Fatigue in older patients has multiple etiologies, as this symptom may be cancer-related, treatment-related, age-related, or part of frailty syndrome. Physicians need to identify this symptom and understand its risk factors but also evaluate the risk/benefit ratio of cancer treatments considering the risk of impairing the patient’s quality of life. This scoping review was aimed to present the level of information currently available on any-grade fatigue and grade 3 or more fatigue for each cancer treatment regimen, either in general or in older populations, for the most prevalent tumors.Fatigue is a highly prevalent symptom in both cancer patients and the older population, and it contributes to quality-of-life impairment. Cancer treatment-related fatigue should thus be included in the risk/benefit assessment when introducing any treatment, but tools are lacking to a priori estimate such risk. This scoping review was designed to report the current evidence regarding the frequency of fatigue for the different treatment regimens proposed for the main cancer indications, with a specific focus on age-specific data, for the following tumors: breast, ovary, prostate, urothelium, colon, lung and lymphoma. Fatigue was most frequently reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) versions 3 to 5. A total of 324 regimens were analyzed; data on fatigue were available for 217 (67%) of them, and data specific to older patients were available for 35 (11%) of them; recent pivotal trials have generally reported more fatigue grades than older studies, illustrating increasing concern over time. This scoping review presents an easy-to-understand summary that is expected to provide helpful information for shared decisions with patients regarding the anticipation and prevention of fatigue during each cancer treatment. Fatigue is defined as a persistent sense of physical, emotional, and/or cognitive tiredness or exhaustion that is not proportional to recent activity and that interferes with usual functioning . It is hWith the development of targeted therapies and their related long-lasting fatigue, the consideration of fatigue has changed; during the last two decades, fatigue has been demonstrated as the most prevalent symptom in oncology ,13, affeA significant step was taken in 2009 with the release of fourth version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) that standardized fatigue with the following grading : (1). FaMoreover, much work has been undertaken to decipher fatigue and its modifiable risk factors. Anemia and non-anemic iron deficiency contribute to fatigue ,20 and fIs this context, it appeared necessary to report the current level of evidence on the frequency of fatigue occurrence for the different treatment regimens proposed for the main cancer indications, with a specific focus on data specific to older adults, as has been done previously for other frequent treatment-related adverse events such as febrile neutropenia  and emesTo be included in the review, studies needed to focus on the treatment regimen currently proposed for the most frequent neoplasias , reporting or not fatigue frequency of occurrence, with data specific to older adults present or absent. The inclusion criteria were that there were original studies that were published in the English or French language. To identify relevant studies, PubMed/MEDLINE was searched until December 2021. The search strategy used a combination of MeSH terms (including “fatigue” and “asthenia”), as well as “lethargy” and “weakness”. Additional manuscripts, not retrieved using electronic search strategy, were also included in the eligibility screening process by the authors. The final search results were exported into ZOTERO v6.0.4 , and duplicates were removed. Titles/abstracts were independently evaluated for eligibility by two reviewers (either L.A. and C.F. or G.A. and C.F.). Any disagreement between reviewers was resolved through discussion. The reviewers assessed the full texts of articles retained after the title/abstract screening. Considering the exclusion of scoping reviews from PROSPERO registration , this anIn the first step of data analysis, reviewers examined the presence or not of information on fatigue and data specific to older adults; treatment protocols were semi-quantitatively classified according to the frequency of grade 3 fatigue as defined by the CTCAE classification.A total of 324 regimens were included; data on fatigue were available for 217 (67%) of these, and fatigue data specific to older patients were available for 35 11%; . There wFatigue during and after localized breast cancer treatment has been a large matter of debate. In a meta-analysis published in 2016, Abrahams et al. identified 27 studies and a total of 12,237 patients treated in trials evaluating the frequency of fatigue occurrence and risk factors of severe fatigue in breast cancer survivors. The tools used for fatigue assessment were highly heterogeneous, sometimes with several different thresholds for the same tool. The overall frequency of fatigue was 27% with a wide range of values 7 to 55%) and a large decrease in this frequency in the first 6 months after treatment completion. The strongest risk factor for severe fatigue was an association of surgery, radiotherapy, chemotherapy and hormonal treatment ; this was followed by the association of surgery, radiotherapy and chemotherapy ; surgery and radiotherapy ; and surgery only  5% and a . In addiIn the adjuvant setting, 34 regimens were identified; data on fatigue (any-grade and/or grade 3 or more) were reported for 25 of these, and data specific to older patients were reported for 3; 32 concerned chemotherapies with or without targeted treatment regimens, and 2 concerned adjuvant hormonal treatments . In the 2 of docetaxel (15 to 24%) and gemcitabine vinorelbine (24%); in the metastatic context and according to the 5th advanced breast cancer conference guidelines, this highlights the need to favor monotherapy in such patients [2 schedule. For hormonal treatments alone, the rates of any-grade fatigue varied greatly between studies; “lethargy” was estimated to be 1% for anastrozole and 3% for tamoxifen in older reports [In the metastatic setting, 48 regimens were identified; data on fatigue (any-grade and/or grade 3 or more) were reported in all but 4 of them; 32 concerned chemotherapies with or without targeted treatment regimens or antibody–drug conjugates, 5 hormonal treatments alone, 9 hormonal treatments associated with targeted therapies and 2 targeted therapies only. In the chemotherapy with or without targeted treatment subgroup of regimens, any-grade fatigue rates (when reported) were highly variable, ranging from 10% for ixabepilone to up to 35 to 54% for eribulin and 60% for metronomic docetaxel capecitabine—two regimens proposed in late lines of treatments. Data were more frequently available for grade 3 or more fatigue than for any-grade fatigue; rates were very low (2%) for pertuzumab + trastuzumab + paclitaxel or nab-paclitaxel (PERUSE study ) and trapatients , and, wh reports ; from 11 reports ,31,83,84 reports ; and fro reports ,88,89,90 reports ). Finall reports ); the BA reports ; finally reports .In contrast to breast cancer, fatigue has been historically poorly evaluated during for ovarian cancer treatments, with the risk/benefit ratio of chemotherapy considered to be largely beneficial, at least as first-line treatment. Again, in contrast to breast cancer treatments, the impact of age on cancer treatments has been by far more explored. In addition, there is greater awareness of the management of targeted treatments in older patients with this disease that is shared by both clinicians and the pharmaceutical industry, which is well-illustrated by the publication in 2019 of a review paper of the Young International Society of Geriatric Oncology (SIOG) reporting several subgroup analyses of pivotal trials according to age; nevertheless, the authors highlighted that these populations remain selected and appealed for specific trials to be conducted in older patients .Considering first-line chemotherapy, 17 different regimens were identified, including the maintenance regimens with bevacizumab with or without PARPi . Data onConsidering platinum-sensitive relapse, 10 regimens were included in the analysis, and data on fatigue were available in all but 2 of them. Any-grade fatigue varied from 28% to 62%, with higher rates in PARPi maintenance regimens , and 32% for w-topotecan) and for grade 3 or more fatigue  was found to more than double the respective rates of any-grade fatigue (33% vs. 14%) and grade 3 or more fatigue (3% vs. 1%) .2/3w led to significantly higher frequency of any-grade fatigue from 20% to 74% and grade 3 or more fatigue from 1–4% to 4–7% [In the metastatic castration-sensitive setting, and with the exclusion of the meta-analysis conducted by Langston et al.  who did  to 4–7% ,146.2), but the frequency of grade 3 or more was the same (5%) [2 regimen to a 25 mg/m2 regimen did not evaluate fatigue as a significant adverse event [In the metastatic castration-resistant setting, the first indication in which next-generation antiandrogens were historically developed, abiraterone acetate poorly impacted fatigue rates compared to ADT only, as in the castration-sensitive setting, but the basal rates were probably due to the cancer itself: any-grade fatigue rates reached 44% (vs. 43%) after docetaxel (COU-AA-301 study) and 39% (vs. 34%) in chemo-naive patients (COU-AA-302 study) ,149. Coname (5%) ; surprisse event . Under Rse event . Olaparise event .2/carboplatin AUC6 regimen (10%) [When considering urothelial cancers, data on fatigue occurrence under standard treatment were sparse . Among fen (10%) , but no en (10%) . In the en (10%) ; vinflunen (10%) . In the en (10%) .Contrary to other tumor models, fatigue has been assessed in studies investigating colorectal cancer for many years in both adjuvant and metastatic settings . In the 2 5-min intravenous bolus, and fluorouracil 2240 mg/m2 46-h intravenous infusion; Cap: capecitabine 1000 mg/m2 orally twice per day on days 1–15 of each 21-day cycle; OxFU: previous FU regimen with the addition of oxaliplatin 68 mg/m2 by 2-h intravenous infusion concurrent to levofolinate; CapOx: previous Cap regimen with the addition of oxaliplatin 104 mg/m2 2-h intravenous infusion every day 1 of each 21-day cycle); oxaliplatin addition had no impact on the frequency of grade 3 or more lethargy , but a trend towards a higher frequency was found with the replacement of FU by capecitabine  [In the metastatic setting, however, reported rates of severe fatigue with the oxaliplatin and 5-FU derivatives (5-FU/leucovorin or capecitabine) reached almost 10% and even higher in older populations  . When co = 0.06) ,209,212  = 0.06) ,214,215. = 0.06) ,194,195. = 0.06) ,208,209, = 0.06) ,211, and = 0.06) ). Data r = 0.06) ), but st = 0.06) ,220,222. = 0.06) ,189 and  = 0.06)  but reac = 0.06)  and even = 0.06) .When considering the trifluridine–tipiracil (TAS-102) ± bevacizumab, the frequencies of fatigue were also heterogeneous; any-grade fatigue ranged from 24 and 85%, illustrating the high level of chronic fatigue, independently of the treatment, in later lines ,228,229.In the field of targeted therapies, beyond bevacizumab and cetuximab, regorafenib was associated in later lines with a manageable tolerance, including fatigue, in the CORRECT pivotal trial ; however2) was historically between 9% and 15% [2 every 3 weeks) [In the context of non-small cell lung cancer, a shift in the assessment of fatigue was observed with the advent of modern treatments—firstly targeted therapies and then immunotherapies—in parallel with the major impact that these had on overall survival rates . Classic and 15% ,233, whe and 15% ,235 and 3 weeks) , and niv3 weeks)  appear tn = 13), and data specific to older adults were reported for 1 only [Considering small cell tumors and given the age of the majority of available trials, potentially as well as the poor prognosis of the disease, data on fatigue have been sparse and limited to the most recent studies. Of the 26 regimens studied, data on fatigue were reported in half of them , particularly in association with rituximab (13 to 23%) ,302,303.This scoping review is, to our knowledge, the first to provide oncologists and oncogeriatricians with a simple and easy-to-understand summary of the level of information available on fatigue, either in general or in older populations, associated with the different treatment regimens proposed for the most prevalent tumors. Such information may enrich the shared decision process of patients and their families, as well as induce guided intervention to prevent fatigue occurrence as soon as care programs are established.From a historical point of view, this work highlights the continuous increase in fatigue assessment in relationship with the evolution of patients’ expectations regarding a better consideration of their quality of life. This point is even more important in the oncogeriatric context, when overall survival is compromised due to cancer or other causes of death. It additionally highlights that this consideration is also dependent on the tumor model, the setting, and the modality of treatment. Notably, a higher consideration was observed for maintenance or continuous treatments compared to treatments of a shorter duration, such as adjuvant treatment for breast cancers and colon cancers. The concept of cancer survivorship, notably in the context of breast cancer, has shed light on the importance of long-lasting fatigue after chemotherapy cessation in general, but little is known on the differential impacts of individual regimens on this.This work has several limitations linked to its conceptualization, which led us to consider information published over a very long period during which there were changes not only in the tools used to assess fatigue  bThis scoping review provides oncologists and oncogeriatricians a simple and easy-to-understand summary of the level of information available on any-grade fatigue and grade 3 or more fatigue for each cancer treatment regimen, either in general or in older populations, for the most prevalent tumors. Despite probably being incomplete due to the very large contours of such a review, it may provide additional information for practitioners when conducting risk/benefit ratio discussions with their patients.


