Complex network analysis is a perspective and method for studying complex systems, which focuses on the structure of individual interactions within the system. By calculating the topological features such as average degree, network diameter, average path length, and average clustering coefficient of nodes in the network, as well as the characteristics of dispersion, concentration, and density between elements, the distribution pattern of elements between things is described [11]. From the perspectives of openness, hierarchy and complexity, traditional Chinese medicine has the same characteristics as complex networks, which is also the basis for using complex networks to analyze traditional Chinese medicine data.

The use of complex network technology to explore the rules of traditional Chinese medicine’s syndrome differentiation and treatment, as well as the formulation of medication, is an effective way to reveal the inherent complex relationships of traditional Chinese medicine [12]. The node degree is one of the criteria for determining the importance (centrality) of traditional Chinese medicine nodes in network analysis. The larger the node degree is, the more times it appears in combination with other nodes, and the higher the centrality of the node is, making it more important in the network [13]. The betweenness centrality refers to the frequency at which any node(drug) appears on the shortest path of the network, reflecting the degree of hub of the node(drug) in the network connection compatibility [14]. The above two indexes can measure the importance of nodes of traditional Chinese medicine in complex networks. The more frequent the node compatibility, the denser the lines between the combinations, and the greater the node degree, the stronger the compatibility and combination ability of traditional Chinese medicine nodes.

The method used in this paper was to extract prescriptions from the classic Shang Han Lun first and then establish a database. After standardizing the data, Python language is used to develop the software for complex network analysis, and then statistical analysis on medication frequency, node degree of each drug, connection strength between drugs, core drugs, etc. were performed.

3.2.1. Frequency

In this section, a complex network analysis was conducted on all 112 prescriptions containing 90 types of traditional Chinese medicine. The data on the frequency of use, node degree, and edge weight of each medicine were obtained. This allows for the analysis of the importance of each medicine, as well as the strength of connections between two drugs.

It is found that those with a usage frequency of more than 10 times are by analysis: Licorice 66 times (accounting for 58.9%), Cinnamomum cassia 41 times (36.6%), Jujube 38 times (33.9%), Ginger 37 times (33%), Paeonialactiflora 21 times (18.8%), Ginseng 20 times (17.9%), Dried Ginger 20 times (17.9%), Pinelliaternata 18 times (16.1%), Aconitum 17 times (15.2%), Scutellariabaicalensis 15 times (13.4%), Rhubarb 15 times (13.4%), Ephedra sinica 13 times (11.6%), Coptischinensis 12 times (10.7%), Poria cocos 11 times (9.8%), Atractylodesmacrocephala 10 times (8.9%).

As can be seen, these drugs are mainly from Guizhi Tang and Mahuang Tang. Please note the importance of these two formulas in Shang Han Lun. The proportion of licorice, cassia twig, jujube, and ginger is significantly higher than other drugs, indicating the widespread use of these drugs in all formulas and their applicability to various diseases.

Among the above drugs, licorice has a slightly cool nature and is good at clearing heat and detoxifying. It is often used for treating heat toxic ulcers and sore throat; Honey roasted licorice has a warm nature and focuses on tonifying the spleen, nourishing Qi, and relieving pain. It is suitable for spleen and stomach weakness, palpitations, and shortness of breath. It belongs to heart meridian, lung meridian, spleen meridian, and stomach meridian. Guizhi has a spicy, sweet, and warm taste, and belongs to the heart, lungs, and bladder meridians. Jujube has a sweet and warm taste, and belongs to the spleen, stomach, and heart meridians. It has the effects of nourishing the middle and Qi, nourishing blood and calming the mind, generating fluids and moistening dryness, and harmonizing medicinal properties. Paeonialactiflora has a bitter and sour taste, with a slight coldness. It belongs to the liver and spleen meridians and has the effects of nourishing blood, regulating meridians, tonifying Yin, stopping sweating, softening the liver, relieving pain, and calming liver Yang. Ginseng has a sweet, slightly bitter, and slightly warm taste, and belongs to the spleen, lung, heart, and kidney meridians. It has the effects of tonifying vital energy, nourishing the spleen and benefiting the lungs, generating fluids and quenching thirst, calming the mind and improving intelligence, and harmonizing medicinal properties. Pinelliaternata has a pungent and warm taste, is toxic, and belongs to the spleen, stomach, and lung meridians. It has the effects of drying dampness, resolving phlegm, reducing nausea and vomiting, dispelling stagnation, and reducing swelling when using externally. Ginger has a pungent taste, a slight warmth, and belongs to the lung meridian. It has the effects of sweating, relieving external heat, and dispersing wind and cold. Dried ginger has a pungent and hot taste, and belongs to the spleen, stomach, kidney, heart, and lung meridians. It has the effects of warming the middle and dispelling cold, returning Yang and promoting blood circulation, and warming the lungs and promoting diuresis. Fuzi has a pungent and sweet taste, a hot and toxic nature, and belongs to the heart, spleen, and kidney meridians. Ginseng has a sweet and slightly bitter taste, a slightly warm nature, and belongs to the spleen, lungs, heart, and kidney meridians. It can tonify the kidneys and invigorate the essence, nourish the spirit, and greatly replenish the Qi. It is the strongest Qi tonifying medicine. Scutellariabaicalensis has a bitter and cold taste, and belongs to the lungs, gallbladder, spleen, large intestine, and small intestine meridians. It has the effects of clearing heat, drying dampness, purging fire, detoxifying, stopping bleeding, and stabilizing pregnancy. Huanglian has a cold taste, and belongs to the spleen, stomach, liver, gallbladder, and large intestine meridians. It has the effects of clearing heat, drying dampness, purging fire, and detoxifying. Ephedra has a pungent, slightly bitter taste, and warm nature. It belongs to the lung and bladder meridians and has the effects of sweating, dispelling cold, promoting lung function, relieving asthma, promoting diuresis, and reducing swelling. Rhubarb has a bitter and cold taste, and belongs to the spleen, stomach, large intestine, liver, and pericardium meridians. It has the effects of purging and attacking accumulation, clearing heat and fire, removing blood stasis and promoting meridian circulation, and relieving dampness and yellowing. Poria cocos has a sweet and mild taste, a calm nature, and belongs to the heart, lungs, spleen, and kidney meridians. It has the functions of promoting diuresis and dampness, strengthening the spleen and stopping diarrhea, calming the heart and mind, resolving phlegm and stopping cough. Atractylodesmacrocephala has a bitter and sweet taste, a warm nature, and belongs to the spleen and stomach meridians. It has the effects of tonifying Qi and spleen, drying dampness and promoting diuresis, stopping sweating, and stabilizing pregnancy.

