The aim of the present study was to analyze and synthesize the available evidence on caries experience (dmft/DMFT) and MIH in children. (2) Methods: A systematic review and meta-analysis were conducted according to the PRISMA statement. (3) Results: 59 papers published between 2007 and 2022 were included in the qualitative synthesis and 18 in the meta-analysis. The total sample of subjects was 17,717 (mean: 896), of which 2378 (13.4%) had MIH (mean: 119), with a girl/boy ratio of 1:1. The mean age of the enrolled participants was 8.6 (age range 7–10 years). Meta-analysis showed that MIH has a positive correlation with both dmft  and DMFT ; (4) Conclusions: Children with MIH should be diagnosed correctly and on time. Treatment and management options for moderate and severe forms of MIH should consider prognosis based on known risk factors, and secondary and tertiary prevention policies should also consider the multifactorial nature of caries etiology. In 2001, Weerheijim and members of the European Academy of Pediatric Dentistry (EAPD) coined the term “Molar Incisor Hypomineralization” (MIH) to define an enamel defect of systemic origin that affects one to four first permanent molars and can possibly affect permanent incisors. The first study in which the clinical features were described was published in 2003  AND (“children” [All Fields] OR “schoolchildren” [All Fields]) AND (“caries experience” [All Fields] OR (“DMFT” [All Fields] AND “dmft” [All Fields])).Reference lists of primary study reports were cross-checked to find further studies. Guided by the inclusion criteria, two authors (MM and AN) independently screened the literature by reading the titles and abstracts. The full text of each identified article was then read to determine its suitability for inclusion. Disagreements were resolved by consensus or by discussion with a third author (KJ).For each study, data were extracted independently by two authors (MM and AN) and analyzed by a third author (KJ) by creating a piloted spreadsheet and comparing them through it, according to Cochrane Collaboration guidelines . For misThe collected data items were: year of screening, country, city, continent, setting , screening setting , total sample, sample with MIH, total girls/girls with MIH, total boys/boys with MIH, age range and mean age in all screened groups , MIH definition, MIH severity, total number of teeth affected, molars/incisor ratio, dmft, and DMFT .As indicated by PRISMA, a methodological quality assessment provides an indication of the strength of the evidence provided by a study, as methodological flaws can lead to bias. For cross-sectional studies, according to the Newcastle-Ottawa Scale (NOS), the quality assessment score can range from zero to nine points, with a high score indicating a good-quality study .Selection bias (consecutive or random sample of patients enrolled), performance and detection bias (participant and operator blinding), attrition bias , and reporting bias  were identified, assessed, and attributed according to Cochrane guidelines .2-statistics and Cochran’s Q [p < 0.05. Publication bias was estimated using a funnel plot and applying Egger’s test of its asymmetry [Heterogeneity was assessed quantitatively using Ihran’s Q . The ressymmetry .Meta-analysis was performed with the R statistical program, v. 4.2.1 , using a random-effect model via the metafor R package . The meaThe influence of individual studies was verified using the difference in fit (DFFITS) diagnostic, Cook’s distance, and leave-one-out meta-analysis to assess how each individual study affected the overall estimate. 95% confidence intervals were used to demonstrate levels of uncertainty.The search strategy identified 591 potential articles: 148 in PubMed, 74 in Scopus, and 369 in Google Scholar. After eliminating duplicates, 356 articles were first screened. Subsequently, 192 articles were excluded because they did not meet the inclusion criteria. Of the remaining 154 articles, 95 were excluded because no relevance to the topic of the study was found. The remaining 59 articles were included in the qualitative synthesis and 18 in the meta-analysis . Table SThe included studies  12,28,2,42,43,44According to the Newcastle-Ottawa scale (NOS) for cross-sectional studies n: 59) [ 59,60,6,83,84,85The majority of studies included in the quantitative synthesis (88%) used random or comprehensive sampling ,42,43,4418 studies reported data on the Decayed, Missing, and Filled Teeth (DMFT) index ,42,43,44p < 0.001) positive effect on DMFT level (higher mean DMFT level in the MIH group). Study results are inconsistent; heterogeneity is significant (p < 0.001), with about 93% of the variability coming from heterogeneity. Egger’s test indicates funnel plot asymmetry (p = 0.026), which can be caused by publication bias.p < 0.001).Influence analysis did not reveal any influential studies in the DMFT meta-analysis . Leave-op = 0.011) positive effect on dmft