AI-based clinical decision support system (CDSS) has important prospects in overcoming the current informational challenges that cancer diseases faced, promoting the homogeneous development of standardized treatment among different geographical regions, and reforming the medical model. However, there are still a lack of relevant indicators to comprehensively assess its decision-making quality and clinical impact, which greatly limits the development of its clinical research and clinical application. This study aims to develop and application an assessment system that can comprehensively assess the decision-making quality and clinical impacts of physicians and CDSS.Enrolled adjuvant treatment decision stage early breast cancer cases were randomly assigned to different decision-making physician panels , each physician made an independent “Initial Decision” and then reviewed the CDSS report online and made a “Final Decision”. In addition, the CDSS and guideline expert groups independently review all cases and generate “CDSS Recommendations” and “Guideline Recommendations” respectively. Based on the design framework, a multi-level multi-indicator system including “Decision Concordance”, “Calibrated Concordance”, “ Decision Concordance with High-level Physician”, “Consensus Rate”, “Decision Stability”, “Guideline Conformity”, and “Calibrated Conformity” were constructed.531 cases containing 2124 decision points were enrolled; 27 different seniority physicians from 10 different grades hospitals have generated 6372 decision opinions before and after referring to the “CDSS Recommendations” report respectively. Overall, the calibrated decision concordance was significantly higher for CDSS and provincial-senior physicians (80.9%) than other physicians. At the same time, CDSS has a higher “ decision concordance with high-level physician” (76.3%-91.5%) than all physicians. The CDSS had significantly higher guideline conformity than all decision-making physicians and less internal variation, with an overall guideline conformity variance of 17.5% (97.5% vs. 80.0%), a standard deviation variance of 6.6% (1.3% vs. 7.9%), and a mean difference variance of 7.8% (1.5% vs. 9.3%). In addition, provincial-middle seniority physicians had the highest decision stability (54.5%). The overall consensus rate among physicians was 64.2%.There are significant internal variation in the standardization treatment level of different seniority physicians in different geographical regions in the adjuvant treatment of early breast cancer. CDSS has a higher standardization treatment level than all physicians and has the potential to provide immediate decision support to physicians and have a positive impact on standardizing physicians’ treatment behaviors. OncologRecently, artificial intelligence has been increasingly applied in medical fields such as medical imaging diagnosis –9, pathoCDSS require a solid clinical evidence base before they can be finally applied to the clinic, including the level of standardized treatment of CDSS and the impact on clinicians’ decision-making –22. HoweThe aim of this study is to construct a comprehensive multi-level multi-indicator system for the assessment of the standardized treatment level of physicians and CDSS; and at the same time, to assess the current status of the standardization treatment level and internal variation in early breast cancer adjuvant treatment decision-making in different geographical regions based on this indicator system, and identified the standardized treatment level of CDSS and its clinical application potential. It also provides a methodological basis for the further construction of a sensible CDSS clinical practice model and clinical impact assessment.22.1http://www.chictr.org.cn, ChiCTR2000039122 and ChiCTR2100047685).This is a prospective, multi-center, comparative clinical study. The design framework was illustrated in 2.2 2.3We have coded different grades of hospitals, different physician seniority, and each decision-making physician independently. The numbering rules are as follows: each code consists of four digits, the first of which represents a different grades of hospital , the middle two digits represent different seniority physicians , and the last digits represents the independent number within the same seniority in the same grade hospital (1-4), e.g. 3034 represents provincial hospital junior physician 4.A total of twenty-seven physicians of different seniority  from ten different grade hospitals  in Anhui province participated in the decision-making, forming a total of nine independently comparable subgroups of physicians (101-303), and each panel consisted of three physicians of the same seniority from the same level of hospital. The senior physician is the chief physician or associate chief physician with 10 years of work experience or more; the middle physician is the attending physician with 4-9 years of work experience; and the junior physician is the hospitalist with 3 years of work experience or less.)Enrolled cases were randomly assigned to three differently senior physicians from different grades of hospitals in group format (G1-9), and each physician independently reviewed all cases in the case group. For each case, the physician first makes an independent “ Initial Decision” and then reviews the CDSS report online and makes a “ Final Decision”. , which is an artificial intelligence-based oncology clinical decision support system developed under the platform of the Chinese Society of Clinical Oncology (CSCO) based on Chinese breast cancer data, guidelines and expert experience, and can provide treatment recommendations for physicians’ reference based on patients’ individualized conditions; it also provides treatment information such as scientific evidence, guideline basis, drug dosage, contraindications and adverse effects associated with each protocol . CSCO AIThe treatment recommendations of CSCO AI are divided into “Recommended” and “Not Recommended”, where “Recommended” is further subdivided into “Level I Recommendations” and “Level II Recommendations”. “Not Recommended” means that the patient is recommended to be exempted from the relevant treatment. “ Level I Recommendation” options are those with strong evidence and high availability, relatively stable tumor treatment value, and definite patient benefit, and are indicated in blue. “ level II Recommendation” is usually a treatment or drug that is poorly available or has a low cost-effectiveness ratio and is beyond the affordability of the population, although it is supported by high-level evidence, and is indicated in green. The specific classification criteria for the level of recommendation are shown in Two senior oncology researchers input the patient’s information into the CSCO AI system and generated artificial intelligence recommendations. Neither the researchers nor CSCO AI knew about the physician’s decision.2.5The CSCO BC guideline experts group was comprised by 3 highly qualified physicians, two of whom were members of the CSCO BC experts committee that participated in the formulation and drafting of the CSCO BC guidelines. The experts group members reviewed the cases and made the relevant treatment recommendations independently by referring to the CSCO BC guidelines [Version 2021 –46]. The2.6The adjuvant treatment for early breast cancer includes adjuvant targeted therapy, adjuvant chemotherapy, adjuvant radiotherapy and adjuvant endocrine therapy; each stages is assessed independently and finally analyzed in aggregate. The following assessment indicators are included, as shown in 2.6.1Decision is considered as concordant when both the physician and the CSCO AI recommend the relevant treatment and the physician’s recommendation is consistent with the CSCO AI’s “Level I Recommendation” or neither is recommended, otherwise it is discordant. Specifically, decision concordance was assessed based on the match between physician and CSCO AI recommendations. There are five situations: “Level I recommendation” means that the physician’s recommendation is the same as the CSCO AI’s Level I recommendation; “Level II recommendation” means that the physician’s recommendation is the same as the CSCO AI’s Level II recommendation; “Not available” means that both the physician and CSCO AI recommended the relevant adjuvant therapy, but the physician’ recommendation was not considered by CSCO AI. “Not recommended” means that both the physician and the CSCO AI recommended not to receive the relevant adjuvant therapy. “ Whether or not to recommend dispute” means that the physician and CSCO AI dispute whether the patient should be recommended to receive the relevant adjuvant therapy. The “ Level I recommendation” and “ Not recommended” were considered to be concordance, while all other situations were discordance. Concordance = *100%. , and can also indirectly reflect the treatment differences across physicians.2.6.2Decision is considered as concordant when both the physician (or CSCO AI’s “Level I Recommendation”) and the high-level physician recommend the relevant treatment and the specific program is same or neither is recommended, otherwise it is discordant. Specifically, decision concordance was assessed based on the match between physician (or CSCO AI’s “Level I recommendations’’) and high-level physician’ recommendations. There are four situations: “Recommended” means that both the physician (or CSCO AI) and the high-level physician recommend the relevant adjuvant therapy, and both the physician’s recommendation (or CSCO AI’s “Level I recommendation”) and the high-level physician’s specific recommendation are the same. “Not available” means that both the physician (or CSCO AI) and the high-level physician recommend the relevant adjuvant therapy, but the physician’ recommendation (or CSCO AI’s “Level I recommendation”) was not considered by high-level physician. “Not recommended” means that both the physician (or CSCO AI) and the high-level physician recommended not to receive the relevant adjuvant therapy. “ Whether or not to recommend dispute” means that the physician (or CSCO AI) and the high-level physician dispute whether the patient should be recommended to receive the relevant adjuvant therapy. The “ Recommendation” and “ Not recommended” were considered to be concordance, while all other situations were discordance. Concordance = *100%.  