Calophyllum soulattri leaves extract (CSLE) on high fat diet-fed rats (HFD) and to predict the molecular docking and pharmacokinetics of selected compounds of Calophyllum soulattri to fat mass and obesity-associated protein (FTO). Daily body weight, organ, carcass fat , body mass index, total cholesterol, and total triglyceride levels were observed after CSLE was given orally for 50 days. Furthermore, body mass index of a CSLE dose of 50 mg/kgbw, 100 mg/kgbw and orlistat (120 mg/kgbw) group are 0.68, 0.57 and 0.52, respectively. The total body weight of the CLSE dose of 100 mg/kgbw group showed the lowest percentage change, followed by a CLSE dose of 50 mg/kgbw compared to the normal and positive control group. The carcass fat index of CSLE dose of 100 mg/kgbw was not significantly different from orlistat, which was in line with its total cholesterol level and triglyceride (p < 0.05). The binding affinity of selected compounds from Calophyllum soulattri  to FTO are –8.27, –9.74, –8.48, –9.34, –8.85, –8.68 and –9.39 kcal/mol, which are better than that of orlistat at –4.80 kcal/mol. The molecular dynamics simulation showed that the interaction between Caloxanthone B compounds and obesity receptors was relatively stable. Lipinski’s rule determined the absorption percentage of all compounds above 90% with good drug-likeness. The results showed the potential of CSLE as an antiobesity drug candidate.This study aims to determine the antiobesity activity of  The prevalence of obesity and metabolic disorders has increased worldwide, associated with an unhealthy lifestyle, such as excessive fast food consumption and low level of physical activities ,2. The WCalophyllum soulattri is an endemic plant in Indonesia, and its leaves extract is commonly used for the treatment of obesity containing several secondary metabolite compounds, including flavonoid, steroid, triterpenoid, phenol, tannin, and saponin [Calophyllum soulattri leaves extract, where this compound was assumedly involved in the hypolipidemic activity of Azima tetracantha Lam. In rodent hyperlipidemia experimental models [Calophyllum soulattri showed a good effect as an antihyperlipidemic candidate through its secondary metabolites, confirmed by the recent in vivo study on male Wistar rats [Calophyllum soulattri with good antioxidant ability, including friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, lambkinaxanthone, and brasixanthone B, are known to exhibit potential antiobesity properties [Calophyllum soulattri leaves extract revealed no mortality or observed clinical signs of toxicity during investigation periods with LD50 > 5000 mg/kgbw, but hepar necrosis was associated with the long-term use of high-dose CSLE, such as 1000 mg/kgbw transaminase. Moreover, the reported dose of Calophyllum soulattri leaves extract was between 100 and 400 mg/kgbw with no adverse effects appearing from long-term use [Calophyllum soulattri as antiobesity agents. Therefore, this study aimed to use an in vivo and in silico combined approach to investigate the potential antiobesity activity of Calophyllum soulattri. The antiobesity effects of the ethanolic extract leaves was evaluated on high-fat diet-fed rats (HFD). The interactions between selected potential compounds and obesity-associated protein (FTO) as the target receptor for antiobesity drugs were predicted by molecular docking simulations. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME), toxicity and drug-likeness predictions were also determined. saponin  Friedelil models ,11 Caloptar rats . Moreoveoperties ,14,15. Aterm use . There aCalophyllum soulattri leaves (CSLE) are shown in The specific and non-specific parameters results of the 96% ethanolic extract of The non-specific parameters of CSLE, including density extract, drying losses, and water content, have been performed as well, with values of 0.8033 g/mL, 16.32 ± 0.66% and 12.76, respectively . The IndCalophyllum soulattri leaves contained alkaloids, polyphenols, flavonoids, steroid-triterpenoids, and saponins , Log P, the number of hydrogen donors (H donors) and acceptors (H acceptors). Based on these parameters, as shown in Calophyllum soulattri have a better binding affinity than orlistat as a positive control, with the lowest ΔG shown by caloxanthone B , where the compound with the lowest ΔG value was predicted to have the strongest and most stable binding to the receptor. Molecular docking results showed that the seven compounds in nthone B . MoreoveCalophyllum soulattri, including their water solubility, intestinal absorption, volume of distribution, total clearance, and the prediction of their toxicity, including general toxicity (LD50) and specific toxicity (AMES toxicity test and hepatotoxicity). Overall, an intestinal absorption value above 90% was shown by all selected compounds. Based on the AMES toxicity results, four compounds are predicted to be mutagens, such as caloxanthone B, macluraxanthone, dombakinaxanthone, and brasixanthone B, but further in vivo tests are required. However, the prediction of hepatotoxicity test showed that most of the compounds are not toxic, except for dombakinaxanthone. The prediction of pharmacokinetic and toxicity parameters was performed based on the similarity of the chemical structure of the predicted compounds to the chemical structure contained in the pkCSM-Biosig Lab. These predictions provide a basis for analysing pharmacokinetic and toxicity parameters based on seven potential compounds in Calophyllum soulattri.Calophyllum soulattri leaves extract (CLSE) was performed to fulfil the requirements as a herbal raw material [The standardization of specific and non-specific parameters of material . It was Chromatogram patterns were also standardized as specific parameters. In contrast, chemical content can be detected under UV wavelengths of 254 nm, but only under UV wavelengths of 366 nm, as shown in Tilapia mossambica in one hour [The foaming index was demonstrated to determine the capability of an extract to produce foam. In contrast, the fish index was obtained by the ability of the most diluted extract to kill three of five one hour . The foaA high-fat diet (HFD) induction was given to induce the body weight of rats as the obese animal model used and to increase the total blood cholesterol and triglyceride value. BMI measurement was calculated on the same day before termination. Results for BMI can be seen in p < 0.05). The results demonstrated that BMI for all groups on day 0 was not significantly different (p < 0.05) and was classified as normal with a BMI range of 0.49 to 0.50. However, a BMI increase was observed in all groups on day 50, after 50 days of HFD induction and 20 days of treatment. The BMI of the orlistat group has the lowest value (0.52), while the negative control given HFD induction for only 50 days without any treatment has the highest value (p < 0.05). Therefore, the doses of CSLE can inhibit the increase of BMI in animals with HFD induction. The body weights of rats were observed each day during the HFD induction period from day 0 to 50  and CSLE dose 100 mg/kgbw on day 50 . This suggests that both doses of CSLE can inhibit the increase of body weight in animals with HFD induction.The normal control group showed up to 33.98% of initial body weight, whereas the negative control increased to 54%. The orlistat group had an increased percentage of body weight of up to 27.77%, but in line with the BMI results, CSLE doses of 50 mg/kgbw and 100 mg/kgbw showed a lower percentage change in body weight, at 28.59% and 24%, respectively. The result indicates that CSLE doses can inhibit the weight increase induced by HFD. However, these values were not significantly different compared to the positive control groups . The results confirm that a CSLE dose of 100 mg/kgbw can decrease renal and anal fat deposits.As an antiobesity agent, orlistat plays a role in reducing fat absorption, which can minimize animal fat storage better than the normal group, as shown in p < 0.05). This is probably because of the lipase inhibition activity of orlistat and CSLE as enzymes involved in lipid hydrolysis, resulting in decreased total cholesterol and triglyceride levels. The results show the potential effect of CSLE in lowering total cholesterol and triglyceride levels compared to orlistat as a positive control. The total cholesterol and triglyceride levels were observed before the drug treatment (day 30) compared to the last day as can be shown in Cholesterol and triglycerides are lipids that circulate in large amounts in the blood that are bound to phospholipids and lipoproteins that dissolve in water and can be carried throughout the body. Increased lipids in the blood may cause hyperlipidemia and abdominal fat accumulation . High leCalophyllum soulattri. These include friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, dombakinaxanthone and brasixanthone B to fat mass and obesity-associated protein (FTO), with their pharmacokinetic prediction. These seven compounds were selected based on a previous study related to the phytochemical determination of Calophyllum soulattri that has been established and was provided in the Pubchem data bank [This section will illustrate the molecular docking of selected potential compounds of ata bank ,15,28,29Re-docking was also performed to validate the docking protocol. It showed that the RMSD value of native ligands on the crystal structure of FTO (PDB ID: 3LFM) was 1.62, implying that the specified docking parameters can be used, since the value is lower than 2 . FurtherCalophyllum soulattri are predicted to have drug-likeness. The docking results of these compounds chosen to fat mass and obesity-associated protein (FTO) using Autodock 4.2 are exhibited in Based on these data, the selected compounds contained in the star parameters were similar to those in the positive control, where molecular weight (<500), hydrogen donor (<5), and hydrogen acceptor (<10) complied with Lipinski’s rule. Therefore, the selected potential compounds from Calophyllum soulattri was lower than that of native ligand and Orlistat. Therefore, it is predicted that these selected compounds have a stronger binding interaction to FTO compared to those of native ligand and orlistat. Caloxanthone B shows the best binding affinity and inhibition constant based on the molecular docking simulation. The binding affinity value explains the strong interaction of these compounds with the receptor [Calophyllum soulattri compared to positive controls from Orlistat is illustrated in Based on the docking results, the binding affinity of all selected potential compounds of receptor . The resThe molecular dynamic was performed during 100 ns of time simulations with the addition of various parameters adjusted to actual body conditions, such as temperature set to 310 K and the presence of solvent. Furthermore, pharmacokinetic and toxicity parameters based on in silico predictions for each selected compound can be seen in G△) was determined from the total of all energy components  were collected from the Mandor region, West Kalimantan Province, Indonesia, and authenticated in the Biology Laboratory of the Mathematics and Science Faculty of Universitas Tanjungpura. CSL was washed to clean any materials left in the leaves and was dried for 2 days. Dry sortation was performed to remove unwanted materials. Subsequently, the leaves were powdered using a blender and stored in a dry and well-ventilated area away from direct sunlight. CSL was extracted by continuous extraction using a Soxhlet apparatus with 96% ethanol. Ethanol was used since it is considered as a universal solvent that may attract the potential compounds of the plants evaluated, and this solvent is appropriate for continuous extraction using the Soxhlet apparatus as well. Compared to other solvents, 96% ethanol is safer to use. After exhaustive extraction, the collected extract was dried under reduced pressure using a rotavapor and dried in a water bath [ter bath . 254 nm and λ366 nm of UV light. Organoleptic, yield percentage, water and ethanol solubility, loss on drying and density of extracts were also determined as non-specific parameters [Phytochemical screening was performed to detect the presence of alkaloids, steroids, triterpenoids, flavonoids, tannins, quinones, and saponins. The extract was screened by the TLC method using a selected mobile phase n-hexane and ethyl acetate combination at the ratio of 7:3, with the observation performed under λrameters .The foam forming capability of powdered CSL is measured in terms of the index. One gram of powdered CSL was diluted in 100 mL of water, heated for 30 min, and then filtered. Furthermore, 10 tubes were prepared, and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 mL of diluted suspension were put into the test tubes, after which 10 mL of water was added into each tube. The test tubes were shacked for 15 s with two strokes per second and were observed for 15 min. The foam index is considered as <100 when the foam layer is <1 cm in the test tube. In addition, the index is considered >1000 when the foam layer is ≥1 cm in the test tube; therefore, further dilution was required. The foaming index is calculated as follows when the foam is more than or equal to 1 cm in the test tube in the most diluted solution (1)FoamiTilapia mossambica with a 2–4 cm length was used as a fish test subject [A stock solution of 2% was prepared by diluting 4 g of powdered CSL into 200 mL of water and was heated for 30 min. A solution of 1%, 0.5% 0.25%, 0.1% and 0.05% were prepared by adding 50, 25, 12.5, 5, 2.5 mL of stock solution into 100 mL of water. The fish index value was measured by determining the most diluted solvents that kill three of five fish in an hour.  subject ,14,38.Rats were acclimatized for 7 days, and the healthy ones without any physical defect were included as animal subjects. Rats were grouped into 5 groups consisting of normal control (chow and water only), positive control (120 mg/kgbw of orlistat), negative control (Carboxymethylcellulose Sodium or CMC Na 1%), CSLE dose 1 (50 mg/kgbw of CSLE), and CSLE dose 2 (100 mg/kgbw of CSLE). Chows of B2 (551) with quail eggs and cattle fat were orally used as a high-fat diet (HFD) induction. Furthermore, the induction with HFD started on day 1, except for rats plotted into normal groups. The CSLE and Orlistat were administered orally. Treatments were given after 30 days of chow, water and HFD feeding and continued for 50 days before termination. p-value of 5% (p < 0.05). The protocol was peer-reviewed by the Animal Ethics Committee of the Faculty of Medicine of Universitas Tanjungpura with an ethical clearance number of 588/UN22.9/TA/2021 [Rats were fed 20 g of chow daily with water supply ad libitum for 50 days. However, CSLE was diluted in CMC Na 1% and was administered orally to the animal model for 20 days at 50 mg/kgbw and 100 mg/kgbw. Orlistat, as the comparative drug, was given at a dose of 120 mg/kgbw for 20 days. Parameters observed included rat body mass index, body weight, organ index, carcass fat index, blood triglyceride and total cholesterol value. All animal subjects were sacrificed after 50 days of experiments. Fat around the kidney and the lower area was measured for perirenal and perianal fat index determination. The pancreas, kidney, spleen, liver, heart and lungs were measured for organ index determination. Colourimetric data were used for the determination of blood triglyceride and total cholesterol value. Data are expressed as mean ± standard deviation (SD) for each group and statistically analyzed with a one-way analysis of variance (ANOVA). All analyses and comparisons were evaluated at a /TA/2021 .Calophyllum soulattri, such as friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, dombakinaxanthone and brasixanthone B, with orlistat as a comparative drug, to fat mass and obesity-associated protein (FTO) were analyzed and visualized using Autodock 4.2 software and Discovery Studio 2021. DOI for the FTO PDB DOI: 10.2210/pdb3LFM/pdb accessed on 12 November 2021. The ligands were accessed in https://pubchem.ncbi.nlm.nih.gov/ on 3 November 2021. The three-dimensional structure of the target FTO receptor (PDB ID: 3lfm) was obtained from the RSCB protein data bank. Selected compounds were obtained from the PubChem website to obtain a three-dimensional structure in pdb format. Active site detection, docking and analysis of the bound receptor amino acids was carried out using the Autodock computer program  with the help of AutoDockTools version 1.5.6 performed on the potential active site (cavity) detected at the FTO receptor via ligand natively bound in the receptor structure. Assessed energy involved via Gibbs free energy . The initial stage for molecular docking is redocking the native ligand before docking the compound to be tested. Redocking was performed to validate that the selected docking parameters are appropriate and can applied for the compound to be tested. The criteria for the overlapping RMSD value of redocking results that meet the standard are less than 2 A [Molecular docking of the selected potential compounds of than 2 A . The docthan 2 A .https://biosig.lab.uq.edu.au/pkcsm/prediction accessed on 15 January 2022 [The parameter analysis of each compound, including absorption, distribution, metabolism, excretion, and toxicity were predicted with the pkcsm. Molecules input data for prediction through pkcsm with smiles format was then entered and analyzed on the website ary 2022 .+ ions for neutralization if the charge is negative and Cl– ions for neutralization if the charge is positive. The results of the molecular dynamic simulation were then visualized and analyzed using UCSF Chimera and BIOVIA Visualizer 2021. An RMSD analysis was carried out to observe the stability of the ligand-receptor interaction over time. The calculation of the value of Gibbs free energy was carried out using the Molecular Mechanis Poisonn-Boltzmann Surface Area (MM-PBSA) method. Calculations were performed on 1000 frames in the last 10 ns [The best molecular docking compounds were then further analyzed by molecular dynamics to determine the stability of the compound binding to the FTO receptor by providing external factors that exist in the body using Amber16 software. Factors that are regulated on the molecular dynamics include pH adjusted to body pH, which is 7.4, the body temperature is 37 °C, the addition of solvent and ions in the body and the duration of the interaction is set to 100 ns simulation. The initial stage for dynamic molecular simulation is the preparation of ligands and receptors. The FTO receptor is formatted according to the Amber16 program. The best compound from docking and positive control of orlistat was optimized by geometry using the method contained in the Amber16 program. The results of the data from the analyzed molecular dynamics are the Gibbs free energy obtained using the MMPBSA method and the RMSD graph. Parameterization used the AMBERff14SB force field for proteins, while the ligand parameterization was carried out using the AMBER force field (GAFF). The preparation stage includes the minimization stage, heating to a temperature of 310 K, temperature equilibration, pressure equilibration, and continuation with the simulation process. The simulation process (production run) was carried out with a timestep of 2 fs for 100 ns. In the dynamic molecular simulation, the water model used is TIP3P and the system is neutralized by adding Nast 10 ns ,44,45.Calophyllum soulattri binding to fat mass and obesity-associated protein (FTO) showed that caloxanthone B has the best affinity compared to those of native ligand and Orlistat. These selected compounds also have a drug-likeness compared to orlistat based on Lipinski’s rule, with the prediction of absorption in the intestinal tract being more than 90%.The metabolite compounds in CSLE were alkaloids, flavonoids, polyphenol, terpenoids, and saponins. CSLE may inhibit the increasing BMI, body weight percentage, anal carcass fat, and total blood cholesterol with the best activity shown by the dose of 100 mg/kgbw but does not affect the triglyceride levels. The molecular docking and molecular dynamic simulations of the selected potential compounds of