The functional descriptions of the principal herbs in terms of their nature, taste, meridian tropism, and therapeutic effects indicate that the commonly used herbs in the Shang Han Lun encompass a comprehensive range of functions, including tonifying deficiency, promoting diuresis and resolving dampness, activating blood and resolving stasis, releasing the exterior, and warming the interior.

3.2.2. Node Degree

The total number of nodes is 90, the number of connected edges is 557. The node degrees are as follows: The licorice is 55, Guizhi 48, ginger 46, jujube 43, ginseng 38, dried ginger 35, Paeonialactiflora 31, Pinelliaternata 31, Poriacocos 29, Scutellariabaicalensis 29, rhubarb 29, Ephedrasinica 27, Angelicasinensis 24, aconitum and Coptischinensis 22, almond, Atractylodesmacrocephala and gypsum 21, paeonialactiflora 20, Asarum and oyster 19, colla corii asini and Bupleurumchinense 17, Anemarrhenaasphodeloides and Fructusaurantii immaturus 16, magnolia officinalis and hemp seed 14, Phellodendronchinense 13, cohosh, asparagus, and verbena officinalis; dragon bone and Alisma 12, Wu Zhuyu, Gualou root, and Shuqi 11, minium 10, Sichuan pepper, black plum, sake, raw ground, japonica rice, Gardenia, kudzu root, and Ophiopogonjaponicus are all 9, Euphorbiakansui and medulla Tetrapanacis 8, Schisandrachinensis and red bean 7, bamboo leaves, stems, pork cocos, ocher, Ophiopogonjaponicus, Shanglu roots, peach kernels, seaweed, spiral flowers, purple bark, roasted licorice, and glutinous rice are all 6, scallion white, white honey, stems, and maltose are all 5, human urine, Gallusgallusdomesticus, talc, cinnamon, fermented black beans, and pig bile are all 4, Hirudo, Tabanus, Chinese bulbul, Daphnegenkwa, Euphorbiapekinensis, Halloysitum rubrum are all 3, fruit of Trichosantheskirilowii, raw aconite and Yinchen 2, female loin, male loin, Platycodongrandiflorum, pedicellus melo, limonitum and egg are all 1.

3.2.3. Edge Weight

Licorice-jujube 32, jujube-Fructusaurantii 26, cassia twig-jujube 23, licorice-radix Paeoniaealba 15, ginger-radix Paeoniaealba 13, Ginseng-jujube 10, jujubes-radix Paeoniaealba 15, Licorice-Ephedra 9, jujubes-Scutellariabaicalensis 8, cassia twig-licorice 8, dried ginger-licorice 7, cassia twig-Scutellariabaicalensis 7, licorice-Scutellariabaicalensis 7, almonds-ephedra 6.

Aconiti Radix-licorice, Coptischinensis-Scutellariabaicalensis, licorice-Pinelliaternata, cassia twig-radix Paeoniaealba, licorice-Poriacocos, licorice-Paeonialactiflora pall, Pinelliaternata-Scutellariabaicalensis, Pinelliaternata-radix bupleuri, jujube-radix bupleuri, Rheumofficinale-mirabilite, ginger-Scutellariabaicalensis, Atractylodesmacrocephala-Poriacocos, Scutellariabaicalensis-radix bupleuri, and ginger-radix bupleuri are all 5.

Cassia twig-Poria cocos, cassia twig-almonds, cassia twig-oysters, cassia twig-ginger, ginseng-Pinelliaternata, ginseng-licorice, dried ginger-jujube, ginseng-radix bupleuri, Coptischinensis-Pinelliaternata, Coptischinensis-jujube, licorice-ginger, gypsum-ephedra, Paeonialactiflora-Scutellaria, licorice-gypsum, ginger-Ephedrasinica, ginger-Paeonialactiflora, jujube-almond, Rheumofficinale-Fructusaurantii immaturus, ginger-almond, and are all 4; the rest are all 2.

It can be seen that the frequency of appearance in the 112 prescriptions of Shang Han Lun of prepared licorice (Figure 1), cassia twig, jujube, ginger, Paeonialactiflora pall is relatively high, such as the prepared licorice appears 64 times, the cassia twig and jujube 38 times, the ginger 36 times, etc. It is in line with Zhang Zhongjing’s actual medication principles. Zhongjing harmonized the Yingqi and Weiqi through the whole treating process, while also caring for the middle-Jiao to harmonize the five organs [1].

Figure 1. Network for the total prescription.

3.2.4. Cluster Analysis

During clustering analysis, the scree plot was first obtained using the considered data to determine the number of cluster; then K-means method was used to process clustering. When the prescriptions of each cluster were obtained, we can analyze the characteristics of each cluster according to the drugs of these prescriptions and compare the function and medication rules among different clusters. The criteria used to label clusters is determined by the K-means distance. K-means clustering is an unsupervised machine learning algorithm whose core objective is to partition a dataset into K mutually exclusive clusters, such that the data points within each cluster are as similar as possible, while the data points between different clusters are as different as possible. Here, K-means clustering will automatically assign every formula to the appropriate cluster once we set the number of clusters.

It can be seen that 6 clusters should be selected according to the scree plot (Figure 2(a)). However, the clustering results are not distinctly separated. Moreover,

(a)

(b)

Figure 2. The clustering results of the total prescription. (a) Scree plot; (b) clustering plot.

examining the specific clustering of each drug, these 6 clusters do not correspond to drugs from the six meridians (Taiyang, Shaoyang, Yangming, Taiyin, Shaoyin, and Jueyin) (Figure 2(b)). It indicates that within diseases categorized by the six meridians, symptoms often overlap, as the medication principles of Shang Han Lun are based not only on the six-meridian classification but also on symptom patterns.