as the standard for decision quality assessment, assesses the standardization treatment level of different physicians as and CDSS in view of the empirical clinical level, and can reflect the treatment differences across physicians.2.6.3Enrolled cases were randomly assigned to three differently senior physicians from different grades of hospitals in group format (G1-9), and each physician independently reviewed all cases in the case group. So, the group of decision-making physicians for the same case in this study consisted of three physicians of different seniority. For example, 59 cases in G1 were assigned to provincial junior physician 4 (3034), municipal senior physician 3 (2013) and county middle physician3 (1023) for decision-making at the same time; similarly, 59 cases in G9 were assigned to provincial senior physician 2 (3012), municipal middle physician 3 (2023) and county junior physician2 (1032) for decision-making at the same time. Consensus was considered to be reached when the decisions of the three physicians were in complete agreement; Otherwise, it was considered not reached. Consensus rate =  * 100%.This indicator assesses the treatment variation across physicians in view of the empirical clinical level, and a lower consensus rate reflects greater internal treatment variation.2.6.4Decision stability was assessed based on changes in the discordance subgroup of physician and CSCO AI decisions. In the discordance subgroup, a decision is assessed as stable if the physician’s “Final Decision” is the same as the “Initial Decision”, otherwise it is assessed as decision instability. Decision stability =  * 100%.This indicator assesses the decision stability  of different physicians in view of the empirical clinical level, which is the probability of treatment strategy change when the physician is interfered by external opinions, and essentially reflects the maturity of the physician’s knowledge system; it can also reflect the internal variation of the physician’s technical maturity.2.6.5It was considered as conforming to the guideline when both the physician (or CSCO AI’s “Level I Recommendations”) and the guideline recommended the relevant treatment and the physician’s recommendation was consistent with the guideline’s “Level I Recommendations” or neither was recommended, otherwise it was not conformity. Specifically, guideline conformity was assessed based on the match between physician and CSCO AI recommendations. There are five situations: “Level I recommendation” means that the physician’s recommendation (or CSCO AI’s Level I recommendations) is the same as guideline’s Level I recommendations; “Level II recommendation” means that the physician’s recommendation (or CSCO AI’s Level I recommendation) is the same as the guideline’s Level II recommendation; “Not available” means that both the physician (or CSCO AI) and guideline recommended the relevant adjuvant therapy, but the physician’ recommendation (or CSCO AI’ recommendation) was not considered by guideline. “Not recommended” means that both the physician (or CSCO AI) and the guideline recommended not to receive the relevant adjuvant therapy. “ Whether or not to recommend dispute” means that the physician (or CSCO AI) and guideline dispute whether the patient should be recommended to receive the relevant adjuvant therapy. The “ Level I recommendation” and “ Not recommended” were considered to be conformity, while all other situations were nonconformity. Conformity = *100%. , and a propensity score matching analysis was performed on the “physician and CSCO AI decision discordance” data for each physician groups using a multivariate logistic regression model to achieve balancing and comparability at the baseline information level. Propensity score matching analysis was based on the following factors: Age, Menstrual Status, Breast Surgery Modality, Axillary Surgery Modality, TNM Stage, Molecular Subtype and Treatment Stage. Pairs of patients were derived using 1:1 greedy nearest neighbor matching within propensity score (PS) of 0.01. Using SPSS 26.0 software for data processing and analysis.33.1P>0.05). As shown in 531 breast cancer patients were enrolled in this study. Patients were randomly assigned to nine groups (G1-9) for review by different physicians; 3.2Overall, the concordance between CSCO AI and physicians’ decisions was 80.1% (5107/6372) ; after calibration, it was observed that senior and middle physicians had significantly higher calibrated concordance than junior physicians . Overall, the decision concordance with the CSCO AI differed across different grades of hospitals; in particular, before calibration, county hospitals had the highest concordance compared to municipal and provincial hospitals ; after calibration, it is observed that provincial hospital had significantly higher calibrated concordance than county and municipal hospital physicians . Overall, the decision concordance with the CSCO AI differed across different seniority physicians in different grades of hospitals; before calibration, provincial-senior physicians (301) and county-junior physicians (103) had a higher concordance than the other physicians, but no statistical difference was found between them ; after calibration, it was observed that provincial-senior physicians (301) had a significantly higher calibrated concordance than other physicians (P<0.001). The concordance between different physicians and CSCO AI fluctuated between 62.7% and 93.2% (P<0.001)  Table S2P<0.05); whereas patient age, menstrual status, and axillary surgery modality had no effect on concordance (P>0.05)  Table S33.3P<0.05) in the reasons of discordance between different physicians and CSCO AI decisions. Specific discordance cases are described in As shown in 3.4vs. 75.0%, 71.6%, P=0.488; G8:83.1% vs. 73.7%, 75.4%, P=0.036; G9:91.5% vs. 87.7%, 85.6%, P=0.127).As shown in P<0.05); whereas axillary surgery modality had no effect on concordance-HL (P>0.05)  Table S63.5Overall, the physicians’ consensus rate was 64.2% (1363/2124) (P<0.05)  Table S73.6vs. 35.8%; P=0.271). Provincial hospitals had significantly higher decision stability than county and municipal hospitals . Overall, decision stability differed across different seniority physicians in different grade hospitals; compared to other physicians, provincial-middle physicians  were the highest, followed by provincial-senior physicians  and county-middle physicians .Overall, physicians’ decision stability was 40.6% (201/495) (P<0.05)  Table S83.7vs. 79.5%, 79.9%; P=0.648); after calibration, it was observed that senior and middle physicians had significantly higher calibrated guideline conformity than junior physicians . Overall, the guideline conformity varied across different grades of hospitals; in particular, before calibration, county hospitals had the highest conformity compared to municipal and provincial hospitals ; after calibration, it was observed that provincial hospitals had significantly higher calibrated guideline conformity than county and municipal hospitals . Overall, guideline conformity differed across different seniority physicians in different grades of hospitals; before calibration, provincial-senior physicians (301) and county-junior physicians (103) had higher conformity than other physicians, but no statistical difference was seen between them ; after calibration, it was found that provincial-senior physicians (301) had significantly higher calibrated guideline conformity than other physicians (P<0.001). The conformity fluctuated between 62.3% and 92.8% across physicians (P<0.001).Overall, the guideline conformity of physician’ decision-making was 80.0% (5100/6372) G–I. Ovevs. 80.2% and 78.9%; P=0.039); but after calibration, however, guideline conformity of patients aged ≥55 years was lowest . Postmenopausal patients had a slightly higher guideline conformity rate than premenopausal patients before calibration, but no statistical significance ; after calibration it was shown that postmenopausal patients had a significantly lower guideline conformity rate than premenopausal patients . For patients with different breast surgery modalities, the guideline conformity of simple mastectomy (SM) was significantly higher than breast conserving surgery (BCS) . For patients with different axillary surgical modalities, guideline conformity of ALND was higher than SLNB . For patients with different stages, the conformity of Stage III patients was significantly higher than that of Stage I and II patients . Before calibration, the guideline conformity of TNBC was significantly higher than other breast cancer subtypes ; however, after calibration, the Luminal type had higher guideline conformity than other subtypes, with the highest rate in Luminal A (85.9%) and followed by the Luminal B (HER2 negative) type (79.7%). Before correction, the adjuvant targeted therapy stage had the highest guideline conformity rate across all adjuvant treatment stages ; however, after correction, the adjuvant endocrine therapy stage had the highest guideline conformity rate (82.5%), while the adjuvant targeted therapy stage had the lowest (49.7%), with a statistically significant difference (P<0.001).In addition, a univariate sublevel analysis for overall conformity showed that physician’ guideline conformity was also influenced by patient’ age, menstrual status, breast surgery modality, axillary surgery modality, TNM stage, molecular subtype, and treatment stage P<0.05); whereas patient’ age, menstrual status, and axillary surgery modality had no effect on guideline conformity (P>0.05); guideline conformity differed by TNM stage, with stage III patients having a higher conformity rate than stage I and II patients ; conformity differed by molecular subtypes, with TNBC having the highest conformity rate ; and the performance of CSCO AI in these subgroups was similar to that of overall physicians. Overall, guideline conformity varied by treatment phase, with the adjuvant radiotherapy phase having the highest conformity (99.8%), while adjuvant chemotherapy had the lowest conformity (94.9%) and adjuvant targeted and adjuvant endocrine therapy had moderate conformity , with statistically significant differences (P<0.001); and the performance of CSCO AI in these subgroups differed from that of overall physicians. No statistical differences were seen in guideline conformity between different physician case groups, different menstrual status, breast surgery modalities and axillary surgery modalities (P>0.05).Overall, the guideline conformity of CSCO AI’ decision-making was 97.5% (6213/6372) Table S9P<0.05); while different decision-making physician case groups and patient’ menstrual status had no effect on guideline conformity (P>0.05), with a 17.5% conformity difference (P<0.01) (P<0.01)  Table S93.10The standard deviation of guideline conformity among different physicians was 7.9%, with a mean difference of 9.3% (3.11Nonconformity occurred in 2.5% (159/6372) of the cases overall in the decision-making performed by CSCO AI. The percentage of nonconformity that occurred varied by treatment stage, with the adjuvant chemotherapy stage having the highest rate of 5.1% (81/1593), and the adjuvant radiotherapy stage having the lowest rate of 0.2% (3/1593); in addition, the adjuvant targeted therapy stage had 1.9% (30/1593), and the adjuvant endocrine therapy stage had 2.8% (45/1593). Except for adjuvant radiotherapy decision nonconformity, which was due to misidentification of case information, all other nonconformities with the guidelines were due to treatment strategy differences.4How is the current status of standardized treatment variation among different geographical regions and how can it be comprehensively assessed? How is the potential for clinical application of CDSS in different geographical regions and how can it be assessed? And How can the actual clinical impact of CDSS be comprehensively evaluated, especially in enhancing the level of physicians’ standardized decision-making and balancing the variation of standardized treatment among different geographical regions? The resolution of these questions is extremely important for advancing the rational clinical application of CDSS and improving the current dilemma of oncology treatment.We have found that the existing indicators of “ decision concordance” and “guideline conformity” –38 have In this context, we have introduced the indicator “Decision Stability” for the first time as an empirical indicator to