Salmonella enterica constitutes a global public health concern as one of the main etiological agents of human gastroenteritis. The Typhimurium serotype is frequently isolated from human, animal, food, and environmental samples, with its sequence type 19 (ST19) being the most widely distributed around the world as well as the founder genotype. The replacement of the ST19 genotype with the ST213 genotype that has multiple antibiotic resistance (MAR) in human and food samples was first observed in Mexico. The number of available genomes of ST213 strains in public databases indicates its fast worldwide dispersion, but its public health relevance is unknown. A comparative genomic analysis conducted as part of this research identified the presence of 44 genes, 34 plasmids, and five point mutations associated with antibiotic resistance, distributed across 220 genomes of ST213 strains, indicating the MAR phenotype. In general, the grouping pattern in correspondence to the presence/absence of genes/plasmids that confer antibiotic resistance cluster the genomes according to the geographical origin where the strain was isolated. Genetic determinants of antibiotic resistance group the genomes of North America  strains, and suggest a dispersion route to reach the United Kingdom and, from there, the rest of Europe, then Asia and Oceania. The results obtained here highlight the worldwide public health relevance of the ST213 genotype, which contains a great diversity of genetic elements associated with MAR. Salmonella enterica is one of the main pathogens associated with food contamination; it is considered responsible for around 94 million cases of gastrointestinal illnesses and 155,000 annual deaths worldwide [S. enterica for nearly 90 years is serotyping [orldwide ,3. The trotyping . The Typrotyping ,8. Howevrotyping ,11. Thisrotyping ,13,14.S. enterica, multi locus sequence typing (MLST) for the assignment of sequence type (ST) through variations in seven loci efficiently identify clonal groups and founder genotypes [S. enterica and detecting the emergence of variants of relevance in the field of public health [S. enterica emerging pathogenic variants.Among the genotyping methods used as epidemiological tools for the study of enotypes ,16. Receenotypes ,18,19, eenotypes ,21,22. Tc health . Beyond c health ,26,27,28S. enterica Typhimurium is ST19, as the most prevalent genotype of this serotype around the world from which the vast majority of other STs have been derived [MLST analysis has clearly established that the founding genotype of  derived ,16. Howe derived ,29. The  derived ,31.In Mexico, a study on clinical and food samples carried out for four years in different states of the country revealed evidence of the replacement of ST19 by ST213 . SubsequS. enterica [It has been documented that bioinformatic genomic analysis allows the robust prediction of phenotypic resistance to antibiotics in enterica ,36. Thann = 64) came from the United Kingdom, 25.9% (n = 57) came from Mexico, 24.5% (n = 54) came from the United States of America, and 9.5% (n = 21) came from Canada, while the remaining 11% (n = 24) were obtained from nine different countries, mainly from Europe  of the strains were obtained from human clinical samples, 15% (n = 33) were obtained from samples of animal origin, and the remaining 15% (n = 33) were obtained from nine other sources in smaller percentages -Iaa, golS, mdsA, mdsB, mdsC, mdtK, and sdiA are present in the 220 (100%) genomes analyzed. The genes aac(3)-IV, aph(3)-IIa, aph(4)-Ia, CARB-3bla, catII, cmlA1, dfrA1, linG, mefB, qnrA1, qnrB19, qnrS1, tetM, and tetU were found in <1% of the genomes studied. The aadA5, ant(3)-IIa, aph(3)-Ia, TEM-1bla, dfrA17, qnrB5, sul1, tetB, and tetC genes were found in between 1 and 15% of the genomes included in this study, while the aac(3)-IId, aadA2, CMY-59bla, dfrA12, floR, oqxA, oqxB, qacH, sul2, and sul3 genes were identified in 20% to 40% of the study genomes. Finally, the aph(3)-Ib, aph(6)-Id, tetA, and tetR genes were found in 50–57% of all the analyzed genomes _1_Kpn3 plasmids were present in all the genomes of all the sample types analyzed here. Plasmids IncP1 and IncQ1 were only found in strains of samples of animal origin, while plasmids Col(BS512), IncFIC(FII), IncFII(pCTU2)_1_pCTU2, IncI2, IncI2_1_δ, IncX4, pESA2, pSL483, and rep14a_4_rep(AUS0004p3) were identified only in strains obtained from human clinical samples. In the case of the plasmids Col(MG828), Col440II, IncFIA, IncFIB(AP001918), IncFII, IncFII(pCoo)_1_pCoo, and IncX, these were found in genomes whose strains came from samples of both animal and human origin. Plasmids IncHI1A and IncHI1B(R27)_1_R27 were identified in strains from samples of animal and undefined origin, while Col156 and ColpVC were found in strains of animal and human origin as well as in food samples. Plasmid IncFIA(HI1)_1_HI1 was only found in strains from undefined samples; IncI_γ_1 was found in strains of animal, human, and undefined origin; and Col440I was not found in the genomes of food-associated strains. Plasmids IncFIB(S), IncFII(S), IncHI2A, IncHI2, and IncI1_1_α_1 were not identified in strains identified from water samples. On the other hand, the plasmids IncFIC(FII), IncI2_1_δ, pESA2 rep14a_4_rep(AUS0004p3), and IncFII(pCTU2)_1_pCTU2 were identified in the genomes of strains isolated in Mexico; pSL483 was identified only in strains from Canada; IncI2 was identified only in strains from the United Kingdom, and Col( BS512), IncFIA(HI1)_1_HI1, IncFIA, IncP1, and IncQ1 were identified only in strains from the United States. Plasmids IncX4 and IncI_γ_1 were found only in the genomes of strains from the United States and the United Kingdom; IncFII was found only in strains from Canada and the United States; and IncFIB(AP001918), IncFII(pCoo)_1_pCoo, IncHI1A, IncHI1B(R27)_1_R27, IncHI2, and IncHI2A were identified only in strains from Mexico and the United States. In the case of the Col(MG828) and IncX plasmids, they were identified in strains from Canada, Mexico, and the United States; Col156 and Col440II in strains from Canada, the United States, and the United Kingdom; ColpVC were identified in strains from Mexico, the United States, and the United Kingdom; Col440I and IncFIB(K)_1_Kpn3 were identified in strains from these three North American countries and the United Kingdom; and ColRNAI and IncC were identified in strains from North America, the UK, and Australia. Finally, the IncI1_1_α_1 plasmid was not found in strains from Australia, France, India, Ireland, the Netherlands, or Portugal, and the IncFIB(S), IncFII(S) plasmids were not present in the genomes of strains from Mexico and Portugal.When the presence/absence of resistance genes in the study genomes is used as a matrix for the generation of clustering patterns, interesting groups can be observed in relation to the country and the sample of origin of the strains. The presence of resistance genes brings together the strains from the three North American countries , as well as those from the United Kingdom and Australia. Mexico and the United States appear together in a subcluster while Canada, the United Kingdom, and Australia are grouped in another branch . In the Regarding the grouping pattern created by the presence/absence of resistance genes from each individual genome/strain, it can be seen that two larger clusters are clearly defined . The firThe plasmid replicons presence/absence grouping pattern shows a similar pattern to that observed for previously described resistance genes. Genomes of countries from North American  strains shape the first big cluster, with one strain from the UK and one from Australia  samples. Thus, such a grouping pattern suggests that ST213 human strains are mainly acquired from farm animals and food and/or interchange some genetic subset(s) with strains from these sources. This hypothesis is consistent with reports of the frequent zoonotic transmission of non-invasive Typhimurium serotype strains in Mexico ,53, CanaAll antibiotic resistance genes detected in the ST213 strains genomes analyzed were predominantly relevant in the North American countries. In the same way, all the resistance genes/mutations were present predominantly in human samples. Both regional and sample type predominancies can be partially explained by the overrepresentation of genomes from strains at regional and sample levels. Furthermore, Mexico or North America are the probable origin of the ST213 as an emergent/reemergent pathogen of global health relevance. Thus, the discussion highlights results for North America and the human ST213 genomes. The ST213 genomes harbor a great diversity of genetic determinants for antibiotic resistance, and the gene/mutations/plasmid replicon combinations per genome are also diverse. The genetic determinants to resistance against quinolones and aminoglycosides are relevant because the World Health Organization classifies them as critically important antimicrobials which are the “Sole, or one of limited available therapies, to treat serious bacterial infections in people”, along with other relevant criteria . qnr and oqxAB genes associated with quinolone resistance are mainly related to plasmids [qnr genes were absent in Typhimurium strains of animal origin [oqxAB genes found here have also been previously reported for several serotypes of human isolates in Mexico [S. enterica strains in the USA, although in this country it has been