3.3.1. Usage Frequency and Node Degree

Licorice 42 times, cassia twig 30 times, ginger and jujube 26 times, ginseng, dried ginger and Pinelliaternata 11 times, Paeonialactiflora 10 times, Aconiti Radix and Rheumofficinale 9 times, Coptischinensis, almond and Ephedrasinica 8 times, Poriacocos and Scutellaria 7 times, Atractylodesmacrocephala and fructus Gardeniae 6 times, Paeonialactiflora pall 5 times, while magnolia officinalis, peach kernel, mirabilite, Euphorbiakansui, gypsum, radix bupleuri, dragon Bone, oyster and sojae semen praeparatum only has 3 times; Hirudo, Tabanus and Fructusaurantii immaturusonly have 2 times, all the rest have only 1 time. It can be seen that compared with the statistical data of overall prescription, the main drugs are basically the same. The importance of Paeonialactiflora in treating Taiyang diseases has increased because the Paeonialactiflora has the taste of bitter, sour and slightly sold, benefits for the liver meridian and spleen meridian. It has the effects of tonifying Yin, stopping sweating, softening the liver, and relieving pain.

The total nodes are 60 and the connection edges are 321. The node degrees are as follows: cassia twig 36, licorice 41, ginger 39, jujube 36, ginseng 26, rheum officinale 24, Pinelliaternata 24, Paeonialactiflora and Poriacocos 18, almond 19, Ephedrasinica and dried ginger 17, Scutellaria and radix bupleuri 14, Aconiti Radix and Paeonialactiflora pall 13, oyster, Atractylodesmacrocephala dragon Bone and coptischinensis 12, red lead and magnolia officinalis 10.

Sake, raw Rehmanniaglutinosa, Ophiopogonjaponicus, seed of hemp, colla corii asini and Fructusaurantii immaturus are all 9. Both Euphorbiakansui and mirabilite are 8. Schisandrachinensis, fructus Gardeniae, Asarum and gypsum are all 7. ruddle, peach kernel, inula flower, bark of Chinese catalpa, red bean, Forsythiasuspensa, prepared licorice and twig and leaf of antifebrile Dichroa are all 6. Maltose, white honey and draba are all 5. Rhizoma Alismatis, Cinnamomumcassia and Polyporusumbellatus are all 4. Daphnegenkwa, Puerarialobata, sojae semen praeparatum, Euphorbiapekinensis, Hirudo and Tabanus are all 3. raw Aconiti Radix, Trichosanthes fruit and Phellodendron are all 2. Halloysitum rubrum and Yu Yu Liang (limonitum) are all 1.

Licorice-jujube 21 jujube-ginger 18 cassia twig-jujube 16 licorice-Paeonialactiflora 9 jujube-Paeonialactiflora 8 ginger-Paeonialactiflora and ginseng-jujube are all 7; dried ginger-ginseng, licorice-ephedra sinica and cassia twig-licorice are all 5;both of almond-ephedra sinica and dried ginger-licorice are 6; dried ginger-jujube, cassia twig-Pinelliaternata, cassia twig-almond, cassia twig-ginger, cassia twig-ephedra sinica, licorice-poriacocos, Pinelliaternata-Scutellaria, Pinelliaternata-Coptischinensis, jujube-Scutellaria, jujube-almond, jujube-Coptischinensis, Scutellaria-Coptischinensis, both of licorice-ginger and ginger-almond are 4;licorice-gypsum, licorice-Aconiti Radix, licorice-Scutellaria, licorice-Coptischinensis, licorice-Paeonialactiflora pall, Pinelliaternata-radix bupleuri, ginseng-Pinelliaternata, ginseng-ginger, dried ginger-Coptischinensis, cassia twig-ginseng, Rheumofficinale-mirabilite, gypsum-Ephedrasinica, fructus Gardeniae-sojae semen praeparatum, cassia twig-oyster, cassia twig-Poriacocos, jujube-radix bupleuri, rheum officinale-peach kernel, oyster-dragon Bone, ginger-radix bupleuri, Atractylodesmacrocephala-Poriacocos, licorice-ginseng, licorice-Pinelliaternata and licorice-almond are all 3; the rests are 2 (Figure 3).

It can be seen that the cassia twig, licorice, ginger, jujube, ginseng, Rheumofficinale, Pinelliaternata, Paeonialactiflora are the core drug among them, and licorice-jujube, jujube-ginger, cassia twig-jujube, licorice-Paeonialactiflora, jujube-Paeonialactiflora, ginger-Paeonialactiflora and ginseng-jujube form the core drug pair, which corresponds to the characteristics of Taiyang disease. Taiyang disease primarily manifests as exogenous wind-induced-cold pathogens invading the body’s superficial regions, leading to a struggle between healthy Qi and pathogenic factors at the body surface. This results in dysfunction of the Ying (nutritive) and Wei (defensive) Qi, with its core pathogenesis being “disharmony” between Ying and Wei Qi, and stagnation of Wei Yang. The treatment of Taiyang disease is mainly based on the “sweating” method, which uses sweating to eliminate the evil

Figure 3. Network for the prescription in Taiyang Chapter (in which HARU-YUYU is a separate connection and is not shown).

from the body surface. The main formulas are Cassia Twig Tang and Ephedra Sinica Tang.

3.3.2. Cluster Analysis

It can be seen that 5 clusters were selected, and there is little overlap between the cluster data, indicating that there is a high degree of differentiation between each prescription, or in other words, the corresponding symptoms of each prescription are clearly different, and the drugs used are also different (Figure 4).

The following formulas belong to the same category: Banxia Xiexin Tang with the function of harmonizing liver and spleen, balancing cold and heat, dissolving masses and resolving stagnation). Dachaihu Tang with the function of the harmonizing and resolving Shao Yang, clearing heat and draining repletion and soothing liver and harmonizing stomach. Xuanfu Daizhe Tang for treating the stomach deficiency, phlegm obstruction and rebellious Qi failing to descend. Chaihu Guizhi Tang with the function of harmonizing Shao Yang. Chaihu Longgu Muli Tang with the function of calming the spirit and tranquilizing the mind, leveling liver and subduing Yang. Banxia Tang: balancing cold and heat, dissolving masses and resolving stagnation.

The following formulas belong to the same category: Tao He Cheng Qi Tang whose function is to drain heat and remove blood stasis, promote bowel movement and relieve pain. Di Dang Tang with the function of resolving stasis and clearing heat in lower Jiao, used for mania, rigid lower abdomen, spontaneous urination, and amenorrhea. Shi Zao Tang with the function of draining water retention caused by fluid accumulation in the chest and ribs, treating generalized edema and ascites. Da Xian Xiong Tang with the function of draining heat and expelling fluid, indicated for hard fullness and pain in the chest with associated rigidity. Da Xian Xiong Wan is for chest hardness, fullness, and pain accompanied by neck stiffness, a modified pill formulation of Da Xian Xiong Tang.