assess the expertise maturity of CDSS and physicians. This indicator assesses the stability of different physicians’ decisions in terms of their experience clinical level, and is the probability of changes in treatment strategies when physicians are disturbed by external opinions, essentially reflecting the maturity of physicians’ expertise system. During the analysis of decision stability, we observed that county junior physicians had the lowest decision stability, and provincial middle senior physicians  had the highest, followed by provincial senior physicians , which is consistent with our expectations. Therefore, we calibrated the “Decision Concordance” and “Guideline Conformity” indicators using “Decision Stability” so as to correct the negligence of these indicators on the technical maturity, and developed the indicators named “Calibrated Decision Concordance” and “Calibrated Guideline Conformity”, respectively. After being Calibrated by “decision stability”, we observed that CDSS and provincial senior physicians (301) had the highest decision concordance (80.9%), while that of CDSS and county junior physicians (103) was the lowest (31.7%). Similarly, after being corrected by “Decision Stability”, we observed that provincial senior physicians (80.9%) had a significantly higher “ calibrated guideline conformity rate” than other strata, while county junior physicians had the lowest (31.4%). That suggests that we should accurately understand the correct meaning of existing indicators like “Decision Concordance” and “Guideline Conformity”. The “Decision Concordance” only reflects the same situation between CDSS and physician decisions, it does not reflect whether the decisions are standardized and individualized to patients. The level of decision concordance does not directly indicate the standardization treatment level of CDSS and physicians. The value of the study of decision concordance is that it can reflect the treatment variation among different physicians as well as empirically assess the decision level of CDSS and initially evaluate whether it has the potential application value in clinical practice. And the “Corrected Concordance” corrected by “Decision Stability” showed better ability in reflecting the standardization level of physicians’ decisions. Similarly, “Guideline Conformity” only reflects the simple conformity between physician’s decision and guideline recommendation in a certain cross-section, and which is accurate in simply assessing the standardization level of physician’s decision, but cannot fully reflect the physician’s treatment level, and needs to consider the factor of technical maturity. The “ Calibrated Guideline Conformity” Calibrated by “Decision Stability” shows a better comprehensive evaluation ability in reflecting the standardization level of physicians and CDSS decisions, and the evaluation results are more in line with the actual clinical situation, because it takes into account the pure standardization based on “Guideline Conformity” and the empirical factor of technical maturity based on “Decision Stability”.Additionally, it is worth noting that indicators such as “Decision Concordance” and “Guideline Conformity” are strongly influenced by the evaluation standards, and there are still no standard reporting principles, which largely affects the comparability between different studies. In the previous clinical studies related to WFO, “ Recommended”  and “ For consideration”  were classified as concordant –38. In tIn addition, besides the standardization treatment level, internal decision variation, especially among different medical regions, is also worth considering. Therefore, we also suggested using “ Concordance Variation”, “Consensus Rate”, and “Guideline Conformity Variation” to assess the intra-physician decision variation, in which “Guideline Conformity Variation” can also be used to assess the decision variation of CDSS among different case groups, which also reflects the decision stability of CDSS. While “ Concordance with High-Level Physicians’ decision making” used high-level physicians  as a criterion to evaluate the decision quality, it assessed the standardized treatment level of different physicians and CDSS in terms of clinical experience and could reflect the treatment variation among physicians. In summary, this study constructed a multi-level, multi-indicator system to comprehensively assess the standardized treatment level of physicians and CDSS, considering the level of empirical clinical and guidelines adherence-based purely standardization level as well as the comprehensive level.Based on this indicator system we first assessed the standardized treatment level and the current status of internal variation among different seniority physicians in different grades of hospitals. At the level of empirical clinical data, different physicians’ decision concordance with CDSS and concordance with high-level physicians were significantly different, fluctuating between 62.7%-93.2% and 71.6%-87.7%, respectively; the overall consensus rate among physicians was 64.2%; the decision stability varied among physicians, compared with other physicians, provincial-middle physicians (54.5%) had the highest, followed by provincial-senior physicians and county-middle physicians (both 52.7%). In the purely standardization level, guideline conformity differed among physicians, with provincial-senior physicians (83.6%) and county-junior physicians (85.6%) having higher conformity than other physicians, but no statistical difference was seen between them; the standard deviation of guideline conformity among physicians was 7.9%, and the mean difference of 9.3%; after calibration, it was observed that at the comprehensive level provincial-senior physicians had significantly higher calibrated guideline conformity than other physicians. The study showed that there is significant internal variation in the standardization treatment levels of different seniority physicians in different levels of hospitals.vs. 80.0%; P<0.001); the standard deviation of guideline conformity of CDSS among different physician case groups was 1.3%, and the mean difference was 1.5%; CDSS had less internal variation in treatment decision-making compared with physicians, and the difference of standard deviation of guideline conformity was 6.6%, and the difference of mean difference was 7.8%. Studies have shown that compared to physicians, CDSS have higher treatment standardization and less internal variation.At the same time, the standardization treatment level of CDSS and its clinical application potential were further comprehensively assessed by comparing it with physicians. At the empirical clinical level, the overall decision concordance between the CDSS and physicians was 80.1%, and the calibrated concordance with provincial-senior physicians was significantly higher than other physicians; at the same time, the CDSS had a higher “decision concordance with high-level physicians” than all physicians, which fluctuated between 76.3%-91.5%. At the purely standardization level, CDSS had significantly higher guideline conformity than the performance of all physicians; the overall difference of conformity reached 17.5% , and was concentrated among stage I and II patients . In fact, whether pT1N0M0 requires chemotherapy has been a controversial clinical issue –51; for Overall, a total of 2.5% (159/6372) nonconformity cases occurred in the decision-making performed by the CDSS. It was mainly caused by treatment strategy differences, and was mainly concentrated in adjuvant chemotherapy and adjuvant endocrine therapy. For example, nonconformity case one is a T1aN0M0  type) case, where the CSCO AI recommended HP (trastuzumab/pattuzumab) regimen and did not recommend combination chemotherapy. In contrast, the guideline experts group recommended the TC+H (docetaxel/cyclophosphamide + trastuzumab) regimen that combines targeted therapy with chemotherapy ; for theThis study has several important strengths. Most importantly, this study developed the first multi-level, multi-indicator system that can comprehensively assess the standardization treatment level of physicians and CDSS, and also provided a methodological basis for the construction of a sensible clinical application model of CDSS and comprehensively assessing the clinical impact of CDSS when it’s implemented in the clinical practice. Second, we have further developed the appropriate connotation of existing indicators that include “Decision Concordance” and “Guideline Conformity”. Thirdly, based on this indicator system, the standardization treatment level and internal variations among different geographical regions were clarified for the first time, and the standardization treatment level of CDSS and its clinical application potential was also examined.This study still contains several noteworthy limitations. First, the decision-making physicians were all sourced from the same provincial medical region, and further assessment of treatment standardization and regional variation among different provincial medical regions is necessary in the future. Second, this study did not assess the impact of CDSS on physician decision-making.5This study constructs the first multi-level, multi-indicator system that can more comprehensively assess the standardization level of physicians and CDSS, and provides a methodological basis for constructing a rational clinical practice model of CDSS and assessing the clinical impact of CDSS in a three-dimensional manner. Based on these indicators, we identified that there are significant internal variation in the standardization treatment level of different seniority physicians in different grade hospitals  in the adjuvant treatment of early breast cancer, and compared with the provincial senior physicians, the standardization treatment level of middle and junior physicians as well as municipal and county hospitals needs to be further improved. CDSS represented by CSCO AI has a higher standardization treatment level than all physicians, and combined with a rational application model, it is expected to provide physicians with immediate decision support and have a positive impact on standardizing physicians’ treatment behaviors. The specific impact of CDSS in improving clinicians’ standardized treatment, balancing medical disparities between different regions, promoting physicians’ own decision-making skills and benefiting patients is yet to be explored in the future, which will establish the overall value of AI-based clinical decision support systems for oncology treatment and will facilitate the formation of best clinical practice models.The original contributions presented in the study are included in the article/The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Ethics Committee of the First Affiliated Hospital of Anhui Medical University . The patients/participants provided their written informed consent to participate in this study.Conceptualization, CH. Data curation, CH, JL, YP, CL, XY, XP, XC，MJ, JZ, CL, ZL, DG and JP. Formal analysis, CH, JL, YP, CL，XY，XP and XC. Funding acquisition, ZJ and JP. Investigation, CH, CL, XY, KW, ZS, HL, GJ, FF, TT, SP, LM, XW, YR, ML and FL. Methodology, CH, JL, YP, XY. Project administration, CH, ZJ and JP. Resources, JP. Software, CH, JL, YP. Supervision, ZJ and JP. Validation, CH. Visualization, CH. Writing-original draft, CH. Writing-review & editing, CH, ZJ and JP.