documented the presence of genes conferring resistance to such antimicrobial compounds in the serotype Typhimurium strains coming from clinical, pork meat, and livestock samples [qnrB and qnrS genes were recently reported in ciprofloxacin-resistant human clinical strains of different serotypes of S. enterica, including Typhimurium, and the oqxAB gene has rarely been found [gyrA) and topoisomerase IV (parC) [gyrA and S80I in parC is interesting, since S. Typhimurium mutations in gyrA, in addition to playing a dominant role in resistance to fluoroquinolones, have a synergistic effect with other resistance mechanisms, while the S80I mutation in parC appears to have no effect on quinolone resistance without gyrA mutations [S. enterica isolated strains of different serotypes in Mexico [The plasmids ,60. Despl origin ,62, but l origin . The oqxn Mexico ,62. Resi samples ,65,66,67en found . Regardiutations . Whereasn Mexico , it appen Mexico ,71.S. enterica, with this species being relevant as a carrier and potentially a means of transfer to other pathogenic bacteria [S. enterica to Escherichia coli, a mobilizable element that carries multiple resistance antibiotics genes, has been experimentally demonstrated [S. enterica strains isolated from farm animals in the USA, showing the geographical variations in its incidence [In relation to aminoglycoside resistance, the ST213 genomes carry the genes coding for the three types of modifying enzymes . Howeverbacteria . The transtrated . It has nstrated . Around nstrated  Additionncidence .sul2 and sul3 predominate over the most frequently reported sul1. Additionally, the genomes carry three modifications of the dihydrofolate reductase enzyme for resistance to trimethoprim, of which dfrA12 predominates. Although three genes that confer resistance to phenicols in the ST213 genomes are also present, the most widely distributed is the efflux bomb-coding gene floR. The strains of the Typhimurium serotype isolated from different sources show high percentages of resistance to these three types of antibiotics [In the case of tetracycline, sulfonamides, and phenicols, these antibiotics are considered by the WHO in the category of highly important antimicrobials, fulfilling the same first criterion of the previous antimicrobials but not adding more criteria . The sixibiotics .aac(6′)-Iaa, mdsA, mdsB, mdsC, golS, sdiA, and the majority carried the qacH gene. The aac(6’)-Iaa gene for aminoglycosides resistance resides in the chromosome of Typhimurium strains and is present in the ancestral ST19 genotype [mdsA, mdsB, and mdsC code for the transporter efflux pump mdsABC golS, a promoter that is related to resistance to novobiocin [sdiA gene codes for a quorum-sensing regulator that mediates the multi-drug resistance AcrAB efflux pump [qacH gene codes for an efflux bomb that confers resistance to the quaternary ammonium compounds, commonly used organic disinfectants [Besides all the previously commented resistance genes, all the analyzed genomes harbor genotype . The genvobiocin , And it vobiocin . The sdilux pump , the ovefectants . This laS. enterica ST213 strains carrying resistance genes that can be transferred to other pathogenic bacteria or directly to humans [All the antibiotics mentioned above are relevant for their use in veterinary and human medicine ,84. The o humans . The divS. enterica North American ST123 strains from the US, Mexico, and Canada harbor 32 of the 33 plasmids, in contrast to the reduced variation in genomes of strains from Europe, but the low number of ST213 strains from Asia and Australia makes comparison difficult within these regions.In this work, 33 different plasmids were bioinformatically identified in the genomes of ST213 strains from around the world. Inc-type plasmids were found in 207 strains, while Col-type plasmids in 103; pESA2, pSL483 and rep14a_4_rep were found in a single strain each. The genomes of S. enterica serotypes, including Typhimurium, which together carry genes for all kind of antibiotics, some of which can be within an integron [S. enterica strains from Asia [qnrS1 and qnrB19 [aph(3″)-Ia in bovine strains [The Inc  conjugative plasmids found in the analyzed genomes are frequently reported in different integron ,38. The rom Asia , Europe rom Asia , and Sourom Asia  for the rom Asia . In addirom Asia , ColpVC,rom Asia ,91, and rom Asia ,92 have d qnrB19 , and spe strains . The Inc strains ,38. Enterococcus faecium; thus, it must be considered to have a narrow host range [E. faecium is associated with tetracycline resistance in strains isolated from human clinical samples, and it has been stated that such plasmids cannot be transferred by conjugation. This intriguing finding indicates the existence of a horizontal gene transfer (HGT) mechanism between E. faecium and S. enterica, which, to the best of our knowledge, has not previously been suggested. Further data on the plasmid sequence are needed to corroborate this result, and it will be relevant to analyze the HGT mechanism between the involved species.The presence of the replicon rep14a_4_rep(AUS0004p3) is surprising because this plasmid belongs to a three-membered family of small mobilizable plasmids only described in the Gram-positive species st range . FurtherS. enterica to humans. Further work is needed to analyze a possible positive relationship between the type of sample and the presence/absence of a particular type of plasmid. Additionally, it is important that further studies define whether there is any significant relationship between the presence of these plasmids and the geographical region of origin of the ST213 strains, as well as its public health consequences.The diversity of plasmid replicons found in the ST213 genomes indicates that such genotypes can be prone to the horizontal gene transfer (HGT) of antibiotic resistance genes. The plasmid diversity and distribution in the genomes analyzed here indicates that the plasmid interchange in ST213 strains features different dynamics between North America and Europe, apparently being more dynamic in the former region. Several plasmid replicons were found in the genomes of ST213 strains from all types of samples but showed different rates of incidence. However, most plasmids are present in samples related to the well-established zoonotic/food transmission chains of S. enterica or are in the process of doing so [It is important to consider that one of the weaknesses of the present study is that the analyzed genomes did not come from a systematic program based on the random sampling of strains. All ST213 genotype genomes available in public databases, of good quality, and with adequate metadata were analyzed. Thus, the trends and rates of prevalence reported here are the result of various factors, including the study of specific outbreaks by country as well as the capacity for genomic sequencing and its use as an epidemiological surveillance tool in different countries. The effect of these variables is reflected in the number of genomes of the ST213 genotype reported by year and by country , where tdoing so ,97,98,99S. enterica can generate results inconsistent with the observed phenotypic resistance [Another factor that may influence the results of the analysis carried out here is the quality of the sequences used, since low-level contamination can affect the detection of antibiotic resistance genes and point mutations associated with resistance . Howeversistance . Howeversistance ,97,98. Isistance , anotherhttps://www.ebi.ac.uk/, accessed on 1 July 2022) and 33 EnteroBase assembled genomes  [Salmonella enterica were retrieved. All read sets and assembled genomes retrieved were filtered for a quality assessment to exclude duplicates, remove low-quality reads, and sampling coverage  of Illumina sequencing reads available in EMBL’s European Bioinformatics Institute (ly 2022) ,103,104 coverage . Additiocoverage  below, 1coverage .draft genomes. The quality parameters used in the bioinformatic filtering to select both the genomes obtained from Enterobase  matrices were constructed to represent the presence (1)/absence (0) of resistance genes or plasmids, as appropriate. The genes/plasmids present in the genomes of all tested strains were excluded from this analysis. Both matrices were analyzed in the Heatmapper server  with theS. Typhimurium variant. The great number of antibiotic resistance genes and plasmid replicons carried by ST213 strains and its simultaneous presence in the same genome indicates that most of them present a multiple antibiotic resistance phenotype and are prone to the HGT of antibiotic resistance determinants. Additionally, the genomes and grouping patterns obtained here suggest a route of dispersion of the ST213 emergent genotype beginning in North America  and moving to the United Kingdom, with further dispersion occurring from here to the rest of Europe and simultaneously to Asia and Oceania. Further detailed epidemiological analysis is necessary in order to clarify this dispersion hypothesis and to understand the mechanisms associated with the differences in the pattern of the presence/absence of antimicrobial resistance genetic determinants by the geographical origin of the strains and the type of sample of precedence.The replacement of the ST19 genotype by other genotypes in different countries represents a serious public health concern worldwide because of the virulence and multiple antibiotic resistance of these emergent genotypes. Thus, the fast increase in the number of genomes deposited in public databases belonging to strains of the ST213 genotype throughout the world is a signal of the need to study this multiple-antibiotic-resistant and virulent