The following formulas belong to the same category: Si Ling San with the function of promoting diuresis and removing dampness. Gui Zhi Ren Shen Tang whose function is to warm the Middle, dispel cold, resolve exterior and tonify the spleen. Gui Zhi Sheng Jiang Da Zao Gan Cao Tang with the function of warming the channels, dispelling cold, harmonizing the nutritive and defensive Qi, strengthening the spleen and harmonizing the Middle. Gui Zhi Fu Zi Gan Cao Gan Jiang Da Zao Tang with the function of warming Yang, resolving exterior, dispelling cold and relieving pain. Gui Zhi Fu Ling Sheng Jiang Gan Cao Tang with the function of warming Yang and transforming Qi, Strengthening the spleen and removing dampness, harmonizing the nutritive and defensive Qi. Fu Ling Gui Zhi Da Zao Gan Cao Tang with functions of warming Yang and transforming fluids, calming rebellious Qi and descending reversal. Gui Zhi Fu Zi Tang with the function of dispelling wind, warming the channels, assisting Yang and transforming dampness. Bai Zhu Fu Zi Tang with the function of warming Yang and dispelling cold, strengthening the spleen and removing dampness. Bai Zhu Gui Zhi Fu Zi Gan Cao Tang having the function of warming Yang and dispelling

(a)

(b)

Figure 4. The clustering results of the prescription in Taiyang Chapter. (a) Scree plot; (b) clustering plot.

cold, removing dampness and relieving pain. Fu Ling Gui Zhi Bai Zhu Gan Cao Tang having the function of warming Yang and transforming fluids, strengthening the spleen and removing dampness. Gui Zhi Gan Cao Long Gu Mu Li Tang having the warming and unblocking the heart Yang, calming the spirit and subduing rebellious Qi. Gui Zhi Gan Cao Long Gu Mu Li Tang for the condition of insufficiency of heart Yang. Fu Ling Si Ni Tang having the regulating spleen and stomach deficiency-cold or internal obstruction due to cold-dampness.

The rest are one category.

The Taiyang disease varies greatly with the course of the disease and presents multiple symptoms, so its medication can be divided into multiple types.

3.4.1. Use Frequency

Licorice 7 times, jujube 6 times, ginger 5 times, Scutellaria and cassia twig 4 times, Pinelliaternata, Paeonialactiflora and Puerarialobata 3 times, radix bupleuri, Ephedrasinica, Paeonialactiflora pall, fructus Melothriae and red bean 2 times, ginseng, dried ginger, oyster and radix Trichosanthis 1 time (Figure 5).

Figure 5. Network for the prescription in Shaoyang Chapter (in which REBE-SWMS is a separate connection and has not been drawn.)

The total nodes are 16 and the connection edges are 57. The node degrees are as follows: licorice 13, cassia twig 12, Scutellaria 10, Pinelliaternata, ginger and jujube 9, Puerarialobata, Paeonialactiflora and Ephedrasinica 7, dried ginger, radix Trichosanthis, oyster and radix bupleuri 6, Paeonialactiflora pall 5, fructus Melothriae and red bean 1.

The connection weights: jujube-licorice 5, cassia twig-licorice and ginger-licorice 4, ginger-jujube, ginger-cassia twig, jujube-cassia twig, jujube-Paeonialactiflora, cassia twig-Paeonialactiflora, ginger-Paeonialactiflora, licorice-Paeonialactiflora and licorice-Scutellaria 3, Pinelliaternata-jujube, Pinelliaternata-licorice, ginger-Puerarialobata, ginger-Ephedrasinica, jujube-Puerarialobata, jujube-Paeonialactiflora pall, jujube-Ephedrasinica, jujube-Scutellaria, Puerarialobata-cassia twig, Puerarialobata-licorice, Puerarialobata-Paeonialactiflora, Puerarialobata-Ephedrasinica, cassia twig-Ephedrasinica, licorice-Paeonialactiflora pall, licorice-Ephedrasinica, Scutellaria-radix bupleuri and Paeonialactiflora-Ephedrasinica are all 2.

It can be seen that there are relatively a few prescriptions for Shaoyang and combined diseases, but in which the licorice, jujube, ginger, Scutellaria, cassia twig are still the core drugs. The core drug pairs are jujube-licorice, cassia twig-licorice, ginger-licorice, ginger-jujube, ginger-cassia twig, jujube-cassia twig, jujube-Paeonialactiflora, cassia twig-Paeonialactiflora, ginger-Paeonialactiflora, licorice-Paeonialactiflora, licorice-Scutellaria.

3.4.2. Clustering Analysis

It can be seen that the clustering differences are more obvious, which may be due to the fact that these prescriptions include Shaoyang disease and the combined disease of Shaoyang and Taiyang and Yangming, with significant differences between them (Figure 6).

Figure 6. The clustering results of the prescription in Shaoyang Chapter.

The following decoctions belong to the same category Banxia Xiexin Decoction (harmonizing liver and spleen, balancing cold and heat, dispersing nodules), Dachaihu Decoction (resolving Shaoyang, clearing heat and purging excess, soothing liver and harmonizing stomach), Xuanfu Daizhe Decoction (treating stomach deficiency with phlegm obstruction and rebellious qi), Chaihu Guizhi Decoction (resolving Shaoyang and harmonizing the nutritive and defensive qi), Chaihu Longgu Muli Decoction (calming the spirit and stabilizing the mind, soothing the liver and subduing yang), and Banxia Decoction (balancing cold and heat, dispersing nodules).

The following are the same category: Gui Zhi Fu Zi Tang (functions are to dispel wind, warm the meridians, assist Yang, and transform dampness). Gui Zhi Hou Po Xing Zi Tang (functions are to harmonize the nutritive and defensive Qi, regulate Qi, transform phlegm, and relieve cough and wheezing). Xiao Jian Zhong Tang (to warm the Middle, tonify deficiency, harmonize the Interior, and relax urgency). Zhi Gan Cao Tang (to nourish Yin and blood, benefit Qi and warm Yang, restore pulse and calm palpitations). Ma Huang Lian Qiao Chi Xiao Dou Tang (to release the exterior, disperse pathogenic factors, clear heat, and promote dampness elimination to reduce jaundice). Ma Huang Xing Ren Gan Cao Shi Gao Tang (Pungent-Cooling and to ventilate, clear the Lung, and relieve wheezing). Gui Zhi Ma Huang Ge Ban Tang has the characteristics of pungent-warm and lightly dispersing to induce a light sweat and release the exterior). Da Qing Long Tang (to release the exterior, disperse cold, harmonize the nutritive and defensive Qi, clear heat, and generate body fluids). Gui Zhi Er Ma Huang Yi Tang (to release the muscles, disperse pathogenic factors, and harmonize the nutritive and defensive Qi). Fu Ling Gui Zhi Bai Zhu Gan Cao Tang (to warm Yang, transform fluids, strengthen the spleen, and promote dampness elimination). Gui Zhi Gan Cao Long Gu Mu Li Tang (to warm and unblock heart Yang, calm the spirit and subdue restlessness)

The others are the other category.