Biodiversity is measured differently depending on the spatial scale of the study. Beta (β)-diversity, for example, is a calculated measurement that addresses changes in diversity across different assemblages in a specific region. Studies of β-diversity often address changes in diversity across gradients of environmental conditions and distance among sites. However, β-diversity of stream insects can be difficult to measure due to their hyper-diversity and challenging taxonomy. Our study investigated the association of β-diversity with habitat conditions and distance among these habitats for insects found in the coastal streams of Alabama, USA. Additionally, we looked for potential influences caused by seasonality  and the level of taxonomic identification . Regardless of season, stream conditions were highly correlated with β-diversity. More specifically, stream size and water chemistry showed the highest associations with β-diversity. Changes in β-diversity were largely driven by species replacement (turnover) rather than species loss (nestedness). The taxonomic resolution had minimal effects on the calculations of β-diversity across environmental conditions. Distance among stream sites was never correlated with β-diversity. As we continue to face global insect declines, our study provides valuable insight into the patterns that drive changes in diversity across environmental gradients.Sorβ, stream conditions were expressed as principal components (PCs), and distances as Euclidean distances (km) among sites. We also investigated the impact of seasonality  and taxonomic resolution  on Sorβ. Regardless of season, Sorβ was significantly correlated  with stream conditions (stream size and water chemistry), while taxonomic resolution had minimal effect on associations between Sorβ and stream conditions. Distance was never correlated with changes in Sorβ (p > 0.05). We extended the use of the Sørensen pair-wise index to a multiple-site dissimilarity, Multβ, which was partitioned into patterns of spatial turnover (Turnβ) and nestedness (Nestβ). Changes in Multβ were driven mostly by turnover rather than nestedness.β-diversity is often measured over both spatial and temporal gradients of elevation, latitude, and environmental conditions. It is of particular interest to ecologists, as it provides opportunities to test and infer potential causal mechanisms determining local species assemblages. However, studies of invertebrate β-diversity, especially aquatic insects, have lagged far behind other biota. Using partial Mantel tests, we explored the associations between β-diversity of insects found in the coastal streams of Alabama, USA, and stream conditions and distances among sites. β-diversity was expressed using the Sørensen index,  A fundamental pattern of great interest to ecologists is how and why species diversity changes with location or time. Species diversity is scale dependent ,2 and, aAlthough β-diversity is simple in concept, there are a bewildering number of indices, with no clear consensus for meaning, measurement, statistical analysis, or interpretation ,10,11,12Studies have examined patterns of β-diversity over various gradients, such as altitude ,14, envi2 relatively pristine area consisting largely of cypress-gum swamps and bottomland hardwood forests interlaced with large rivers, streams, canals, bayous, and marshes [Though some studies have been conducted in similar stream systems in the southern United States ,24 littl marshes .Sorβ, among pairs of stream sites [Sorβ is calculated using presence/absence data and can be expressed as:C is the number of species the two communities have in common, S1 is the total number of species found in community 1, and S2 is the total number of species found in community 2 [We calculated β-diversity as Sørensen pair-wise indices, am sites . βSor ismunity 2 . Hence, Sorβ of lotic insects in these historically understudied coastal streams of Alabama changed over gradients of environmental conditions and distance. We also explored how seasons  and different taxonomic resolutions  influenced patterns of Sorβ. We then extended the use of the Sørensen pair-wise index to a multiple-site dissimilarity index, Multβ. [Multβ provides a measurement of dissimilarity among all sites in a region. This latter index can further divide into diversity due to species turnover (change) among sites (Turnβ) and species nestedness (loss) among sites (Turnβ). Hence, Mult = βTurn + βNestβ.Accordingly, our aim was to explore how patterns of , βMult. . WhereasDetails of the study area, sampling protocols, and measurements of stream conditions can be found in McCreadie and Bedwell ; here wen = 5), taken (randomly) within this length at each site for both the fall and summer sampling regimes. Insects were sampled using a standard 1 m × 1 m kick-net, mesh size 0.3 mm, over a standard quadrate size (PVC pipe) of 60 cm × 60 cm [3 s−1), was calculated as “W × D × U = Q”. Latitude and longitude were recorded using Garmin GPS units (Rino 110) . Water hardness was measured using CHEMetric®  titration cells. The above variables are considered to be influential determinants (or at least strong predictors) of species assemblages in stream habitats [At each stream site, a 100-m representative length of stream  was delineated, and samples . In addition, while species keys exist, they are often only useful for later instars. Accordingly, all specimens were identified by either the level of genus or species. Hence, three taxonomic levels were subject to statistical analysis—mixed taxa of genus/species, generic data only, and species data only. Voucher specimens for identification were deposited in the University of South Alabama’s Arthropod Depository.Samples were transported to the laboratory on ice and preserved in 95% ethanol until identification. For each sample, an effort was made to remove all insects, with no samples being sub-sampled. Of the separated insects, five taxonomic orders were selected for study due to their high abundance, functionalities, ease of identification, and broad representation of functional feeding groups. Specimens were identified following the keys of Epler  for Colep < 0.05, unless otherwise stated. To determine if our sampling protocol produced a reasonable estimate of the species present in the regional pool, species accumulation curves, using a bootstrap approach [All statistical tests were considered significant at approach , were cap-value set at p < 0.01) to provide a rigorous interpretation of the PCs [Sorβ, a comparison of diversity between each site [Each partial Mantel test  was base the PCs . The thiach site .Sorβ andstream conditions (accounting for distance effects) and the Sorβ and distance matrix (accounting for stream conditions). Partial Mantel tests were calculated separately for both season and taxonomic resolution, with the significance of each partial correlation based on 5000 random permutations between matrices. Mantel tests have been used by previous authors and are considered a powerful approach for detecting spatial correlations [For each set of matrices, partial Mantel tests  were useelations .Sorβ pairwise index to a multiple-site dissimilarity index, Multβ, following Baselga [Multβ can further partition the pattern of species occurrences in the site-by-species matrix into spatial turnover (Turnβ) and nestedness (Nestβ) or combinations thereof [We then extended the use of the  Baselga . βMult c thereof ,45. Thes thereof . These w thereof ,46,47. S thereof .PCA was conducted using Minitab v 20, and bootstrap estimators of number of taxa using Primer v 6.0 . PartialDubiraphia, Stenelmis) and Leuctridae (Leuctra). A total of 20,739 specimens were identified from 23 sites in the fall for either genus or species, in 27 families and 66 genera. In these collections, the most frequent genera encountered (>80% of sites) included the Elmidae , Coenagrionidae (Argia), Philopotamidae (Chimarra), Hydropsychidae , Gomphidae (Progomphus), Perlidae (Acroneuria), and Leuctridae (Leuctra).Differences between the number of taxa observed and the estimated bootstrap estimate of taxa  were betp < 0.001) for the fall collections (p < 0.001) for the summer collections  with stream variables expressed as PCs. Given the correlations between stream variables and PCs, we interpreted this to indicate that β-diversity changed largely along gradients of stream size and water chemistry for both fall and summer collections, as well as riparian vegetation for summer collections. Mantel test correlations for species-level identification data were slightly lower than data for generic or mixed levels, regardless of season . In addition, changes in Multβ diversity among sites were largely the result of species turnover (Turnβ = 0.7084 to 0.7916) as opposed to local species loss (Nestβ = 0.0697–0.1220) (–0.1220) .Sorβ was calculated as the dissimilarity for each pairwise site comparison, whereas Multβ extended to all sites, producing a single estimate of overall β-diversity. Our results suggest that stream conditions had a profound effect on β-diversity of lotic insects, as indicated by the significant correlations between site conditions (expressed as PCs) and Sorβ. In contrast, spatial factors  showed no significant correlations with Sorβ at a regional scale. The level of taxonomic precision  had minimal influence on the correlation, with Sorβ correlations using species-level identification being marginally lower than data using mixed or generic-level identifications. Correlations between stream condition and taxonomic level of identification showed little difference between seasons . The complementary analysis of multisite estimates of β-diversity indicated that species turnover, Turnβ, was consistently higher than species loss, Nestβ, for all data sets.We examined two aspects of β-diversity: β-diversity is a measurement of differences in species composition among sites across gradients of habitat conditions or time. Accordingly, there has been substantial interest in β-diversity recently ,12,44,50Turnβ and Nestβ, respectively. Species turnover is generally viewed as a result of niche-based species sorting along abiotic and biotic factors [Multβ into these components of turnover and nestedness shows species turnover (Turnβ) was much higher than nested patterns (Nestβ) in all six data sets. Hence, Turnβ is essentially a measure of Multβ at a regional scale in our study. To date, the majority of studies that have partitioned Multβ show that changes in species composition are largely the result of species turnover (Turnβ), with nested effects having minimal influence at regional scales [Nestβ values and the nonsignificant results of distance in the Mantel tests suggest dispersal limitation was not an important mechanism for structuring species assemblages. However, the use of spatial variables as proxies for dispersal is not without criticism [Change in β-diversity among habitats is generally considered the result of two different processes, species turnover and species loss or gain , measure factors ,44,57, a factors . Our anal scales . Nestednl scales ,61. The riticism . The lowriticism . The secThe minimal influence of taxonomic resolution  may be advantageous for studies of diversity that include taxa that are difficult or impossible to identify as species based on the morphology of early instars. We suggest the minimal effect of the season  in our results may be due to the fact that many of the species encountered in our study are multivoltine and are thus present throughout most or all of the year.Despite the importance of aquatic insects as bioindicators of stream health, little is known about the spatiotemporal patterns of aquatic insect diversity. Additionally, even less is known about those that inhabit the coastal streams of Alabama, which drain into the highly diverse Mobile-Tensaw River Delta. Researching patterns of diversity in these insect communities has become especially pertinent as we continue to face a global crisis of insect decline. Our study provides foundational insight into the influences that drive aquatic insect diversity in coastal Alabama, but there is still more work to be done to understand the specific impacts and extent of these environmental changes over time. We suggest that future studies address the impacts of stream conditions on coastal Alabama’s insect diversity across both spatial and temporal scales.


