1/68）， lower than 12.1% （8/66） in the control group （<italic>χ</italic>²=4.328， <italic>P</italic><0.05）. Conclusion:The modified Huangqi Biejiatang combined with auricular acupressure alleviates DPN due to Qi and Yin deficiency， which may be attributed to the regulation of serum MyD88/I<italic>κ</italic>B signaling pathway.

Traditional Chinese medicine foot bath combined with acupoint massage for the treatment of diabetic peripheral neuropathy: A systematic review and meta-analysis of 31 RCTs.

In this study, we aim to evaluate the efficiency and safety of traditional Chinese medicine foot bath combined with acupoint massage for the treatment of diabetic peripheral neuropathy. A total of eight online databases were searched to collect studies published up to February 2019. Study quality of each included article was evaluated by the Cochrane Collaboration risk of bias tool. Systematic reviews and meta-analyses were conducted based on the Cochrane systematic review method by using the RevMan 5.3 software. Traditional Chinese medicine foot bath combined with acupoint massage was the main therapy in experimental group. Interventions in control groups include western medicine, oral traditional Chinese medicine, other symptomatic treatment of western medicine, and blank control. Primary outcomes in this study include sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), total effective rate, and neuropathic syndrome score. Finally, 31 trials involving 3284 participants were included. The results of systematic reviews and meta-analyses showed that traditional Chinese medicine foot bath combined with acupoint massage was significantly better compared with the control groups in terms of the total effective rate, SNCV, MNCV, and neuropathic syndrome score. No case of adverse effect was reported. These findings show that traditional Chinese medicine foot bath combined with acupoint massage may be safer and more effective for the treatment of DPN. However, due to the low methodological quality, further research with randomized controlled trials (RCTs) of higher quality is required to prove its efficacy and better evidence for clinical treatment.

Analysis on Medication Rules of Traditional Chinese Medicine for Treatment of Diabetic Peripheral Neuropathy Based on Clinical Literature / 中国实验方剂学杂志

Objective:To investigate the medication rules of traditional Chinese medicine (TCM) for the treatment of diabetic peripheral neuropathy (DPN).Method:The literature published in China Knowledge Resource Integrated Database (CNKI), Wanfang Database, China Biomedical Literature Service System (SinoMed), VIP Database and PubMeb from 2008 to 2019 were retrieved by setting the topics of diabetic peripheral neuropathy and TCM. After screening, a database was established to analyze the medication rules (efficacy, frequency, flavor and meridian tropism, common couplet medicinals and core medicines) of TCM by frequency statistics, association rules and data statistical methods of constructing complex networks.Result:A total of 461 papers for treatment of DPN were included in this study, including 275 kinds of TCM and a total frequency of 6 361 times. Astragali Radix had the highest frequency. Among all kinds of medicinal materials, activating blood circulation and removing stasis was the most commonly used medicine, followed by Qi-invigorating medicine. Flavor of medicines was mainly sugariness and warm, and most of their meridian tropism was liver meridian. After the analysis by association rules, the couplet medicinals with the highest support was Astragali Radix-Angelicae Sinensis Radix. The core medicines obtained by complex network analysis were Astragali Radix, Angelicae Sinensis Radix, Chuanxiong Rhizoma, Spatholobi Caulis, Cinnamomi Ramulus, Carthami Flos, Pheretima, Paeoniae Radix Rubra, Salviae Miltiorrhizae Radix et Rhizoma and Persicae Semen.Conclusion:This study comprehensively analyzes the medication rules of TCM clinical treatment of DPN. The main treatment methods of TCM for DPN are invigorating Qi and blood, activating blood circulation and removing stasis, activating meridians to stop pain, which can provide guidance for the TCM clinical use and new Chinese medicines research and development of DPN.

[Discussion of acupuncture for diabetic peripheral neuropathy based on blood stasis theory].

Based on the understanding of TCM and western medicine on diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN), the relationship between DPN pathogenesis and blood stasis of TCM is discussed from the perspective of modern medicine. It is indicated blood stasis is the key pathogenesis to DPN, and a two-step acupuncture treatment of DPN from the theory of blood stasis is proposed. The first step is to analyze the pathogenesis of blood stasis, which could block the progress of the disease and diminish the symptoms. The second step is to apply acupuncture for pathological result of blood stasis by following the principle of eliminating exogenous pathogen, as a result, the purpose of treating both symptoms and root cause is achieved.