To compare the efficacy and psychology of breast-conserving surgery and modified radical mastectomy in patients with early breast cancer (BC) under graded nursing.  Forty-one early breast-conserving surgery BC patients admitted to our hospital from April 2020 to March 2022 were regarded as group A, and 52 with modified radical surgery were seen as group B. The operating time, intraoperative bleeding, postoperative drainage, and hospital stay were compared, and the postoperative adverse effects were counted. In addition, patients' psychology and quality of life were assessed using the HAMD, HAMA, and QLSBC rating scales. At the time of discharge, a treatment satisfaction survey was conducted. P < 0.05). After treatment, the HAMD and HAMA scores were lower in group A than in group B, while the QLSBC scores and treatment satisfaction were higher (P < 0.05).  The operative time, intraoperative bleeding, postoperative drainage, and hospital stay of patients in group A were lower than those in group B ( Breast-conserving surgery under graded nursing is less damaging to early BC patients. It can effectively shorten the postoperative recovery process and improve the psychology and quality of life, so it has higher clinical applicability. Breast cancer (BC), an extremely common clinical malignancy, has a high incidence worldwide . It mostIn modern health care, the intervention of nursing tools is likewise one of the most vital aspects of improving patient outcome . SeveralThus, this research will provide a reliable reference and guidance for future clinical treatment of early BC patients by comparing the assessment of outcomes and the impact of psychology between breast-conserving surgery and modified radical surgery under graded nursing.The study was carried out at Department of Thyroid and Breast Surgery, Affiliated Hospital of Nantong University from April 2020 to April 2022.Ninety-three patients with early BC admitted to our hospital from April 2020 to March 2022 were enrolled to this research. Among them, 41 patients received breast-conserving surgery were regarded as group A, and 52 with modified radical mastectomy were considered as group B. All the above subjects signed the informed consent form.Inclusion criteria: all the selected patients were confirmed as early BC by pathological examination, and all of them chose to be treated in our hospital after diagnosis; patients have not received chemotherapy, radiotherapy, or endocrine therapy either preoperatively or prior to puncture; those with TNM stage I-II (The staging standard is based on the BC Staging Guidelines ) and thoExclusion criteria: those with other malignancies; those with multiple chronic diseases; those with cardiovascular and cerebrovascular diseases; those with organ dysfunction; those with drug allergies; those who suffer from mental illness or physical disability that prevents them from taking care of themselves; contraindication to surgery; transferred patients.Both groups of patients were admitted to the hospital using graded nursing . The nurThe surgeries of both groups were performed by the same surgical team in our hospital. Group A: with the lesion as the center, radial, transverse, or curved incision was chosen according to the location of the tumor, and the base of the tumor and normal breast tissue were excised at 1 cm from the tumor. The excised tissues were subjected to rapid cryopathological examination to mark the internal, external, upper, lower, and basal locations of the incision margin. When the diagnosis is positive at the incision margin, it is necessary to expand the excision again until the test is negative. Then, lymph node dissection is performed in the range of axillary vein, deep surface of pectoralis minor muscle and anterior border of latissimus dorsi muscle, and a drainage tube is disposed in the incision, sutured, and pressure bandaged. Group B: after intravenous compound inhalation anesthesia, the surgical incision was decided according to the size of the affected breast and the location of the tumor, etc. The surgical incision was made 2-5 cm from the outer edge of the tumor and a fusiform incision was made. After cutting the skin of patients' affected breast, the affected breast was excised from the surface of the pectoralis major muscle using an electric knife to free the flap superiorly to the clavicle, inferiorly to the superior edge of the rectus abdominis sheath, internally to the parasternal sternum, and externally to the anterior edge of the latissimus dorsi. Patients' axilla was disposed of by making an incision and lifting the pectoralis major and pectoralis minor muscles inward and upward with a thyroid pull hook to fully expose his axilla. The axillary lymph nodes on the affected side of patients and the lymph nodes between the pectoralis major and minor muscles were removed. Patients' surgical wound was irrigated and soaked using distilled water (45°C), followed by routine placement of a drainage tube and suturing of the incision.The operative indexes of both groups were compared, including operation time, intraoperative blood loss, postoperative drainage, and hospital stay. The postoperative complications of the two groups of patients were counted, and the incidence of complications = the number of complications/total number × 100%. And the treatment satisfaction before discharge was calculated through the self-made satisfaction scale, the alternative answers are very satisfied, satisfied, dissatisfied, total satisfaction = (very satisfied + satisfied)/total × 100%. The psychological scores after treatment were evaluated by HAMD  and HAMA−χ ± s) and assessed through t-test and paired t-test. The difference was statistically marked (P < 0.05).Data were analyzed statistically using SPSS24.0 software. Thereinto, the counting data were represented as (%) and compared through the chi-square test, while the measurement data were expressed in (P < 0.05). After treatment, the HAMD and HAMA scores were lower in group A than in group B, while the QLSBC scores and treatment satisfaction were higher (P < 0.05).The operative time, intraoperative bleeding, postoperative drainage, and hospital stay of patients in group A were lower than those in group B (P > 0.05), suggesting that there was comparability between groups and that subsequent experimental analysis could be performed.The general data such as age and BMI of patients were counted . Both grvs.96.19 ± 12.85 min, P < 0.05, P < 0.05, P < 0.05, P < 0.05, It can be seen that the operative time was shorter in group A than in group B  of patients had incision infection, 2.44% (1 case) had nausea and vomiting, 2.44% (1 case) had upper limb swelling, and 2.44% (1 case) had subcutaneous effusion. The total incidence of adverse reactions was 9.76%. While in group B, 1.92% (1 case) of patients had incision infection, 3.85% (2 cases) had nausea and vomiting, 3.85% (2 cases) had upper limb swelling, 1.92% (1 case) had flap necrosis, and 1.92% (1 case) had subcutaneous effusion. The total incidence was 13.46%. There was no marked difference in the incidence of postoperative adverse reactions between groups (P > 0.05). The HAMD score in group A was (8.78 ± 3.18) after treatment, which was lower than that in group B .Changes in patients' psychology are equally one of the important aspects that need to be brought to clinical attention in healthcare services nowadays. Thus, we compared the changes in psychological scores of patients before and after treatment. It turned out that the differences in HAMD and HAMA scores before treatment were not statistically obvious (P > 0.05), while the somatic function score in group A was (58.10 ± 5.64) after treatment, which was dramatically higher than that in group B (P < 0.05, P < 0.05, P < 0.05, P < 0.05, Likewise, quality of life, another aspect of modern clinical services that deserves attention, is a direct reflection of patient recovery and prognosis to a large extent. There was no difference in the scores of each dimension of QLSBC score between groups before treatment (P < 0.05, The treatment satisfaction survey in both groups denoted that 58.54% of patients in group A were very satisfied and only 7.32% were dissatisfied, with an overall satisfaction rate of 92.68%. While only 36.54% of patients in group B rated very satisfied, and 26.92% rated unsatisfied, for a total rate of 73.08%. The total satisfaction was dramatically higher in group A than in group B (x patients to soothe the psychological burden caused by mastectomy and provide them with prognosis [BC, one of the most common female tumors, has seriously affected the lives of more than 1.2 million female patients worldwide . For earrognosis . Graded rognosis , 20, butCurrently, personalized care strategies are also one of the extremely important key aspects in modern oncological diseases. Among them, graded nursing, as an excellent nursing management model, has the core concept of patient-centeredness and different treatment measures for patients' conditions through environmental management, psychological guidance, health education, and adjustment of restraint measures under the guidance of nursing humanistic care principles and other methods. It cannot only improve their hospital comfort and eliminate negative emotions but also enhance their treatment effects and recovery to a certain extent , 22. In First, we compared the surgical conditions of both groups, and the operative time, intraoperative bleeding, postoperative drainage, and hospital stay of patients in group A were shorter than those in group B, suggesting that our breast-conserving surgery is less damaging to those with early BC and can effectively shorten their postoperative recovery. In a previous study, we also found that the postoperative recovery process was shorter in patients undergoing breast-conserving surgery than those with conventional radical surgery , which cBreast-conserving surgery under graded nursing is less damaging to early BC patients. It can effectively shorten the postoperative recovery process and improve the psychology and quality of life, so it has higher clinical applicability.