This study compared remimazolam tosylate with propofol or midazolam to assess its safety and effectiveness for long-term sedation of intensive care unit (ICU) patients requiring mechanical ventilation.Adult patients in the ICU receiving sedation and mechanical ventilation for longer than 24 h were included in this single-center, prospective, observational study. Depending on the sedatives they were given, they were split into two groups . ICU mortality was the main result. Laboratory tests, adverse events, and the length of ICU stay were considered secondary outcomes.P = 0.182), gender (P = 0.325), and the amount of time between being admitted to the ICU and receiving medication infusion (P = 0.770) did not substantially differ between the two groups. Multivariate analysis revealed no statistically significant difference in ICU mortality between the two groups. The remimazolam group showed less variability in heart rate (P = 0.0021), pH (P = 0.048), bicarbonate (P = 0.0133), lactate (P = 0.0002), arterial blood gas analyses, liver, and kidney function. The Richmond Agitation and Sedation Scale scores, length of ICU stay, and occurrence of adverse events did not exhibit significant differences between the two groups.A total of 106 patients were involved (46 received propofol or midazolam versus 60 received remimazolam). Age (Remimazolam tosylate did not increase the total inpatient cost, the incidence of adverse events, and ICU mortality in patients with mechanical ventilation. These findings suggest that remimazolam may represent a promising alternative for sedation in the ICU setting.The online version contains supplementary material available at 10.1186/s40001-023-01440-9. In the intensive care unit (ICU), mechanical ventilation is a vital form of life support, but it also has several negative side effects , 2. As aRemimazolam is a benzodiazepine sedative with an ultra-short half-life that acts on γ-aminobutyric acid type A (GABAa) receptor receptors , 12. In This single-center, prospective, observational study compared the effectiveness and safety of remimazolam with propofol or midazolam for long-term sedation in patients on mechanical ventilation in the ICU. This study adhered to the Helsinki Declaration and was authorized by the Clinical Research Ethics Committee of Renmin Hospital of Wuhan University (WDRY2021-K008). Everyone who took part, or members of their close family, gave written informed consent. Before it began, this study was registered in the Chinese Clinical Trial Registry (ChiCTR2100051478). The study was carried out between October 2021 and December 2022.Age greater than or equal to 18 years, continuous use of mechanical ventilation and sedative use  greater than or equal to 24 h are the inclusion criteria for this study. Exclusion criteria: (1) using two or more sedatives concurrently; (2) women who are pregnant or lactating; (3) patients allergic to benzodiazepines, opioids or propofol, or have contraindications; (4) patients with a history of drug use such as heroin, marijuana, and methamphetamine; (5) patients with positive serum ethanol test, with a history of alcoholism or alcohol dependence; (6) patients with mental illness; (7) patients with severe liver or kidney dysfunction  –22; (8) The patients were divided into two groups (the remimazolam group and the propofol or midazolam group) depending on the sedative drugs they used . The treatment plan of all enrolled patients was formulated by the responsible physician of each patient according to the patient's condition. During the study period, the patient's existing treatment plan was not interrupted, and we did not intervene in the patient’s treatment plan. All of the medications put to the test were continuously infused intravenously. The dosage schedule was as follows: (1) Remimazolam , the first dose was 0.2 mg/kg, and the maintenance dose was 0.16 mg/kg/h; (2) Propofol , initial dose 2.0 mg/kg, maintenance dose 1.5 mg/kg/h; (3) Midazolam , the first dose of 0.12 mg/kg, maintenance dose of 0.075 mg/kg/h. Analgesic regimen: (1) remifentanil, 4 ~ 9 μg/kg/h; (2) Nalbuphine hydrochloride, 1.0 ~ 1.4 mg/kg/h. Patients with mild to moderate liver and kidney dysfunction and elderly patients (age ≥ 60 years) were given a reduced infusion of midazolam and propofol based on the above doses. According to previous studies, the pharmacokinetics of remimazolam are not affected by liver and kidney function , so the 2) ≤ 0.5, Peripheral Oxygen Saturation(SPO2) ≥ 95%; (2) Set Positive End-Expiratory Pressure(PEEP) ≤ 8 cm H2O; (3) Normal arterial blood gas analysis; (4) No dependence on pressor drugs; (5) Hemodynamic stability; (6) Consciousness judgment. If the above standards are met, the second step is carried out. (2) Step 2: Brief spontaneous breathing test, measuring rapid shallow breathing index(RSBI); (1)The ventilator was set to ‘Continuous Positive Airway Pressure(CPAP)’ mode, FiO2 ≤ 0.5, pressure support(PS) 5 ~ 8 cm H2O, PEEP ≤ 5 cm H2O; (2) Under this setting, mechanical ventilation was performed for 2 ~ 3 min, and the RSBI was measured. If RSBI < 105, the third step is carried out; otherwise, restore mechanical ventilation. (3) Step 3: Spontaneous breathing test. (1) The ventilator was set to ‘CPAP’ mode, set FiO2 ≤ 0.5, PS was 5 ~ 8 cm H2O, PEEP ≤ 5cm H2O. (2) Continuous 1 h of spontaneous breathing without interruption, that is, the spontaneous breathing test was successful. If the following conditions occur, the spontaneous breathing test is interrupted: (1) respiratory rate > 35 times/min, more than 5 min; (2) SPO2 < 95%, more than 3 min; (3) Heart rate increased by more than 20% compared with baseline; (4) Systolic blood pressure was higher than 160 mmHg or lower than 90 mmHg. If the Spontaneous breathing test is successful, take the fourth step; otherwise, restore mechanical ventilation. (4) Step 4: Weaning. The mechanical ventilation was stopped, and oxygen was given at 2–3 L/min through a tracheal intubation catheter after weaning. (5) Step 5: Extubation. If Arterial Oxygen Saturation(SaO2) ≥ 95% and arterial blood gas analysis were normal under the condition of 2–3 L/min oxygen supply through tracheal intubation catheter, the tracheal intubation was pulled out after sufficient sputum suction, and the nasal catheter or mask was given oxygen at 1–2 L/min. There was no obvious difference between the two groups in terms of the length of ICU and hospital stays. In the current study, tachycardia and hypotension predominated; adverse events associated with bradycardia did not occur. The frequency of adverse events did not significantly differ between the two groups. Remimazalam patients paid more on average for sedatives . However, we found that the total inpatient cost and ICU inpatient costs of patients in the remimazolam group were lower than those in the propofol or midazolam group.All-cause mortality was greater in the remimazolam group , but there was no difference during long-term use. The heart rates of patients who received remimazolam were consistent over time, but those who received propofol or midazolam showed a significant downward trend with time , while all of the heart rates were still within the normal range.Vital indicators including respiration rate and systolic and diastolic blood pressure were more stable in the remimazolam group during the observation period, but there was no statistically significant difference . During the observation period, there was no statistically significant difference between the two groups in terms of bilirubin, liver enzyme, albumin, urea, creatinine, and troponin  mg/h, which is equivalent to the sedative effects of midazolam or propofol. The infusion dose of remimazolam in this study was lower than that in previous studies –30, mainP = 0.0021), indicating that remimazolam had less of an inhibitory effect on the cardiovascular system over time, which was consistent with previous research results [Between the two groups, there was no discernible difference in ICU mortality or ICU stay time. This study's findings were in line with those of a randomized controlled study that found no appreciable difference between remimazolam and propofol in terms of 28 day mortality or the length of mechanical ventilation . The sam results . We also results , however results . TachycaThe arterial blood gas analysis, and liver, and kidney function were not significantly different between the two groups in this study, however, it is obvious that the aforesaid indicators of patients in the remimazolam group fluctuated less. Remimazolam is an ultra-short-acting sedative that does not rely on liver and renal metabolism, according to prior research , 33. ThaThis research has several restrictions. First off, this study has a tiny sample size and is a single-center observational study. Although the essential traits of patients can be compared well, there is not a 1:1 match, therefore, some judgments may be skewed. Second, no changes were made to the patient's initial treatment schedule during the course of the trial. After the observation period was over, some patients received further sedative medications; hence, some findings might not be accurate. Third, we cannot guarantee that every physician will adhere to the recommendations for the use of sedative drugs, which may result in inconsistent dosages of the study medication. Finally, additional consideration should be given to patient delirium in the future as this study did not evaluate other unfavorable occurrences like them.The results of this single-center, prospective, observational study showed that compared with propofol or midazolam, the long-term sedation of remimazolam tosylate for patients with mechanical ventilation in ICU did not increase the total inpatient cost, the incidence of adverse events, and ICU mortality. It indicates that remimazolam may be a promising alternative to ICU sedation. However, larger sample studies are needed to provide more accurate conclusions.Additional file 1: Table S1. Results of the analysis of the ICU mortality using a COX Proportional-Hazards Model. Figure S1. Hemodynamics of patients during observation period. * represents a statistically significant difference in univariate analysis between groups. P-value is the result of repeated measures analysis of variance. P<0.05 was considered statistically significant. Figure S2. Arterial blood gas analysis during the observation period. * represents a statistically significant difference in univariate analysis between groups. P-value is the result of repeated measures analysis of variance. P<0.05 was considered statistically significant. Figure S3. Liver and kidney function indexes and other laboratory test results of patients during observation period. * represents a statistically significant difference in univariate analysis between groups.


The effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China.Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders.− 1·d− 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg− 1·d− 1) (p < 0.05). At first follow-up, 44 patients (41.9%) reported experiencing at least one treatment-emergent adverse events.105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kgThis real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy. Pediatric patients are more likely to suffer from epilepsy compared to adults, and it has been estimated that approximately 6 million pediatric patients in China suffer from epilepsy, which leads to a prevalence of approximately 7 per 10,000 Chinese pediatric patients , 3. In CClinical studies have indicated a favorable short- and long-term effectiveness, as well as tolerability of lacosamide –7. In reThus far, there has been limited data on the use of LCM among Chinese pediatric patients with refractory epilepsy. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM for the first time among children and adolescents with refractory epilepsy in Xinjiang, Northwest China.This was a retrospective, observational study among children and adolescents with refractory epilepsy, conducted under normal clinical practice at two hospitals in Xinjiang, China. All children and adolescents met the diagnostic criteria for epilepsy, as issued by the International League against Epilepsy in 2017 .The inclusion criteria were as follows: treatment with LCM for refractory epilepsy, and treatment with LCM for at least 2 weeks. The exclusion criteria were as follows: the lack of key research data, cognitive impairment, alcohol or drug abuse within the last 5 years, if patients had any medical or psychiatric condition.The International League Against Epilepsy (ILAE) defines refractory epilepsy as: after a reasonable selection according to the type of epilepsy and correct use of at least 2 well-tolerated ASMs (single or combined), the patient’s seizure-free duration did not reach three times the longest seizure interval before treatment or one year (depending on whichever was longer) .Anonymized information was retrospectively gathered from medical records without the involvement or participation of any other individuals, with a study cutoff date of May 2022. All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki). This study was approved by the Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region .The need for informed consent was waived by the ethics committee/Institutional Review Board of People’s Hospital of Xinjiang Uygur Autonomous Region, because of the retrospective nature of the study.Data collected included age, sex, height, weight, body mass index (BMI), age at seizure onset and duration of epilepsy, final LCM dosage and adverse events that occurred at any time during the treatment.Seizure frequency was recorded at an average per month for the past 3 months at baseline, and at each follow-up period for 3, 6, and 12 months. Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months’ follow up compared with baseline. The baseline was 3 months before the addition of LCM and the seizure frequency was based on the patients’ seizure diary. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders. The term “seizure-free” was defined as having complete seizure control using LCM.Seizure frequency was assessed through documented ‘seizure diary’ and subjects or caregiver reports. Seizure frequency was classified as monthly (1–3 seizures per month) or yearly (≤ 12 seizures per year). To avoid possible influence on treatment decisions, the last documented visit had to be performed prior to initiation of the chart review. Most of the clinical records at our study did not document seizure frequency in a standardized way, such as “there was a decrease in seizures”, “no seizures since last visit”, and “four seizures since last visit”. These narrative descriptions are very inconsistent. Therefore, in addition to inquiring clinical records, we also inquired and recorded the frequency of epileptic seizures through telephone follow-up.The safety and tolerability depended on type and frequency of any one adverse event during epilepsy treatment across all patients, as well as LCM-related events that were recorded at any time from start of LCM treatment to 12 months adverse events . AdverseAll psychiatric adverse reactions in pediatric patients were diagnosed by clinical psychologists according to the “Chinese Expert Consensus on the Diagnosis and Treatment of Epilepsy and Depression (2022 Revised Edition)”, and “Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder”. Psychiatric adverse events in the treatment of LCM mainly refer to depression and bipolar disorder.p-value of < 0.05 was considered statistically significant. Descriptive statistics for clinical data presentation were applied. Comparisons between groups and response outcomes were made using the chi-square (χ2) test or Fisher’s exact test for qualitative variables and Student’s t-test or the Mann-Whitney U test for quantitative variables whose distribution was normal and nonnormal, respectively.Analyses were performed using SPSS version 19.0 software , and a − 2 (median: 17.8). The mean epilepsy duration at LCM treatment was 3.4 years (median: 3.0 years). Median follow-up length from LCM initiation to last evaluation was 0.6 years. Thirty-two patients (30.5%) received LCM as add-on for generalized epilepsy and 12 (11.4%) for focal epilepsy, while 43 patients (41.0%) manifested both generalized and focal seizures (combined epilepsy).Overall, from September 2019 to March 2022, 105 children and adolescents from two hospitals were enrolled in the study, demographics and clinical data are summarized in Table t-test and chi-square (χ2) test showed no statistically significant significance between responder and non-responder groups for age, body mass index, duration of seizures, duration of seizures, duration of seizures, concomitant ASM, and maintenance LCM (p > 0.05).The 105 patients were divided into two groups according to whether the treatment was effective or not. This included the responder group (n = 50), and the non-responder group (n = 55). The results of the Student’s 2) test showed a significant difference in gender and the number of ASMs were used before LCM between the response group and the non-responder group, the proportion of male patients within the responder group (68.0%) was significantly higher compared to the non-responder group (54.5%) (p = 0.049), the proportion of one ASM used before LCM within the responder group (54.0%) was significantly higher compared to the non-responder group (29.1%) (p < 0.001), and the proportion of two ASMs used before LCM within the responder group (30.0%) was significantly lower compared to the non-responder group (45.5%) (p = 0.023) (Table t-test results showed that the maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg− 1·d− 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg− 1·d− 1) (p = 0.019) . At follow-up within 12 months, 23 patients discontinued LCM treatment . In most cases, these cases were rated mild. At the 12 months, 28 patients (40.6%) reported experiencing treatment-emergent adverse events at a mean daily dose of 8.3 mg·kg− 1·d− 1 , which, in most cases, were rated mild  experienced psychiatric adverse events, with one patient presenting with depressive symptoms and three patients with bipolar disorder. Among the nonpsychiatric adverse events, mild dizziness, somnolence, nausea/vomiting and depression were the most common, and were reported by 24, 24, 6 and 4 patients, respectively. Other adverse events included gastrointestinal discomfort in two patients, and double vision in another.+ channels are an important class of therapeutic targets for many anticonvulsant drugs, including both classical anticonvulsants and third-generation ASMs [+ channel slow inactivation markedly, LCM shows a pronounced effect on slow inactivation properties [Voltage-gated Naion ASMs . One sucoperties . LCM is operties .Determining the effectiveness, safety and optimal dosage of LCM among pediatric patients is vital for safe and rational use of LCM in clinical practice. Various endogenous factors  and exogenous factors  can have an effect on drug pharmacokinetics . In receThe children and adolescents in this study are representative of the real-world refractory epilepsy population, and despite limited clinical experience with LCM therapy for refractory epilepsy, there is a growing body of research that suggests that LCM may be useful for children and adolescents with refractory epilepsy , 21–22. Rosati et al. discovered that 38.6% (34/88) children and adolescents were responders that received add-on LCM treatment for refractory epilepsy and nine (26.4%) of the 34 responders were seizure-free . Kleist et al.,. [This real-world study of children and adolescents with refractory epilepsy with a follow-up period of at least 12 months demonstrated response rates of 47.6%, 39.2%, and 31.9% at 3, 6, and 12 months, respectively. In particular, the proportion of pediatric patients who achieved seizure freedom gradually decreased over time, at 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. These results were consistent with Rosati et al.,.  Kleist eet al.,.  and Rüeget al.,.  studies LCM was found to be relatively well tolerated, with an adverse event rate of 41.9% at the 12-months. This was consistent with the incidence of adverse events that were reported in observational studies by Del Bianco et al.,  and CascThe strengths of this study are the longer follow-up. The major limitation of this study is investigators must rely on clinical records, as well as the fact that all children and adolescents with refractory epilepsy were treated by the same physician, it could be a limitation since the cases were not discussed with others. Nonetheless, this study may provide some real-world evidence for the effectiveness and safety of long-term adjunctive use of LCM for the treatment of refractory epilepsy within the children and adolescents population. LCM was found to be well tolerated, with relatively few adverse events.In conclusion, this real-world study of 105 children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy, even at long-term follow-up and low doses. These important findings suggest that LCM is likely to become a widely-used ASM for the treatment of epilepsy in clinical practice, and in children and adolescents.