Shaoyang disease refers to the syndrome characterized by pathogenic invasion of the Shaoyang gallbladder viscera. Dysfunction of the pivotal mechanism, unfavorable channel Qi, alternate attacks of chill and fever, bitter mouth and dry throat, and dizziness are the main syndromes. The core treatment method is to reconcile with Shaoyang, and the representative formula is Xiao Chaihu Tang. The characteristic of Taiyang Shaoyang syndrome is the coexistence of Taiyang surface syndrome and Shaoyang syndrome, where downward or upward pathogenic heat can cause abdominal pain and vomiting. The Scutellaria decoction (Scutellaria, paeonialactiflora pall, licorice, jujube) is suited for diarrhea. If the patient shows vomiter syndrome, the Scutellaria plus Pinelliaternata and ginger decoction is suited; The characteristics of Shaoyang-Yangming combined disease include diarrhea with retained food accumulation, The pulse shows a slippery-rapid or deep-firm characteristics, and the Dachengqi decoction is for the case of full pulse. These characteristics are confirmed with the core drugs of licorice, jujube, ginger, Scutellaria, cassia twig. Xiao Chaihu Tang is only used for Shaoyang disease and rarely used in all comorbidities.

3.5.1. Use Frequency

Rheum officinale 5 times, licorice, Fructusaurantii immaturus and magnolia officinalis 3 times, anemarrhenaasphodeloides, gypsum, japonica rice and mirabilite 2 times, ginseng, polyporusumbellatus, poriacocos, rhizoma Alismatis, colla corii asini, talc, Yinchen, fructus Gardeniae, pig gall, seed of hemp, almond and paeonialactiflora pall are all 1 time (Figure 7).

The total nodes are 19, the number of connection edges is 39. The node degrees are as follows: Rheumofficinale 9, magnolia officinalis and Fructusaurantii immaturus 6, licorice, almond, seed of hemp and Paeonialactiflora pall 5, mirabilite, rhizoma alismatis, talc, colla corii asini, Polyporusumbellatus and Poriacocos 4, japonica rice, Anemarrhenaasphodeloides and gypsum 3, fructus Gardeniae and Yinchen 2.

The weights of the connection edges are as follows: magnolia officinalis-Rheumofficinale and Fructusaurantii immaturus-Rheumofficinale 3, Rheumofficinale-mirabilite and magnolia officinalis-Fructusaurantii immaturus 2.

There are also relatively a few drugs for Yangming disease, with a total of 19 nodes, which is far less than 90 for all 112 nodes and 60 for Taiyang disease. The drugs with high frequency of use are Rheumofficinale, licorice, Fructusaurantii immaturus, magnolia officinalis. The node degrees of these drugs are also higher than other drugs.

Figure 7. Network for the prescription in Yangming Chapter

3.5.2. Clustering Analysis

It can be seen that there are relatively few prescriptions for Yangming disease, but the differences between clusters are still quite obvious (Figure 8).

Figure 8. The clustering results of the prescription in Yangming Chapter.

Maren Pill belongs to Category I (laxative for constipation), the rest fall into Category II.

Yangming disease belongs to the stage of internal heat syndrome characterized by excessive Yang heat during the development of exogenous diseases, and its core pathogenesis is excess of stomach and intestine (excess heat in the stomach and large intestine). Yangming disease can be divided into two types meridian syndrome and organ syndrome, with the former usually being more severe than the later. The pathogenesis of Yangming meridian syndrome is characterized by excessive pathogenic heat, which fills the Yangming meridian and has not yet formed dry feces with the intestinal waste. The representative formula is Baihu Tang (gypsum, Anemarrhenaasphodeloides, japonica rice, licorice) which has the function of clearing heat and generating fluids. If the syndrome changes to heat disturbance to the chest and diaphragm, the decoction of cape jasmine and fermented soybean is suited. For both Qi and Yin injuries, it’d better to choose white tiger decoction plus ginseng. For water-heat intermingling in the lower energizer, the Polyporusumbellatus decoction is suitable. The pathogenesis of Yangming Fu syndrome involves the internal transmission of pathogenic heat to the large intestine, where it combines with waste matter, leading to stagnation of Fu-Qi. The representative formula is Dachengqi Decoction (Rheumofficinale, magnolia officinalis, Fructusaurantii immaturus, mirabilite), a strong purgative that resolves sensation of fullness, dryness, and solid stagnation. Xiaochengqi Decoction is the mild purgative and is primarily used to treat stagnation and sensation of fullness with solid accumulation. Tiaowei Chengqi Decoction (Rheum officinale, Mirabilite, Licorice) is a kind of slight purgative and is primarily used to treat dryness-heat syndromes.

The results obtained by the above analysis that the Rheumofficinale, licorice, Fructusaurantii immaturus, magnolia officinalis are the core drugs precisely reflects the pathogenesis and therapeutic characteristics of Yangming disease.

Cassia twig, Paeonialactiflora, licorice, ginger and jujube are all 2 times, Rheumofficinale 1 time.

The total nodes are 6 and the connection edges are 15. The node degrees are as follows: jujube, Rheumofficinale, cassia twig, licorice, ginger and Paeonialactiflora are all 5 (Figure 9).

The medications for Taiyin disease are fewer than those for Yangming disease, with only 6 nodes, primarily based on variations of Cassia Twig Decoction‌.

Figure 9. Network for the prescription in Taiyin Chapter.

Because there are few prescriptions, cluster analysis cannot be performed.