Discussion of acupuncture for diabetic peripheral neuropathy based on blood stasis theory / 中国针灸

Based on the understanding of TCM and western medicine on diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN), the relationship between DPN pathogenesis and blood stasis of TCM is discussed from the perspective of modern medicine. It is indicated blood stasis is the key pathogenesis to DPN, and a two-step acupuncture treatment of DPN from the theory of blood stasis is proposed. The first step is to analyze the pathogenesis of blood stasis, which could block the progress of the disease and diminish the symptoms. The second step is to apply acupuncture for pathological result of blood stasis by following the principle of, as a result, the purpose of treating both symptoms and root cause is achieved.

[Rules of acupoint selection for diabetic peripheral neuropathy based on data mining technology].

The rules of acupoint selection for diabetic peripheral neuropathy (DPN) based on data mining technology are analyzed. Literature regarding acupuncture for DPN published in core journals from January of 2005 to December of 2014 was retrieved in CNKI database and Wanfang database to establish a database of acupuncture prescriptions, which were included into the TCM Inheritance Platform software (Version 2.0). The data mining methods, including rule analysis, revised mutual information, etc. were applied to analyze the acupuncture prescriptions and the frequency of each acupoint was calculated. The results indicated Zusanli (ST 36), Sanyinjiao (SP 6), Quchi (LI 11), Yanglingquan (GB 34), Hegu (LI 4), Shenshu (BL 23), etc. were mostly selected in acupuncture for DPN; in addition, 19 acupoint combinations were acquired. It is concluded that acupuncture for DPN applied reinforcing methods as main rules, accompanied with promoting blood and qi circulation; the acupoint selection focused on yangming meridians and back-shu points.

Rules of acupoint selection for diabetic peripheral neuropathy based on data mining technology / 中国针灸

The rules of acupoint selection for diabetic peripheral neuropathy (DPN) based on data mining technology are analyzed. Literature regarding acupuncture for DPN published in core journals from January of 2005 to December of 2014 was retrieved in CNKI database and Wanfang database to establish a database of acupuncture prescriptions, which were included into the TCM Inheritance Platform software (Version 2.0). The data mining methods, including rule analysis, revised mutual information, etc. were applied to analyze the acupuncture prescriptions and the frequency of each acupoint was calculated. The results indicated Zusanli (ST 36), Sanyinjiao (SP 6), Quchi (LI 11), Yanglingquan (GB 34), Hegu (LI 4), Shenshu (BL 23), etc. were mostly selected in acupuncture for DPN; in addition, 19 acupoint combinations were acquired. It is concluded that acupuncture for DPN applied reinforcing methods as main rules, accompanied with promoting blood andcirculation; the acupoint selection focused onmeridians and back-points.

Treatment of Neuropathic Pain.

OPINION STATEMENT: Neuropathic pain is notoriously variable in its severity and impact on patients, as well as in its response to treatment. Certain therapies for neuropathic pain have better evidence for their use; however, it is apparent that although some therapies provide relief for only a minority of patients, the relief may be significant. Without a trial of therapy, there is no way to know if that relief is achievable. Our treatment experiences have shown that occasionally unexpected benefit is obtained through a thorough investigation of all options, even in the setting of failure of those with the most compelling evidence or indication. Chronic neuropathic pain is generally best treated with regularly dosed medications, balancing efficacy and tolerability. Evidence supports first-line trials of anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors, alone or in certain combinations. While opioid medications, particularly methadone, can be effective in treating neuropathic pain, they are best used only in refractory cases and by experienced clinicians, due to concerns for both short- and long-term safety. Some therapies have a long history of successful use for certain syndromes (e.g., carbamazepine for trigeminal neuralgia pain), but these should not be considered to the exclusion of other more recent, less-supported therapies (e.g., botulinum toxin A for the same), particularly in refractory cases. We find the principles of palliative care highly applicable in the treatment of chronic neuropathic pain, including managing expectations, mutually agreed-upon meaningful outcomes, and a carefully cultivated therapeutic relationship.