Rubus spp. Ningzhi 4′ in 2020 (S-SV-RS-014-2020). In the future, ‘Ningzhi 4’ could be promoted as an advantageous thornless blackberry cultivar in the main production regions of China.The thornless blackberry cultivar ‘Ningzhi 4’ was developed by the Institute of Botany, Jiangsu Province and the Chinese Academy of Sciences . The new blackberry cultivar was selected from the ‘Kiowa’  and ‘Hull Thornless’  F1 hybrid. ‘Ningzhi 4’ had excellent plant characteristics, including thornlessness, semi-erect to erect canes, vigorous growth and good disease resistance. ‘Ningzhi 4’ had large fruit and high yield. In addition, the parents of the superior hybrid plant were further identified by SSR markers, which provided the basis for the fingerprint of the new blackberry cultivar ‘Ningzhi 4’. This is a commercial cultivar to be grown for fruit production for either shipping or local sales. It also has value as a home-garden plant. This unique type of blackberry fruit was a traditional summer fruit. This new cultivar has thornless semi-erect to erect canes and produces high-quality berries with large size, good firmness, excellent flavor, and potential for shipping and postharvest storage. The new blackberry cultivar ‘Ningzhi 4’ is adapted to all areas of southern China and is expected to replace or complement ‘Kiowa’, ‘Hull Thornless’, ‘Chester Thornless’ and ‘Triple Crown’. A local cultivar patent has been approved by the Jiangsu Variety Approval Committee as ‘ Rubus L. plants have the characteristics of strong ecological adaptability, easy cultivation, fast forest formation, early yield and rich fruit nutrition [Rubus species have perennial roots and crowns. Blackberry (Rubus spp.) is a perennial shrubby fruit tree of Rubus in Rosaceae, which has been planted for more than 100 years [utrition ,2. All R00 years . Origina00 years . Blackbe00 years . Blackbe00 years . Blackbe00 years . For exa00 years . The ant00 years . Mountin00 years . It is a00 years ,5,8. Wit‘Ningzhi 4’ was developed from a cross-breeding of ‘Kiowa’ (♀) × ‘Hull Thornless’ (♂) made during the blackberry flowering period in May 2006 at the Institute of Botany, Jiangsu Province and Chinese Academy of Sciences , Nanjing, China. A total of 100 blackberry flowers were hybridized by emasculation and bagging, and 86 hybrid fruits and nearly 4000 hybrid seeds were obtained. The seed coat of blackberry was broken through concentrated sulfuric acid treatment, and the dormancy of seeds was broken through 2 months of wet sand storage and stratification. The seeds were sown in the early spring of 2007, and 168 hybrid seedlings were obtained. After one year of tending, the seedlings were planted in the breeding nursery in 2008. Through the investigation of growth, fruit quality and other character indices from 2008 to 2009, 6-6-3 plants (named ‘Ningzhi 4’) were selected in June 2009 from a population of 168 plants in a seedling field. During the ripening season, ‘Ningzhi 4’ was noted to have large fruit, good quality, and thornless and vigorous canes. In 2009, the plants were rapidly propagated by layering and tissue culture, and more than 200 clones were obtained. The parent ‘Hull Thornless’ is a vigorous, thornless, semi-erect type blackberry cultivar that is high yielding, with medium-sized and fairly soft fruit [Rubus SSR markers [False hybrids are often mixed in hybrid offspring. Accurate and rapid identification of true and false hybrids can improve the selection efficiency of breeding . The tra markers ,16 were The cross of elite thornless and large fruit selections results in the thornless plant and the enhancement of fruit size and quality in this cultivar. ‘Ningzhi 4’ combines the excellent characteristics of both parents, showing strong adaptability, large growth potential, high yield, large fruit and long fruit maturity . The fruThe bloom date of ‘Kiowa’ was usually earlier than all comparison cultivars. ‘Ningzhi 4’ began to bloom 12 d later than ‘Kiowa’, 5 d before ‘Hull Thornless’ and 8 d before ‘Chester Thornless’ plants . The datThe size, shape index and color of the fruit are the key factors that determine the price of fresh fruit . There iThe contents of soluble solids, acid and anthocyanin determine the nutritional value and taste of fruit . The matAnthocyanins are the most studied bioactive substances in blackberries at present, and their content determines the color of the fruit . The conThe main indicators for evaluating fruit trees include fruit quality, yield, fruit tree growth and adaptability. The yield of the Lishui test site was higher than that of Nanjing for all the cultivars. The production for ‘Ningzhi 4’ averaged 14.43 and 16.49 t/ha at Nanjing and Lishui, respectively, less productive than ‘Kiowa’  but more productive than ‘Hull Thornless’  and ‘Chester Thornless’ .Colletotrichum spp.) was found on berries or leaves of ‘Ningzhi 4’ after 5 years of planting. Moreover, this cultivar has very good field tolerance to root rot (Phytophthora fragariae var. rubi). The reaction of plants to rosette/double has not been determined definitively, but no symptoms have been observed on ‘Ningzhi 4’ after 5 years of planting. White drupelet development occurs during the ripening stage in some blackberry cultivars [Canes of ‘Ningzhi 4’ were thornless and semi-erect to erect, similar to ‘Chester Thornless’ plants . The ‘Niultivars . Very feIn recent years, the application of molecular marker technology in fruit tree germplasm identification, genetic relationship analysis, and early selection of breeding materials has developed rapidly ,24. SSR The amplification results of 11 pairs of polymorphic primers on the female parent ‘Kiowa’, male parent ‘Hull’ and excellent strain ‘Ningzhi 4’ showed that the proportion of polymorphic primers was 14.10%. The amplified bands of P4, P15, P21, P61 and other primers were the same as those of the male parent . P5, P6,After selection, 2 test plots of ‘Ningzhi 4’ were established at Lishui Scientific Research Base  and Nanjing Botanical Garden  of the Institute of Botany, Jiangsu Province and Chinese Academy of Sciences in 2009. The test design was a randomized block design. In Nanjing, 40 ‘Ningzhi 4’ plants were planted, and 20 plants of other cultivars were planted. In Lishui, 150 ‘Ningzhi 4’ plants (1.0 mu of land) were planted, and 50 plants of the other cultivars were planted. The planting row spacing was 2.50 m × 1.50 m, with optimal management conditions, sufficient fertilizer and water, and microirrigation conditions. The plants were obtained through rapid propagation by means of layering and tissue culture. Then, the regional tests were carried out to survey the plant growth and fruit outcome. In February 2011, ‘Ningzhi 4’ was planted with ‘Kiowa’, ‘Hull Thornless’ and ‘Chester Thornless’  in the 2 test plots, respectively.The plants were spaced 1.5 m apart in a row and 2.5 m apart. Trellises with wires at 1.8 and 2.0 m were used for all plants. The soil at Lishui is acidic clay loam with an organic matter content of 18.67 g/kg, a total nitrogen content of 1.25 g/kg, an available phosphorus content of 4.83 mg/kg and an available potassium content of 94.21 mg/kg. The soil in Nanjing is slightly acidic clay loam with an organic matter content of 11.25 g/kg, a total nitrogen content of 1.24 g/kg, an available phosphorus content of 7.54 mg/kg and an available potassium content of 62.21 mg/kg. In all plantings, standard cultural practices were used, including annual hand weeding, nitrogen fertilization (78 kg/ha N) using organic and inorganic compound fertilizers, normal irrigation through the drip system , summer topping (the plants were topped at 0.8–1.0 m), the dead branches removal (after fruit harvest) and winter pruning (after defoliation and before sprouting) ,27.The observational data were collected at the 2 sites in 2014 and 2015. Ask 30 professionals engaged in the fruit tree industry to visually observe the plant growth traits  and rate them on a scale of 1–10, of which 10 = erect, vigorous or thornless and 1 = trailing, poor growth or thorny. The fruit ratings included firmness  and flavor . Data for 10% and 50% bloom, and first (5%), peak (50%), and last harvest (95%) dates were recorded for 2014 and 2015 and averaged for the replicated plots at Nanjing and Lishui.A total of 25-berry samples  collected randomly once each season for 2 years were used to determine the fruit size and quality. The berry fruit size  was measured by using a Vernier caliper . The fruit shape index was used to calculate the ratio of the longitudinal diameter to the transverse diameter of blackberry fruit. The blackberry weight was calculated by the weighted mean through an electronic balance with a sensitivity of 10 mg. Seeds were extracted from the berries using a blender and dried at 70 °C for 24 h. Then, the 100-seed weight was measured. The data for fruit compositional characteristics (based on 25 berry samples randomly collected once each season for 2 years) included soluble solid, total acid and anthocyanin contents. The content of soluble solids was measured by the handheld refractometer . Use the automatic potentiometric titrator  to determine the total acid content. The content of anthocyanin in blackberry fruit was determined by the pH differential method using an ultraviolet spectrophotometer . The data for yield were calculated by the actual yield per plant × the average area per plant during fruit ripening in 2015. These trials consisted of 4 replications.At the beginning of May, 4–6 young leaves from the top down on the annual branches of 3 blackberry cultivars were collected. After collection, wipe off the dust on the surface of the leaves, place them in liquid nitrogen for rapid storage, and then place them in an—80 ultra-low temperature refrigerator for subsequent DNA extraction. The leaves of ‘Ningzhi 4’, ‘Kiowa’ and ‘Hull Thornless’ plants were collected to extract genomic DNA using a cetyltrimethylammonium bromide Plant Genomic DNA Kit . The DNA concentrations were estimated with a NanoDrop-1000 spectrophotometer . DNA quality was assessed for each DNA sample on 1% agarose gel. A total of 78 pairs of SSR primers were used, including 4 pairs from the red raspberry cultivar ‘Meeker’, 8 pairs from the blackberry hybrid ‘Marion’ , and the2O 5.7 μL. The PCR conditions were as follows: 94 °C for 5 min followed by 35 cycles of 94 °C for 30 s, 45 °C for 30 s, 72 °C for 30 s and final elongation at 72 °C for 10 min. PCR amplification for all SSR markers was carried out using an ABI Veriti 96 PCR system . The PCR products were resolved on an 8% nondenatured polyacrylamide gel (PAGE) and stained using a silver-staining protocol.PCR was carried out in a final volume of 10 μL containing: 1 μL 10 × buffer, 0.2 μL 2.5 mmol/L dNTPs, 2 μL 5 pmol/μL primer, 0.1 μL 5 U/μL Taq enzyme, 1 μL DNA template, and ddHp ≤ 0.05).The statistical analysis of all experimental data was performed using SPSS 22.0 software  by LSD and Duncan’s multiple range test (To develop blackberry cultivars suitable for local use and with independent intellectual property rights, it is particularly necessary to conduct cross-breeding research using domestic and foreign resources. ‘Ningzhi 4’ had excellent plant characteristics. This cultivar is a thornless shrub with vigorous growth, mature black fruit, good flavor and sweet taste. Its yield is higher than that of the ‘Hull’ and ‘Chester’ cultivars. Fruits were easily harvested, making them well suited to hand or machine harvesting. ‘Ningzhi 4’ is expected to perform well in areas where the ‘Kiowa’, ‘Hull Thornless’, ‘Chester Thornless’ or ‘Triple Crown’ cultivars are adapted. ‘Ningzhi 4’ should be planted in slightly acidic soil, loam or sandy loam, which can be popularized in most provinces of the Yangtze River basin in China, such as Jiangsu, Anhui, Zhejiang, and Hubei provinces.