The core pathogenesis of Taiyin disease is spleen-stomach deficiency-cold with dysfunction of transportation and transformation. Its essence lies in the spleen’s characteristics of deficiency, cold, and dampness, with the fundamental pathological mechanism being spleen-Yang decline, internal excess of cold-dampness, impaired transformation, and disordered ascending-descending functions. The fundamental pathological characteristics of Taiyin disease are internal deficiency-cold, and its treatment principle should be “warming”, primarily focusing on warming Yang to dispel cold and strengthening the spleen to resolve dampness. This is why the main formulas for this condition are still based on variations of Cassia Twig Decoction as the foundational prescription.

3.7.1. Usage Frequency

Aconiti Radix 7 times, licorice, dried ginger, Paeonialactiflora 3 times, scallion white 3 times, Ephedrasinica, Poriacocos, ginseng, Atractylodesmacrocephala, ginger, Pinelliaternata 2 times; Asarum, Evodiarutaecarpa, jujube, urina pueri, pig gall juice, Paeonialactiflora pall, Coptischinensis, colla corii asini, Scutellaria, egg yolk, halloysitum rubrum, japonica rice, pork skin, Platycodongrandiflorum, cassia twig, Gallusgallusdomesticus, Fructusaurantii immaturus and radix bupleuri 1 time (Figure 10).

Figure 10. Network for the prescription in Shaoyin Chapter.

It can be seen that the usage frequency of Aconiti Radix, licorice, dried ginger, Paeonialactiflora, scallion white is high.

The total nodes are 27 and the connection edges are 62. The node degrees are as follows: Aconiti Radix 12, Paeonialactiflora 11, licorice 10, dried ginger, ginseng and ginger 7, Atractylodesmacrocephala and Poriacocos 6, scallion white 5, urina pueri, pig gall juice, Coptischinensis, Paeonialactiflora pall, colla corii asini, egg yolk and Scutellaria are all 4, Evodiarutaecarpa, jujube, Pinelliaternata, Fructusaurantii immaturus and radix bupleuri are all 3, cassia twig, japonica rice, halloysitum rubrum and Ephedrasinica 2, Gallusgallusdomesticus and Platycodongrandiflorum 1.

The wights of the connection edges are as follows: Atractylodesmacrocephala-poriacocos, licorice-Aconiti Radix and dried ginger-scallion white 2, the rest are all 1.

Compared to Taiyin disease, Shaoyin disease involves more medicinal ingredients and node degrees, but the edge weights are generally smaller, indicating that pairwise co-occurrence of drugs is less frequent in different prescriptions.

The herbs with significant influence in the network of Shaoyin syndrome are Aconiti Radix, Paeonialactiflora, licorice, ginger, ginseng, Atractylodesmacrocephala, Poriacocos. An analysis of the actual medication patterns in Shaoyin syndrome reveals that this condition represents a critical stage in the progression of exogenous diseases, characterized by deficiency, Yin, and coldness. Therefore, its treatment often employs the combination of Aconiti Radix and Paeonialactiflora pall to warm Yang, regulate water metabolism, and promote urination.

Moreover, Shaoyin syndrome encompasses both the heart and kidney organs and their associated meridians. Since kidney Yang deficiency can lead to water retention and fluid accumulation, its treatment often employs Aconiti Radix to tonify fire and reinforce Yang, disperse cold and resolve dampness, and additionally use Poriacocos to promote diuresis and drain dampness.

3.7.2. Clustering Analysis

It can be observed that the distinctions among Shaoyin syndrome clusters are quite evident, indicating that the disease can also be clearly categorized into these types, leading to significant differences in the medications used (Figure 11).

Wu Zhu Yu Tang (to warm the Middle and dispel cold, tonify deficiency and descending counterflow) belongs to Category I. Fu Zi Tang (to warm the channels and dispel cold, strengthen the spleen and remove dampness) and Zhen Wu Tang (to warm Yang and promote urination) belong to Category II. Ma Huang Fu Zi Gan Cao Tang (to assist Yang and resolve exterior symptoms), Zhu Fu Tang (to nourish Yin and moisten dryness, benefit the throat and relieve pain), Gan Cao Tang (to clear heat and detoxify, relieve urgency and pain), Jie Geng Gan Cao Tang (to clear heat and detoxify, benefit the throat and transform phlegm), Gui Zhi Gan Cao Ban Xia Tang (to warm and unblock heart Yang, transform phlegm and descend counterflow), and Ku Sha Tang (to dispel phlegm and disperse nodules, reduce swelling and benefit the throat) belong to Category III. The rest fall into Category IV.

Shaoyin syndrome represents a critical stage of externally contracted diseases, where the pathological mechanism involves decline of heart-kidney Yang Qi or fire excess from yin deficiency. The Shaoyin includes the Hand Shaoyin Heart Meridian and the Foot Shaoyin Kidney Meridian. The heart governs fire, while the kidney governs water. Their coordination maintains Yin-Yang balance. The fundamental treatment principles are as follows:

(a)

(b)

Figure 11. The clustering results of the prescription in Shaoyin Chapter. (a) Scree plot; (b) clustering plot.

For the cold-type transformation, the focus is on restoring Yang and reversing collapse, emphasizing supporting Yang Qi.

For the heat-type transformation, the priority is nourishing Yin and clearing heat, with attention to preserving Yin fluids.

3.8.1. Usage Frequence

The usage frequencies of drugs are as follows: licorice 6 times, ginseng 5 times, dried ginger, cassia twig and angelica sinensis 4 times, Asarum, Coptischinensis, Paeonialactiflora, jujube and Scutellaria 3 times, Phellodendron, Tetrapanax pith, ginger, gypsum, Atractylodesmacrocephala and Pinelliaternata 2 times, the rest are all 1 time (Figure 12).

Figure 12. Network for the prescription in Jueyin chapter.

The total nodes are 42 and the connection edges are 198. The node degrees are as follows: licorice 25, Scutellaria 20, Angelicasinensis, cassia twig, gypsum and Paeonialactiflora 18, dried ginger 15, Atractylodesmacrocephala and ginseng 14, Poriacocos, cimicifuga rhizome, asparagus officinalis, Ophiopogon rhizome, Anemarrhenaasphodeloides, jujube, ginger and Ephedrasinica 13, Pinelliaternata 11, Evodiarutaecarpa, Asarum and Tetrapanax pith 8, mirabilite and radix bupleuri 7, japonica rice, leaf of henon bamboo, Ophiopogon tuber, Phytolacca root, radix Trichosanthis, Hai Zao, Coptischinensis, rhizoma Alismatis, draba seed, twig and leaf of antifebrile Dichroa and oyster 6, pulsatillae radix, ash bark and Phellodendron 3, Fructusaurantii immaturus, fructus Gardeniae and sojae semen praeparatum 2, Nü Kun and Nan Kun 1.