level. Study results are inconsistent—heterogeneity is significant (p < 0.001), and about 98% of the variability comes from heterogeneity. Egger’s test does not indicate funnel plot asymmetry (p = 0.798).p = 0.015) in the case of study out [p < 0.022) in other cases.Influence analysis reveals one influential study  in the dtudy out  and confThis systematic review aimed to highlight the experience of caries in children with and without MIH. Fifty-nine articles were included in the qualitative evaluation and 18 in the meta-analysis. It was shown that MIH has a positive correlation with both dmft  and DMFT , from a total of 17,717 subjects.The results of this systematic review are not uniformly reflected in the literature, as there are studies both confirming and denying the presence of a correlation between MIH and dental caries.For example, the study by Lago et al.  showed nMolar incisor hypomineralization is a clinical condition that is often underestimated and left untreated. It affects school-age children from the time of eruption of the first permanent molars, although similar forms have been described that can also affect deciduous molars ,88.Despite the Global Oral Health Goals for 2020 set by the World Dental Federation, WHO, and the International Association for Dental Research to minimize the impact of dental caries on individuals and society and to formulate efficient strategies for caries prevention, detection, and management , caries The presence of MIH in the oral cavity is correlated with developmental defects in enamel, which can affect one or more first permanent molars and/or permanent incisors. Clinical signs are characterized by qualitative defects in the enamel. In severe cases, post-eruptive breakdown can occur on the occlusal surface of affected teeth, with dentin exposure and subsequent pulpal inflammation. Children presenting with severe occlusal forms can manifest behavioral problems because of the pain and hypersensitivity experienced . StrategIt is probable that the correlation between MIH and increased experience of caries in children is due to the fact that hypersensitivity acts as a barrier to the proper and regular performance of oral hygiene measures at home . A recenChildren with moderate and severe forms of MIH should be examined not only for caries risk but also for periodontal defects. In fact, the alteration of these parameters in childhood is prognostic for the adult individual’s oral health . MoreoveSurprisingly, no studies in the literature on dietary counseling in children with MIH were available, even though the clinical picture of the developing patient presenting with moderate and severe forms of MIH characterized by hypersensitivity should also be framed from the point of view of solid foods and beverages in the daily diet to decrease the risk of caries and periodontal inflammation as much as possible.The results must be carefully interpreted, as selection bias may affect the main outcomes (dmft/DMFT in subjects with/without MIH). Selection bias may occur when the age range of enrolled samples is different, as higher DMFT may be correlated with older populations; when MIH is assessed by different diagnostic criteria; or when the enrolled sample is from a dental clinic or is population-based, as those from dental clinics will be in greater need of treatment. In the present study, two studies (11%) ,38 were The results of the present systematic review and meta-analysis are in accordance with previous works. A systematic review published in 2017 evaluating the correlation between MIH and dental caries over a period from 2003 to 2015 in 14 countries showed a significant association between dental caries and MIH in 17 studies. The sample was smaller than the present one, and the authors warned that caution was needed in interpreting the results. Moreover, the OR was not comparable with the present results, as there was no meta-analysis .A case-control study on children aged 7–13 years presenting with MIH by Grossi et al. showed a higher caries experience in the permanent but not in the deciduous dentition . This laThe first permanent molars that have MIH are subject to the possible evolution of lesions over time. As already extensively documented in the literature, colorimetric alterations in MIH have prognostic value, as yellow-brown demarcated opacities have a faster evolution toward enamel breakdown and dentin exposure ,101.Children with MIH should be monitored at shorter intervals and should be followed up with a preventive therapeutic approach that can treat hypersensitivity in order to allow proper dental hygiene of mineralized surfaces and soft tissues and with a focus on household lifestyles in order to reduce risk factors for dental caries. The use of organic-based toothpastes with mineralizing and desensitizing agents should be encouraged, as they are claimed to be more biocompatible for children .Preventive measures for dental caries should include: (a) early diagnosis of caries and individual caries risk assessment; (b) methods that focus on enamel and dentin remineralization; (c) minimally invasive treatments; and (d) repair rather than replacement of restoration . In partA decrease in the incidence of dental caries has been demonstrated when prevention is targeted at developmental age in subjects with active but non-cavitated lesions. Applying minimally invasive methodology to routine dentistry leads to an early assessment of caries, which is important in avoiding overtreatment .The process of demineralization and remineralization of enamel constantly moves between mineral loss and gain. The long-term outcome is determined by the composition and amount of dental plaque, frequency and timing of sugar consumption, fluoride exposure, quality and quantity of salivary flow, enamel quality, and individual immune response ,103.S. mutans. These changes in oral biofilm increase the potential for enamel mineral loss, subsequent acid production, and a change in the oral microbiome that leads to an increased risk of developing carious lesions.Repeated consumption of carbohydrates, especially sucrose, leads to the predominance of cariogenic bacteria such as The use of sugar substitutes is one measure that helps people reduce their total intake of cariogenic sugars .Furthermore, regenerative medicine deals with dental caries. Several new protocols have been proposed to reconstruct the enamel surface. In situ regeneration of apatite crystals can create thick layers between the enamel and the restoration, while the enamel-like structure due to amelogenins can improve the properties of the etched enamel and prevent dental caries by preventing bacterial infection . For exaFinally, therapeutic strategies should include secondary preventive interventions to be implemented depending on the prognostic factors associated with individual MIH enamel changes and defects to prevent dentin exposure.Indeed, the authors often point out that since severe forms of MIH are not included in screenings, the DMFT index is often recorded with higher values due to the presence of caries after dentin exposure following post-eruptive enamel breakdown .The results of the present study, based on a sample size of 17,717 individuals with a mean age of 8.6 years, showed that molar-incisor hypomineralization is significantly correlated with a higher risk of caries in both the permanent and deciduous dentitions in children.


The lack of specific regulatory guidelines for nanotechnology-enabled health products (NHPs) is hampering development and patient access to these innovative technologies. Namely, there is an urgent need for harmonized regulatory definitions and classification systems that allow establishing a standardized framework for NHPs regulatory assessment. In this work, a novel classification system for NHPs is proposed. This classification can be applied for sorting nano-based innovations and regulatory guidelines according to the type of NHPs they address. Said methodology combines scientific and regulatory principles and it is based on the following criteria: principal mode of action, chemical composition, medical purpose and nanomanufacturing approach. This classification system could serve as a useful tool to sensor the state of the art of NHPs which is particularly useful for regulators to support strategy development of regulatory guidelines. Additionally, this tool would also allow manufacturers of NHPs to align their development plans with their applicable guidelines and standards and thus fulfill regulators expectations. This aDespite scientific and economic interests, there is still a considerable gap between the number of NHPs in research and development and those eventually reaching society. This becomes more evident when comparing the number of scientific publications or patents (NHPs at an early-medium stage of research and development) and the number of clinical studies with NHPs  with the number of approved NHPs.nanomedicine OR “nanomedical device” OR >> in scientific literature repository Scopus has considerably increased up to a total of 83,826 results as of May 2023  (nano’ by using the following search string: <<EN_TI:(nano*) AND CPC:(A61) AND DP:([01.01.2003 TO 31.05.2023])>> .Over the last 20 years, the number of scientific references in NHPs under search string <<May 2023 . Most spctively) . With reClinicalTrials.gov database under the keyword ‘nano’ with <<study start date>> in the last 20 years. Additionally, NHPs currently placed on the market, meaning that have reached regulatory approval, have also been considered to have a complete picture of NHPs in different stages of health product lifecycle. This is such a complicated task since there is no official repository of all NHPs currently marketed globally. Notwithstanding, the Nanotechnology Product Database (NPD) has been taken into account. This directory is regarded as one of the most reliable