Concerns over food safety issues during the coronavirus pandemic (COVID-19) have sparked worldwide interest. Being part of a farm-to-fork food safety chain, food handlers at home are the final line of defense in reducing foodborne diseases. The present study used a cross-sectional survey to investigate the knowledge, attitudes, and practices (KAP) of women food handlers in Jordan. The survey investigated the effect of the COVID-19 pandemic on women who handle food at home in terms of food safety KAP. One thousand one hundred twenty-six respondents completed a food safety questionnaire during the COVID-19 pandemic. With a mean score of 22.1 points out of 42, the results showed that women who handle food in their houses had insufficient knowledge, negative attitudes, and incorrect practices concerning food safety. The respondents demonstrated high knowledge, attitudes, and practices in the personal hygiene, cleaning and sanitation areas (≥ 60.0%). On the other hand, participants’ knowledge, attitudes, and practices regarding contamination prevention, health issues that would affect food safety, symptoms of foodborne illnesses, safe storage, thawing, cooking, keeping, and reheating of foods, as well as COVID-19 were all low (< 60.0%). The correlations between participants’ total food safety KAP scores and education, age, experience, region, and the pandemic effect on food safety were statistically significant (P ≤ 0.05). To the best of our knowledge, this study is the first conducted in Jordan to investigate food safety knowledge, attitudes, and practices by women handling food at home during the COVID-19 pandemic. Concerns about food safety have been raised globally after the World Health Organization’s (WHO) declaration of the COVID-19 pandemic in early 2020 as a worldwide crisis. This emergency inspired a global effort to adapt hygienic measures to prevent viral spread through respiratory droplets, generated via sneezing, coughing, or simply by breathing and talking .Salmonella, 16,260 Shigella, and 6912 Brucella outbreaks every year Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********  4. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********  5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: It is a well planned study to assess the food safety literacy among women food handlers at homes in Jordan.I have few questions. How the sample size was calculated? The designed questionnaire was in which language? As it is mentioned that questionnaire was distributed on social media, how it was ensured that it was rightly filled by a house woman? Please mention the necessary actions that can be taken on the basis of findings of this study to improve the knowledge of food safety.Reviewer #2: See the attached word,, Specific comments, as well as the revised pdf manuscript showing notes.See also below:IntroductionPage 3, Lines 56-58. What about studies conducted in developing countries, related to women food handlers? You should provide examples, if available, related to women food handling, in the Middle East area, and what data showed.Page 3, Lines 56-59. The EU studies, have these shown that the FBIOs are related to women food handlers? At home, be more specific. What it food prepared at home, or purchased from outlets other than home, or badly handled at home . I do not see how this study relates to women food handlers… unless you provide more details. .Page 3, Line 63. Did any of these studies, involve women? If any of those, did, what were the results? In summary? Expand on 1 or 2 studies…Page 3, Line 64. Do you perhaps mean “regional” instead of local? And if local is meant in Jordan, in what is your study being different from previous? And what were the results from these studies? If you meant, regional like Lebanon etc… state and give a short paragraph on these results.Page 3, Lines 68-80. Move this paragraph, in the beginning of the Introduction, best after line 41.Page 4, Line 73-76. Delete lines… that is…starting from “Most to situation”.Page 4, Line 81. Reword “Confront” to confronted… Use also past tense in other cases…in text, such as line 83; There “was” an urgent need…Pages 4-5, Line 83-87. Too long paragraph and needs splitting in 2 shorter sentences.Page 5, Line 86. “KAP” of what?Pages 4-5, Line 83-89. Are there any other related data on women food handlers, regional or global, and what the data showed? Include a paragraph, if available, to justify the need of limited regional or global studies, on women, especially handling food in the Middle East.Materials and MethodsPage 5, Line 103. Capitalize, “the Dep. of Statistics”Page 6, Line 122. Rewrite in these two parts…. In the second and third part.Page 6, Line 126. Reword “accurately assess what was meant to be assessed”. Why was a validation was conducted to those interviewed “face to face”?Page 6, Line 127. Replace people with “women” and the word “subjects” throughout the manuscript, also Line Page 7, Lines 149, 150 etc.Page 7, Line 140. Correct “Not” to not.Page 8, Lines 164-165. Have other studies used a different % (60) value? And why did you decide to use the 60% value, based on 1 study only? Justify.Results and DiscussionPage 8, Lines 168. In all, 1126 Jordanians. Reword better to “Jordanian” women…Page 8, Lines 172, 174. Replace the word “polled” with voted, as this is a word used for elections, and in other sentences.Page 9, Lines 186-187. “women food handlers in Jordan had inadequate knowledge, negative attitudes, and inappropriate practices”…. Is there a reason/reasons for that? Can you provide, why this is the case?Page 10, Line 205 . Replace the word “discovered” with reported or corroborated.Reword Legends of Figs 2-8. “Was given”.. Does not sound correct, perhaps reword with “given by”…Page 11, Line 229. Did the “Canadian” study involve women food handlers? If yes, include it to validate your results.Page 11, Line 230-231. “just 41.3 % segregate ready-to-eat food from raw food in the231 refrigerator”, you meant here “separate” or reword.Page 12, Line 237. Reword “Slovenian customers”.Page 12, Line 238. Edit the word “About” to “about”.Page 12, Lines 240, 245. Edit the word “identical” to “similar”, and food germs to “food bacteria”.Page 13, Line 255. “These findings are better than “that”. Reword these 2 words.Page 13, Lines 259, 263, 268. “of household women heat leftovers until they are boiling”. Reword. Also, “however, women in Lahore had a higher rate”. Include “of knowledge”. Also, and chicken tissue with “chicken meat”, and in Jordan's north… does not make sense. Page 14, Line 284. “tasting meals with the same utensils used to mix them”. Reword.Pages 14, 15…... Lines 388, 387, 383, 365, 360, 309, 301, 302, 299, 288, 289, 294. “subjects and polled”. Reword.Page 18, Lines 358, 369. “60th percentile”, should that be 60% or percentage?Page 20, Lines 378, 381, 385. Perhaps “correlations”? instead of connections?Discussion: Well supported, reasoned and being comprehensive.Tables: Well presented, as well also Figures, with statistical evaluations included.Conclusions: Adequate and well drawn.*“Please also refer to the revised Pdf copy” for additional corrections.Reviewer #3: Some minor corrections:page 9, line 191, some references were mentioned directly. Corrections should be done for all the references.Page 11, line 217, Figures mentioned but there were no figures in all the manuscript.**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Yes: Hafiz Muhammad ShahbazReviewer #1: Reviewer #2: NoReviewer #3: No**********https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, AttachmentPONE-D-22-35672 revised.pdfSubmitted filename: Click here for additional data file.AttachmentPONE-D-22-35672 revised.docxSubmitted filename: Click here for additional data file. 26 May 2023The manuscript has been revised to reflect all the comments. The "Response to Reviewers' file is now attached to the files section.AttachmentResponse to Reviewers PONE-D-22-35672 R1 25.05.2023.docxSubmitted filename: Click here for additional data file. 26 Jun 2023Food Safety Knowledge, Attitudes, and Practices Among Jordanian Women Handling Food at Home During COVID-19 PandemicPONE-D-22-35672R1Dear Dr. Osaili,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Ayechew Ademas Tesema, MScAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author  1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: All comments have been addressedReviewer #3: All comments have been addressed**********  2. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #3: Yes**********  3. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #3: Yes**********  4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #1: YesReviewer #3: Yes**********  5. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #3: Yes**********  6. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The authors have addressed my concerns and made the manuscript acceptable for publication. The abstract is comprehensive. Methodology followed is correct. The data is correctly analysed.Reviewer #3: Good Job and all the corrections have been done according to our suggestions. Best wishes for the authors**********  7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Yes: Hafiz Muhammad ShahbazReviewer #1: Reviewer #3: No********** 28 Jun 2023PONE-D-22-35672R1 Food Safety Knowledge, Attitudes, and Practices Among Jordanian Women Handling Food at Home During COVID-19 Pandemic Dear Dr. Osaili:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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A 19-year-old woman with a history of adjustment disorder presented with abdominal pain, bloating, and chronic diarrhea. Colonoscopy revealed multiple flat whitish areas, less than 3 mm in diameter, diffusely distributed throughout the entire colon and rectum. These findings were prominent under narrow-band imaging (NBI)  and morVideo 1 Flat nodular lymphoid hyperplasia resembling “apple tree branches” is seen in the colon during colonoscopy.A prior study reported that functional gastrointestinal disorders, now called disorders of gut–brain interaction (DGBI), were diagnosed in 63 % of the symptomatic patients with NLHDuring endoscopy, the lymphoid follicles may be seen as flat, slightly elevated, or polypoid areas. Usually, their size does not exceed several millimeters. Sometimes, the lymphoid follicles have a reddish outline, which has been referred to as the “red ring sign.” Currently, there are no clear guidelines for the follow-up and surveillance of patients with NLHEndoscopy_UCTN_Code_CCL_1AD_2AC