The weights of the connection edges are as follows: ginseng-licorice, jujube-licorice, licorice-Angelicasinensis and licorice-cassia twig, Angelicasinensis-cassia twig, cassia twig-Paeonialactiflora and Angelicasinensis-Paeonialactiflora 3; Pinelliaternata-licorice, jujube-Angelicasinensis, jujube-cassia twig, jujube-Paeonialactiflora, jujube-Asarum, jujube-Tetrapanax pith, dried ginger-licorice, licorice-ginger, licorice-Tetrapanax pith, licorice-gypsum and licorice-Asarum, Angelicasinensis-Asarum, Angelicasinensis-Tetrapanax pith, cassia twig-Asarum, cassia twig-Tetrapanax pith, Paeonialactiflora-Asarum, Paeonialactiflora-Tetrapanax pith and Asarum-Tetrapanax pith 2.

It can be seen that the usage frequencies of licorice, ginseng, dried ginger, cassia twig, angelica sinensis are higher than the others, in which the others are the main ingredients of Cassia Twig Decoction besides Angelica sinensis. Most medications are used only once, indicating that the symptoms of Jueyin disease are diverse and require different treatments. Those with more node degrees are licorice, Scutellaria, Angelicasinensis, cassia twig, gypsum, Paeonialactiflora, dried ginger, Scutellaria, gypsum, Paeonialactiflora. These drugs demonstrate high compatibility with other drugs, but their edge weights are relatively low, indicating that the use of drug pairs appears infrequently across different formulas.

3.8.2. Clustering Analysis

There are relatively few formulas for Jueyin disease, and the distinctions between clusters are not very clear, indicating that the differences in its clinical manifestations are subtle (Figure 13).

Jueyin disease is the final stage of the six-channel syndromes in Shanghan Lun, characterized by the disharmony of Yin and Yang Qi and the intermingling of cold and heat. Its core pathogenesis involves liver wind carrying cold and heat internally disturbing the body, manifesting as complex syndromes of upper heat and lower cold, with alternating cold and heat. The fundamental therapeutic principle is to harmonize Yin and Yang, which involves combining cold and warm herbs, using acrid-sweet flavors to support Yang, and sour-bitter flavors to consolidate Yin. To restrain liver wind and extinguish internal wind, sour-astringent herbs are prioritized to calm liver wind. This is the reason that the usage frequencies of licorice, Scutellaria, Angelicasinensis‌, cassia twig, gypsum, Paeonialactiflora, dried ginger are high.

3.9.1. Usage Frequencies of the Herbs

Three Yang is defined as the total of the Taiyang Channel, Shaoyang Channel and Yangming Channel. So in this section the characteristics of key herbs and drug pairs associated with the Three Yang Channels are analyzed. The usage frequencies are as follows: Licorice is 52 times, cassia twig 34 times, jujube 32 times, ginger 31 times, Rheumofficinale and Pinelliaternata 14 times, Paeonialactiflora and ginseng 13 times, dried ginger 12 times, Scutellaria 11 times, Ephedrasinica 10 times, both of Aconiti Radix and almond 9 times; Poriacocos, Coptischinensis, paeonialactiflora pall are all 8 times; fructus Gardeniae 7 times, both of Atractylodesmacrocephala and magnolia officinalis 6 times; mirabilite, gypsum, radix bupleuri, Fructusaurantii immaturus are all 5 times; both Puerarialobata and oyster 4 times; peach kernel, Euphorbiakansui, dragon bone, sojae semen praeparatum are all 3 times; Polyporusumbellatus, rhizoma Alismatis, Hirudo, Tabanus, colla corii asini,

(a)

(b)

Figure 13. The clustering results of the prescription in Jueyin Chapter. (a) Scree plot; (b) Clustering plot.

seed of hemp, red bean, Anemarrhenaasphodeloides, japonica rice are all 2 times; the others are 1 time (Figure 14).

The total nodes are 66 and the connection edges are 368. The node degrees are as follows: licorice 44, ginger 40, cassia twig 38, jujube 37, both of Rheumofficinale

Figure 14. Network for the prescription of three Yang (HARU-YUYU is independently connected so is not drawn.)

and ginseng are 29, Pinelliaternata 25, almond 21, Poriacocos 20, dried ginger 20, Paeonialactiflora 19, Paeonialactiflora pall 18, Ephedrasinica 18, Scutellaria 17, radix bupleuri 16, oyster 15, both of magnolia officinalis and seed of hemp are 14, colla corii asini, Aconiti Radix and Fructusaurantii immaturus are 13; Atractylodesmacrocephala, dragon Bone and Coptischinensis are 12; red lead, gypsum and mirabilite are 10; Ophiopogonjaponicus, fructus Gardeniae, Puerarialobata, sake and raw Rehmanniaglutinosa are 9; Euphorbiakansui 8, red bean, Schisandrachinensis and Asarum are 7; prepared licorice, rhizoma Alismatis, Polyporusumbellatus, ruddle, twig and leaf of antifebrile Dichroa, peach kernel, radix Trichosanthis, inula flower, bark of Chinese catalpa, jujube and Forsythiasuspensa are all 6; maltose, white honey and draba are 5; Anemarrhenaasphodeloides, talc, Cinnamomumcassia and japonica rice are 4; Daphnegenkwa, Hirudo, Tabanus, Euphorbiapekinensis and sojae semen praeparatum are 3; both of Trichosanthes fruit and Phellodendron are 2; fructus Melothriae, both of raw Aconiti Radix and Yinchen are 2; both of halloysitum rubrum and Yu Yu Liang are 1.