Background: The number of elderly diabetic patients has been increasing recently, and these patients have a higher morbidity of dementia than those without diabetes. Diabetes is associated with an increased risk for the development of dementia in elderly individuals, which is a serious health problem. Objectives: The primary aim was to examine whether diabetes is a risk factor for dementia among elderly individuals. The secondary aim was to apply grey theory to integrate the results and how they relate to cognitive impairments in elderly diabetic patients and to predict which participants are at high risk of developing dementia. Methods: Two hundred and twenty patients aged 50 years or older who were diagnosed with diabetes mellitus were recruited. Information on demographics, disease characteristics, activities of daily living, Mini Mental State Examination, sleep quality, depressive symptoms, and health-related quality of life was collected via questionnaires. The grey relational analysis approach was applied to evaluate the relationship between the results and health outcomes. Results: A total of 13.6% of participants had cognitive disturbances, of whom 1.4% had severe cognitive dysfunction. However, with regard to sleep disorders, 56.4% had sleep disturbances of varying degrees from light to severe. Further investigation is needed to address this problem. A higher prevalence of sleep disturbances among diabetic patients translates to a higher degree of depressive symptoms and a worse physical and mental health-related quality of life. Furthermore, based on the grey relational analysis, the grey relation coefficient varies from 0.6217~0.7540. Among the subjects, Participant 101 had the highest value, suggesting a need for immediate medical care. In this study, we observed that 20% of the total participants, for whom the grey relation coefficient was 0.6730, needed further and immediate medical care. Diabetes, the fifth highest cause of death reported in 2018, is highly prevalent, with an estimated 642 million people predicted to have diabetes by 2040 . In geneThere is a relationship between diabetes and cognitive dysfunction, and factors such as abnormal glucose metabolism, insulin deficiency, insulin antagonists, or abnormal protein build-up in the brain  may be tIn Taiwan, the prevalence of diabetes among individuals aged 18 and over is 11.8% (13.1% for men and 10.5% for women), and there are an estimated 2.28 million diabetic patients and 25,000 new cases per year. The prevalence rates of diabetes among elderly men and women are 27.7% and 24%, respectively, showing that the incidence tends to increase with age in both sexes , not onlThe results of the Ministry of Health and Welfare’s epidemiological survey of dementia in 2011 and demographic information from 2017 estimated that there were 3,192,477 people aged 65 years and older in Taiwan, of whom 586,068 (18.36%) had mild cognitive impairments. The number of people with dementia was 253,511, or 7.94%; this included 102,926 (3.22%) people with mild or worse dementia and 150,585 (4.72%) people with mild or worse dementia, showing that 1 in 13 people over 65 years of age had dementia and that 1 in 5 people over 80 years of age was mentally impaired. In addition, poor glucose control for diabetic patients may consequently impact complications and thus increase the risk of dementia. Although the Ministry of Health and the medical profession are beginning to pay attention to this problem, we should be more active in preventing this serious health condition and developing more effective preventive strategies for dementia risk factors.Since dementia causes a tremendous social burden, the prediction of dementia in individuals with diabetes is important to prevent or treat early-stage dementia. In recent years, many studies have been devoted to exploring prediction models. Lieza et al.  adopted The relationship between cognition and the duration of diabetes among elderly individuals is unclear. The primary aim of this study was to examine whether incident diabetes is a risk factor for dementia in elderly individuals and to clarify the relationships among diabetes characteristics, activities of daily living, cognitive function, sleep quality, depressive symptoms, and health-related quality of life. The secondary aim was to use grey theory to integrate the results and how they relate to cognitive impairments in elderly diabetic patients and to predict which participants are at high risk of developing dementia.The grey relational theory was proposed by Deng  and desiThe relationship between diabetes duration and cognitive impairments in elderly patients is unclear. Our aims are as follows: (1) The primary aim was to examine whether diabetes duration is a risk factor for dementia in elderly diabetic individuals and clarify the relationships among diabetes characteristics, activities of daily living, cognitive function, sleep quality, depressive symptoms, and health-related quality of life. (2) The secondary aim was to use grey theory to integrate the investigation results and study how they relate to cognitive impairments in elderly diabetic patients.A predictive study design was used to conduct a cross-sectional survey between September 2020 and March 2021. A questionnaire developed from previous studies and validated by expert review was used to investigate the relationships among demographic factors, disease characteristics, depressive symptoms, and health-related quality of life. The attrition rate was 96.8%.A convenience sample of outpatients was recruited from two metabolic departments at two general hospitals in the southern region of Taiwan. The eligibility criteria were as follows: (1) patients diagnosed with type 2 diabetes by a physician; (2) adults over 50 years of age; and (3) patients with no mental disorders. The exclusion criteria included a history of depression or psychosis and treatment with psychiatric medication.Permission was obtained from the Institutional Review Boards of the participating hospitals. The study design was used to improve generalizability by selecting eligible subjects from the diabetic population. To determine an adequate sample size, the significance level of α, effect size, and power were estimated. Cohen  suggesteThe measures consisted of demographic information, disease characteristics , sleep quality, activity of daily living, Mini-Mental State Examination, Geriatric Depression Scale, and a health-related quality of life scale as follows:1C); demographic information included age, sex, household monthly income reported in New Taiwan currency , marital status , and education . Cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), types of chronic diseases , weight, height, abdominal circumference, amount of exercise per day, exercise frequency, smoking habit, alcohol consumption, complications, and diabetes treatment  were all collected.Disease characteristics included duration of diabetes, numbers of complications of diabetes, fasting glucose, and glycated hemoglobin , developed by Folstein and Mc Huge , includeSheikh and Yesavage simplified the Geriatric Depression Scale to the GDS-SF15 based on the original Geriatric Depression Scale developed in 1982 , a 15-quWe applied the 36-item Short-Form Health Survey as a generic indicator of health. This survey measures HRQOL and includes eight subscales that are applicable to the general health of individuals, comprising physical function, role limitations, bodily pain, social function, general mental health, vitality, energy or fatigue, and general health perceptions. HRQOL is typically divided into a physical QOL (PQOL) component and mental QOL (MQOL) component, which were used in this study. The Cronbach’s alpha values in our study ranged from 0.76 to 0.84 among these subscales.We received approval from the Institutional Review Board of the general hospital. Endocrinologists referred eligible participants to the investigator. Participants were provided information about the purpose, benefits, risks, and data collection procedures of the current study. All information was provided in both verbal and written form, and participants could drop out of the study at any time. After receiving written informed consent from the participants, the investigator performed a face-to-face interview. Studies were conducted between September 2020 and March 2021. We maintained privacy and confidentiality for each participant and assigned each participant a code number; only the researchers had access to the data.p value of 0.05 indicated statistical significance.After coding the valid questionnaires in this study, the data were entered into the computer in the Statistics Package for Social Science for Windows 20.0 software package. The statistical analysis methods applied were descriptive statistics and Pearson’s correlation statistical methods. Preliminary data analysis included a description of the sample using frequency distributions for categorical variables and descriptive statistics. Pearson’s correlation was used to evaluate the degrees and strengths of the relationships among the study variables. A x0, which is composed of the measured results of all instrument tools, was calculated by grey relational analysis, and the comparison series ixs was collected from each participant. The grey relation coefficient, γ, between the reference series and comparison series was calculated by grey relational analysis. If γ ≧ γ, ix has a greater relationship with x0 than jx, that is, ix > jx ; in general, the distinguishing coefficient is 0.5 and can be adjusted as needed. The adjusted value will change only the relative value and will not affect the order of the grey relational grade .Step 4: The grey relational grade was obtained using the mean value of the grey relational coefficient:The closer the value of the grey relational grade is to unity, the higher the relational grade of the reference sequence; otherwise, it is lower.Step 5: The grey relational order was obtained.ix and x0 is greater than that between jx and x0, that is, ix is more similar to x0.The grey relational grade indicates the relational grade between each sequence and the reference sequence. The order is determined by ranking the relational grades from the highest value to the lowest, which is called the grey relational order. It means that the relational grade between 1C) ranged from 5.4% to 12.7%   from outpatient departments in two urban hospitals in southern Taiwan. The majority of participants were male (52.7%), approximately 61% of the participants (or less) had a high school diploma, and the majority of patients (47.3%) had a household income less than TWD 25,000 per month. The duration of diabetes varied from 4 months to 420 months (M = 136.3); two patients had a duration of 4 months and one patient had a duration of 420 months, which could be treated as outliers. Most patients had a uniform duration of the disease. Approximately 89.5% of the participants had at least one complication of diabetes. Participants’ fasting glucose levels ranged from 58 to 557 mg/L (M = 140.7), glycated hemoglobin (HbA = 1.2%) , mean boGeriatric depression symptom (GDS) scores of 0 to 4 indicate no symptoms of depression, scores of 5 to 10 indicate mild depressive symptoms, and scores of 10 to 15 indicate severe depressive symptoms. Only 13.6% of the participants had depression: 12.2% had mild depression, and 1.4% had moderate to severe depression. Depression status scores ranged from 0 to 13 . On the MMSE, 13.6% of patients with diabetes had mild and moderate cognitive impairments, and most (86.4%) participants had normal cognitive function .r = −0.42, p < 0.01), income , and MMSE score . In addition, age was negatively correlated with fasting glucose  and positively correlated with diabetes duration . There was a significant positive correlation between education and income , MMSE score , and MQOL and PQOL . There was a significant positive correlation between the duration of diabetes and HbA1C . Household monthly income was significantly positively correlated with MMSE score . Glycemic control (fasting glucose and HbA1C) was not significantly related to DSs, SQ , MQOL, or PQOL; however, glycemic control was significantly positively correlated with triglycerides (TGs). Total cholesterol was positively correlated with LDL-C and TG; HDL-C was negatively correlated with HbA1C and fasting sugar. TG was significantly positively related to GDS, and GDS had a strong negative relationship with MQOL and PQOL and a significant positive relationship with SQ . In addition, SQ had a significantly negative correlation with PQOL and MQOL .In this research, the variables collected were tested and complied with normality. 