The weights of connection edges are as follows: licorice-jujube 27, jujube-ginger 22, cassia twig-jujube 19, licorice-Paeonialactiflora 12, jujube-Paeonialactiflora 11, ginger-Paeonialactiflora 10, ginseng-jujube 8, jujube-Scutellaria and licorice-Ephedrasinica are 7, almond-Ephedrasinica, dried ginger-licorice, cassia twig-Ephedrasinica, licorice-Scutellaria are 6, Rheumofficinale-mirabilite, licorice-Paeonialactiflora pall, dried ginger-ginseng, cassia twig-licorice, licorice-Pinelliaternata, Pinelliaternata-Scutellaria are 5, dried ginger-jujube, licorice-Poriacocos, Pinelliaternata-Coptischinensis, Pinelliaternata-radix bupleuri, Rheumofficinale-Fructusaurantii immaturus, jujube-Coptischinensis, cassia twig-almond, jujube-almond, jujube-radix bupleuri, licorice-ginseng, cassia twig-oyster, licorice-ginger, cassia twig-ginger, ginger-almond, ginger-radix bupleuri, ginger-Ephedrasinica, Scutellaria-radix bupleuri, Scutellaria-Coptischinensis and ginger-Scutellaria are all 4, the rest are less than 4.

It can be seen that the drugs with high usage frequency are licorice, cassia twig, jujube, ginger, Rheumofficinale, Pinelliaternata, Paeonialactiflora, ginseng, dried ginger, Scutellaria, and Ephedrasinica, which is just correspondent with those with high node degree. The weights of the connection edges of licorice-jujube, jujube-ginger and cassia twig-jujube is significantly higher than that of other herb pairs, this can explain the importance of these drugs in treatment of Three Yang disease. The reason is that the common characteristic of the Three Yang diseases (Taiyang, Yangming, and Shaoyang) is the body’s defensive energy is intact and exuberant pathogenic influence. It is shown as excess-heat syndrome. The fundamental treatment principles are as follows For Taiyang Disease “Resolve through sweating”, using pungent-warm herbs to release the exterior; for Yangming Disease “Treat heat with cold”, employing heat-clearing or purgative methods; for Shaoyang Disease Harmonize the pivot mechanism.

3.9.1. Clustering Analysis

It can be seen that there is overlap among the formula clusters for the Three Yang Diseases (Taiyang, Yangming, Shaoyang), making distinctions difficult. This suggests that the differences between their subtypes are not significant, and the medications used are often similar (Figure 15).

3.10.1. Usage Frequency

Three Yin is defined as the total of the Taiyin Channel, Shaoyin Chnaell and Jueyin Channel. So in this section the characteristics of key herbs and drug pairs associated with the Three Yin Channels are analyzed. The usage frequencies are as follows: licorice 14 times, Paeonialactiflora and Aconiti Radix, dried ginger 8 times, cassia twig and ginseng 7 times, ginger and jujube 6 times, Asarum, Atractylodesmacrocephala, Coptischinensis, Scutellaria, Pinelliaternata and Angelicasinensis 4 times, Ephedrasinica, Poriacocos and scallion white 3 times, japonica rice, Fructusaurantii immaturus, radix bupleuri, Phellodendron, Tetrapanax pith and gypsum 2 times, The others are all 1 times. Those with high usage frequency used in three Yang disease are used infrequently in three Yin disease such as Rheumofficinale, Anemarrhenaasphodeloidesare used only 1 time, radix bupleuri 2 times, ephedra sinica 3 times (Figure 16).

The total nodes are 56 and the connection edges are 285. The node degrees are as follows: licorice 30, Paeonialactiflora and cassia twig 26, dried ginger 25, ginseng and Angelicasinensis 24, Scutellaria 22, ginger and Aconiti Radix 19, gypsum 18, Poriacocos and Atractylodesmacrocephala 17, Asarum 16, Ephedra

(a)

(b)

Figure 15. The clustering results of all the prescription in three Yang Chapter. (a) Scree plot; (b) clustering plot.

sinica 15, jujube and Coptischinensis15, Pinelliaternata, cimicifuga rhizome, asparagus officinalis, Anemarrhenaasphodeloides and Ophiopogon rhizome 13, Phellodendron 11, Wu Mei, radix bupleuri and Sichuan pepper 9, japonica rice, Tetrapanax pith and Evodiarutaecarpa 8, mirabilite 7, Ophiopogon tuber, Phytolacca

Figure 16. Network for the prescription of all three Yin Chapter.

root, radix Trichosanthis, Hai Zao, leaf of henon bamboo, rhizoma alismatis, draba seed, twig and leaf of antifebrile Dichroa and oyster 6, Rheumofficinale, scallion white and Fructusaurantii immaturus 5, Paeonialactiflora pall, colla corii asini, egg yolk, urina pueri and pig gall juice 4, pulsatillae radix, ash bark and Evodiarutaecarpa 3, fructus Gardeniae, sojae semen praeparatum and halloysitum rubrum 2, Gallusgallusdomesticus, Nü Kun, Nan Kun and Platycodongrandiflorum 1.

The weights of the connection edges are as follows: jujube-licorice 4, Pinelliaternata-licorice, jujube-ginger, jujube-Paeonialactiflora, ginseng-licorice, licorice-ginger, Angelicasinensis-licorice, Angelicasinensis-Paeonialactiflora, cassia twig-jujube, cassia twig-licorice, cassia twig-Paeonialactiflora and cassia twig-Asarum 3, the rest are all 2.

The node degree of licorice is still the largest, e.f., the most important. the second largest drugs are Paeonialactiflora, cassia twig, dried ginger, ginseng, Angelicasinensis, Scutellaria, ginger and Aconiti Radix, gypsum, Poriacocos and Atractylodesmacrocephala, Asarum, Ephedrasinica, jujube, Coptischinensis. The weights of the connection edge are all relatively small. The largest is jujube-licorice with value of 4. This indicates that these herb pairs are rarely used together across all syndromes, which can be explained by the pathogenesis and medication characteristics of the three Yin diseases The three Yin Diseases (Taiyin, Shaoyin, and Jueyin) are a collective term in the six meridians syndrome differentiation system of treatise of Shang Han Lun, representing three types of Yin syndromes Taiyin disease (spleen Yang deficiency), Shaoyin disease (heart-kidney deficiency), and Jueyin disease (cold-heat complex). Their common characteristic is deficient healthy Qi with remaining pathogenic Qi, manifesting as deficiency-cold or cold-heat complex syndromes. The treatment principles are as follows Warm the middle jiao and disperse cold for Taiyin disease; as for the Shaoyin disease, restore Yang to rescue from collapse for cold-transformation syndrome and nourish Yin and clear heat for heat-transformation syndrome; Harmonize Yin-Yang and combine cold-heat therapies for Jueyin disease.

3.10.2. Clustering Analysis

The clustering of prescriptions for three Yang diseases shows clear distinctions, indicating significant differences among subtypes, with markedly varied therapeutic approaches (Figure 17).