1C, fasting sugar, total cholesterol, HDL-C, LDL-C, TG, SQ, MMSE, GDSs, PQOL, and MQOL were collected for further grey relational analysis. The results of the grey relational analysis are shown in In this study, data on BMI, HbAThere was no direct association between sleep quality or sleep segments and the lipid profile status of the patients, including triglyceride level, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in this study. However, there were significant relationships between SQ and mental and physical QOL; SQ was significantly related to mental and physical QOL in diabetes patients. We consider that there may be some connections between variables that need further study.According to β-amyloid peptide accumulations, which have been considered to be the fundamental cause of AD (Alzheimer’s disease), the occurrence of diabetes is related to insulin resistance and hyperinsulinemia and might interfere with β-amyloid peptide metabolism. Additionally, insulin can cross the blood–brain barrier, and insulin levels in the brain are initially higher and then downregulated in diabetic patients. In our study, 86% of the participants had normal MMSE scores, and 86% had normal GDS scores. It might be that most participants’ blood sugar was well controlled. Only 15% of DM patients had mild to severe MMSE scores, but we found that depressive symptoms were significantly associated with MMSE scores and TGs, which might be related to dementia after a longer diabetes duration in the future. Because a previous study mentioned that diabetes has been reported to be associated with AD [The relationship between DM and AD has been noted in recent years. In our research, 15% of DM patients were found to have abnormal MMSE scores, which require more attention about the risk of dementia. Compared to a previous study, DM almost doubled the risk of dementia in elderly subjects after an average 2-year follow-up . Since D1C were both significantly positively correlated with TG.According to Pearson’s correlation, there were no direct associations between sleep quality and glycemic control. However, fasting sugar and HbAThe duration of diabetes may play an important role in AD pathogenesis and lower MMSE scores; however, there was no significant association between MMSE scores and the duration of diabetes mellitus in our study, which might be because the duration of diabetes was not long enough to reflect the progression of AD. However, this risk factor should be studied further.Consistent with a previous study ,37, we fThere were a few limitations of the study. First, the participants were all aged 50 years or older, which may impact the results. Huang et al.  mentione1C, BMI, and biological markers in patients with diabetes in Taiwan. More than half of the participants had sleep disturbances of varying degrees from light to severe. Further tracking is needed to solve this problem and prevent complications for diabetic patients. The more sleep disturbances there are in diabetic patients, the higher the degree of depressive symptoms and the worse their physical and mental health-related quality of life. Furthermore, based on grey relational analysis, the grey relation coefficient varied from 0.6217~0.7540. In this study, we proposed that 20% of the total participants, of whom the grey relation coefficient was 0.6730, needed further and immediate medical care.This is the first study to use grey theory to predict cognitive function, depressive symptoms, and health-related quality of life by applying fasting glucose, HbA


Unilateral primary aldosteronism (UPA) and bilateral primary aldosteronism (BPA) are the two subtypes of PA. Discriminating UPA from BPA is of great significance. Although adrenal venous sampling (AVS) is the gold standard for diagnosis, it has shortcomings. Thus, improved methods are needed.The original data were extracted from the public database “Dryad”. Ten parameters were included to develop prediction models for PA subtype diagnosis using machine learning technology. Moreover, the optimal model was chose and validated in an external dataset.In the modeling dataset, 165 patients  were included, while in the external dataset, 43 consecutive patients  were included. The ten parameters utilized in the prediction model include age, sex, systolic and diastolic blood pressure, aldosterone to renin ratio (ARR), serum potassium, ARR after 50 mg captopril challenge test (CCT), primary aldosterone concentration (PAC) after saline infusion test (SIT), PAC reduction rate after SIT, and number of types of antihypertensive agents at diagnosis. The accuracy, sensitivity, specificity, F1 score, and AUC for the optimal model using the random forest classifier were 90.0%, 81.8%, 96.4%, 0.878, and 0.938, respectively, in the testing dataset and 81.4%, 90.0%, 73.9%, 0.818 and 0.887, respectively, in the validating external dataset. The most important variables contributing to the prediction model were PAC after SIT, ARR, and ARR after CCT.We developed a machine learning-based predictive model for PA subtype diagnosis based on ten clinical parameters without CT imaging. In the future, artificial intelligence-based prediction models might become a robust prediction tool for PA subtype diagnosis, thereby, might reducing at least some of the requests for CT or AVS and assisting clinical decision-making. Primary aldosteronism (PA) accounts for approximately 4-10% of hypertension; approximately 30% of PA is a unilateral subtype that is associated with a higher risk of cardiovascular complications and can be cured by surgery, whereas the bilateral subtype is best treated with medication . HoweverMeanwhile, supervised machine learning technology has been used widely and is gaining recognition in medical research since it can automatically formulate computational models by processing the variables with complex relationships, and therefore, frequently presents optimal results compared with traditional methods , 9. Due 22.1https://Datadryad.org). Validation data were obtained from XiangYang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, China. Ethics approval was obtained in the original study by the ethics committee of Chiba University Graduate School of Medicine , maintains high-quality research data with the aim of forming an academic exchange for the protection and reuse of research data in scientific publications. The raw data of the present study were offered publicly by Nagano et al. in 2020 . The oriThe models were validated in an independent external PA cohort from XiangYang Central Hospital, an affiliated hospital of Hubei University of Arts and Science, China. Forty-three consecutive patients with PA who underwent AVS and SIT from 1 May 2021 to 30 April 2022 were included retrospectively based on the following criteria: (1) inclusion criteria: patients with PA and who had undergone successful AVS for subtype diagnosis. (n=54) (2) exclusion criteria: (a) patients without accessible data. (n=0) (b) patients who lacked a definite or correct classification of PA in the postoperative follow-up. (n=6) (c) Patients who did not undergo SIT. (n=5). Finally, 43 patients were included (details are shown in 2.22.2.1Data extraction in the modeling process included age (year), sex, systolic blood pressure , diastolic blood pressure , plasma renin activity , PAC (pg/ml), ARR, serum potassium , urine aldosterone (μg/day), ARR after 50 mg CCT, PRA after the furosemide standing test, PAC after SIT, PAC reduction rate after SIT (%), and the number of types of antihypertensive agents at diagnosis. Blood pressure was measured three times consecutively after the patient sat for at least 15 minutes, and the average value was adopted. Blood samples were collected from the patient in the recumbent position after they rested for at least 30 minutes, and commercial radioimmunoassay kits  were applied to these samples for the measurement of PAC and PRA. For the measurement of cortisol concentrations, the IMMULYZE (Siemens K.K.) assay was used. Serum potassium was measured by standard methods. Before and during patient examinations, calcium channel blockers or alpha-l blockers were administered, while patients with a severe condition were also treated with diuretics or other antihypertensive drugs. To make a definitive diagnosis of PA, patients underwent one or more of the following tests: saline infusion test, captopril challenge test, or furosemide upright test; notably, 91.8% of patients underwent more than two of these tests. AVS was performed with 0.25 mg of adrenocorticotropic hormone for stimulation. A selectivity index  above 5 was considered the threshold for successful adrenal vein cannulation. UPA was highly suspected when the lateral index  was above 3 after ACTH infusion and was confirmed in the postoperative follow-up , as described in the original study .Python 3.6.13  was used to develop and validate the machine learning-based algorithm. Patients with PA were stratified by subtype diagnosis and split randomly into either the training set 70%, N=115) or the testing set  (random seed=1). To find an optimal prediction model, five supervised machine learning classifiers were used, including random forest (RF), support vector machines (SVM), gradient boosting decision tree (GBDT), logistic regression (LR), and AdaBoost. First, all possible available variables were used to build models, according to previous research reports 0%, N=115, 11. Two2.3Data extracted for the validation process included age, sex, SBP, DBP, ARR, serum K, ARR after 50 mg CCT, PAC after SIT, PAC reduction rate after SIT (%), and number of types of antihypertensive agents at diagnosis. The measurements of PAC and PRA in the recumbent position were extracted and tested using commercial radioimmunoassay kits , and cortisol concentrations were measured by the same method. The methods used to measure other variables were consistent with the original study . PA was 2.4Python 3.6.13  was used for development and validation of the models. STATA Version 16  was used for statistical analysis. Continuous variables are presented as the mean ± standard deviation or the median with an interquartile range , and categorical variables are reported as counts with proportion (%). The student’s t test was used to analyze continuous variables when they were normally distributed, if not, the Mann-Whitney U test was used. The chi-square test was used for categorical variables. Accuracy was calculated as the primary endpoint to evaluate the performances of the prediction models, and secondary endpoints included sensitivity, specificity, F1 score, and AUC. Little missing data was replaced by the mean value (Details were shown in 33.1P<0.05). Accordingly, PAC reduction after SIT was significantly lower in the UPA subgroup than that in the BPA group (P<0.05). The serum potassium level was lower in patients with UPA than in those with BPA in both the modeling and the external dataset. Comparisons of other clinical and biochemical parameters were not significantly different between the two groups  were included, while in the external dataset, we included 43 consecutive patients  that underwent a successful AVS with accessible data. As expected, those with UPA had higher ARR, higher ARR after CCT, and higher PAC after SIT than those with BPA in both datasets (https://github.com/shaominbaby/PA). A demonstration of how to apply the predictive model is shown in http://misetech.cn:83/xyszxyy.jsp, for Chinese users).Among the classifiers assessed in the testing set, the best performance was observed in the model utilizing the RF classifier , the accuracy was 100%, while when it was equal to or more than 0.7, the accuracy was 95%. Thus if AVS was only performed in those whose subtype predicition probability < 0.7, then 51.2% of the AVS and 23.3% of the CT would have been avoided, with the sensitivity of 0.950 and specificity of 0.957 . The process of using this predictive model is shown in Based on Chinese population, CCT and SIT were reported to be accurate alternatives for each other . Since C44.1PA is associated with a higher risk of cardiovascular and cerebrovascular risk compared with essential hypertension . UPA and4.2Over the last few decades, many methods for the diagnosis of PA subtypes have been proposed. Although CT and magnetic resonance imaging (MRI) are the easiest and most accessible diagnostic tools, they are not reliable in differentiating subtypes of PA, with a pooled sensitivity of 68% and pooled specificity of 57% . Other c4.3Machine learning is based on nonlinear algorithms, and consequently, can compute multidimensional variables simultaneously resulting in consistent levels of increased accuracy. This tool has been gaining increasing attention and recognition in medical decision-making .Currently, the SIT and CCT tests are most commonly used in clinical practice for subtyping PA . In the via AVS. Thus, the proportion of UPA in our external dataset was 46.5%, which is higher than that of the modeling dataset and previous reports ; Science and Technology Research Key Project of Education Department of Hubei Province, China (Grand number D20212602); Sanuo Diabetes Charity Foundation, China.This study uses data from Dryad database. We thank the authors of the original study  for their excellent work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.