tools for institutions and policymakers involved in the establishment of their country policies and national strategic plans , the Food and Drug Administration (FDA) guidance FDA-2017-D-0759 on products involving nanotechnology, the European Commission (EC) recommendation on nanomaterial definition (2022/C 229/01), International Organization for Standardization (ISO) standard ISO TS 80004–1 on nanotechnology definitions and regulations on novel food, cosmetics, chemical substances and on biocides. Despite this, there are different nuances regarding what is considered at the nanoscale. For example, no lower limit is specified by the US-EPA or the novel food regulation. Additionally, regarding FDA-2017-D-0759 guidance, the upper limit is flexible up to 1,000 nm. Finally, the EC recommendation 2022/C 229/01, the chemical substances regulation and the biocides regulation limit the applicability of the nanomaterial definition to materials for which at least 50% of their particles are within the size range of 1–100 nm . ConsequOn the other hand, there are several classification systems for NHPs based on different criteria depending on the field of knowledge . NonetheThis work presents a novel classification system for NHPs with the aim of unlocking the development of NHP-specific harmonized regulatory guidelines that are useful for scientific and regulatory purposes.2.The following steps have been taken in the development of the proposed nanomaterials classification system: (i) defining key parameters, criteria, to consider, (ii) generating different NHP categories based on those parameters, and (iii) testing the proposed classification system against current developing and published regulatory guidelines.2.1.Guidelines and other regulatory documents have been gathered in a regulatory database that includes references identified as of May 2023 from the following sources:o Competent authorities:▪ EMA:https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-nanomedicines•▪ FDA:https://www.fda.gov/science-research/nanotechnology-programs-fda/nanotechnology-guidance-documents•o EC:https://ec.europa.eu/jrc/en/research-topic/nanotechnology▪ EU Science Hub: ▪ Scientific Committee on emerging and newly identified health risks (SCENHIR):https://ec.europa.eu/health/scientific_committees/emerging•o Organization for the Economic Co-operation and Development (OECD), Safety of manufactured nanomaterials:https://www.oecd.org/science/nanosafety/•o Standard emitting organizations:https://www.iso.org/committee/381983.html▪ ISO, Technical committee ISO/TC 229 on Nanotechnologies: ▪ American Society for Testing and Materials (ASTM), Technical subcommittee E56.08 on Nano-enabled medical products:https://www.astm.org/COMMIT/SUBCOMMIT/E5608.htm•2.2.Databases have been generated with Excel macro-enabled workbook format . Data processing and plotting was carried out by using dynamic tables.3.3.1.3.1.1.Quality, safety, performance and efficacy requirements applicable to a health product depend on the regulatory qualification of the product, i.e., its regulatory category . Additionally, these requirements are detailed in the legislative framework applicable to each regulatory category. Therefore, the first aspects to consider for the proposed classification system are characteristics determining the qualification of a given NHP under the regulatory categories for products for medical purposes, namely medicinal product, or medical device .purpose of the technology, the product shall be intended to be used for one or more specific medical purposes in humans. This aspect is common for medicines and medical devices regulatory categories at the EEA and the USA.The primary mode of action by which the technology achieves its medical purpose, i.e., whether the product exerts its principal action by pharmacological, immunological or metabolic means or not  include chapters and monographs with standardized methods for the assessment of quality parameters of medicinal products, which in most of the cases do not address specifically NHPs , 43. In Guidance on physico-chemical characterization of engineered nanoscale materials for toxicological assessment , setting up own methods or referring to relevant published literature. In order to bring some light to this issue, EC published a guidance addressing specific parameters for the safety evaluation of nanomaterials used in medical devices . Furthersessment . This inPhysicochemical characterization parameters addressed in the above-mentioned guidance documents have been listed in Next, the suitability as classification criterion of each of the ISO/TR 13014:2012(E) parameters is discussed . The firwhat is the chemical composition of the NHP? This question shall have a limited number of answers (previously referred to as categories). These accepted answers have been defined based on ISO/TR 11360:2010: Nanotechnologies — Methodology for the classification and categorization of nanomaterials (3 to 109 atoms])  which are dispersed in a solvent. They are thermodynamically unstable and lyophobic (hydrophobic colloids).Molecular colloids: nanomaterials made up of all types of polymers  and that are dispersed in a solvent. They are thermodynamically stable and lyophilic.Associated colloids: nanomaterials made up of amphipathic molecules (mainly carbon-based molecules) that self-assemble in the presence of a solvent and a tension-active surfactant. They are thermodynamically unstable and lyophilic.As concluded from aterials . This te atoms]) :Disperso3.1.3.in vitro, animal and/or human studies.Another general requirement for the regulatory assessment of health products is the demonstration of the mode of action of the NHP and the evaluation of its efficacy based on what is the medical use of the NHP?The regulatory strategy to address performance and efficacy of NHPs and the parameters to be assessed will depend on the medical use, including clinical indication and attributed benefits or claims. Therefore the next criterion considered for the proposed classification system is the broad medical use of the NHP. The question that this criterion would address is: On the one hand, for medicinal products, the definitions given by the EMA and the FDA include products with diagnostic, preventive or treating actions. In addition, apart from the active pharmaceutical ingredients (APIs), medicinal products also include excipients which, by definition, are the constituents of the pharmaceutical form apart from the API that can modify the pharmacokinetic profile of the formulated active substance . On the in vitro or in vivo) and (v) technological or galenic action.Based on the different possible general uses , the following categories are proposed for this criterion: (i) pharmacological therapeutic action, (ii) pharmacological prophylactic action, (iii) non-pharmacological therapeutic (treating/prophylactic) action, (iv) diagnostic action  published a study on the risks of environmental effects of medicinal products. According to this study, residues of various types of health products have been detected in various environmental compartments, such as surface water, groundwater, soil, air and biota , 67. ThiBearing this in mind, regulatory measures have been put in place to control environmental risk during health products development and manufacturing. At EEA level, for medicinal products all new marketing authorization applications are required to undergo an environmental risk assessment following a tiered assessment procedure . In the Focusing on NHPs, there are mainly two approaches for the nanomanufacturing: top-down  and bottom-up  . As a gewhat is the approach for the NHP nanomanufacturing? The possible answers to this question would be either a top-down or bottom-up approach.Consequently, it would be useful to include a criterion addressing the two main nanomanufacturing approaches within the proposed classification system. This criterion would allow identifying NHPs which, due to their nanomanufacturing approach, need a specific focus when assessing their environmental risk. The question this criterion addresses would be: 3.2.3.2.1.The classification system proposed includes a total of four classification criteria: principal mode of action, chemical composition of the core, medical purpose and nanomanufacturing approach . FurtherTargeting the qualification of the NHP based on its primary mode of action.Defining a battery of studies to meet the quality and safety requirements.Defining the strategy by which compliance with performance and/or efficacy requirements will be assessed.Including green nanotechnology and occupational risk considerations.The scope of the proposed classification system is intended to include both NHPs, as well as the corresponding regulatory documents that address relevant aspects to be considered during development for achieving regulatory approval of such products. Based on the latter, regulatory documents are classified in the compiled regulatory database according to the NHP they are referring to.3.2.2.in vivo and which is manufactured based on a bottom-up approach, the applicable signature would be 2.1.2.1 ..in vivo As indicated in the previous section, this classification system can also be applied for classifying regulatory documents, depending on their main scope or specific NHP category they relate to. In case a regulatory document does not meet one of the classification criteria, this can take the value “0” in the corresponding position of the signature. As examples:EMA reflection paper on surface coating: general issues for consideration regarding parenteral administration of coated nanomedicine products , working groups (EU Science Hub and SCENHIR) and standards issuing bodies . As a whole, this database reflects current knowledge in the regulation of NHPs and has therefore been considered as the NHP’s regulatory state of the art for the purposes of this work .All regulatory references included in said database are compiled in Next, This scenario of ‘regulatory science specialization’ resembles a similar situation taking place, at a greater advantage, for advanced therapy medicinal products (ATMPs). The assessment of ATMPs for regulatory approval requires very specific expertise, which went beyond the traditional pharmaceutical field and covers areas bordering on other sectors such as biotechnology, nanotechnology itself and medical devices . In respComing back to NHPs, a regulatory state of the art becoming more specialized can be noticed . Regulat4.The proposed classification system could allow regulators to monitor the regulatory state of the art of NHPs for performing strategic regulatory development. By using future-oriented methodologies such as Horizon Scanning, it would be feasible to elucidate the main trends in the future development of NHPs. By mapping the classification signatures of these future trends with the regulatory state of the art, it will be possible to foresee the existence of possible gaps in regulation that will hamper the regulatory approval of these developments. Regulators will be able to anticipate these future regulatory needs and target the development of guidelines and standards in an efficient manner.valley of death.Furthermore, this classification system could be also useful for developers and manufacturers to link their technologies with the applicable regulatory guidelines. By applying this classification system to the regulatory state of the art and integrating it in a platform, developers could query on their NHPs with a specific classification signature. The platform would return all the regulatory guidelines potentially applicable to that technology, from the most general to the most specific documents. All in all, the potential uses of the proposed classification system are aimed to foster NHPs development, NHPs regulatory approval and, consequently, mitigate current The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.FDRG conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft, visualization, and project administration. PRG, DM, and OP: conceptualization, validation, writing—review and editing, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.This work was supported by the Industrial Doctorates Plan of the Department of Research and Universities of the Generalitat de Catalunya (Grant n° 202015).Authors FDRG, OP, and DM were employed by company Asphalion SL.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Internal loading can significantly delay the improvement of eutrophication in lakes. When external nutrient inputs are controlled and internal loading intensifies, the dissolved oxygen condition at the water-sediment interface improves during non-algal bloom seasons, but more anaerobic conditions occur during algal bloom seasons. Macroinvertebrates, living at the water-sediment interface, are particularly sensitive to such changes. Our results indicate that, in large shallow Lake Taihu, the changes in dissolved oxygen conditions at the water-sediment interface, caused by intensified internal loading, significantly affect the community structure, diversity, and response to eutrophication of macroinvertebrates.In eutrophic lakes, even if external loading is controlled, internal nutrient loading delays the recovery of lake eutrophication. When the input of external pollutants is reduced, the dissolved oxygen environment at the sediment interface improves in a season without algal blooms. As an important part of lake ecosystems, macroinvertebrates are sensitive to hypoxia caused by eutrophication; however, how this change affects macroinvertebrates is still unknown. In this study, we analysed the monitoring data of northern Lake Taihu from 2007 to 2019. After 2007, the external loading of Lake Taihu was relatively stable, but eutrophication began to intensify after 2013, and the nutrients in the sediments also began to decline, which was related to the efficient use of nutrients by algal blooms. The community structure and population density of macroinvertebrates showed different responses in different stages. In particular, the density of oligochaetes and the Shannon–Wiener index showed significant differences in their response to different stages, and their sensitivity to eutrophication was significantly reduced. Under eutrophication conditions dominated by internal loading, frequent hypoxia occurs at the sediment interface only when an algal bloom erupts. When there is no bloom, the probability of sediment hypoxia is significantly reduced under the disturbance of wind. Our results indicate that the current method for evaluating lake eutrophication based on oligochaetes and the Shannon–Wiener diversity index may lose its sensitivity. Excessive accumulation of nutrients resulting from human activities has led to eutrophication, posing significant threats to lake ecosystems. Internal loading is an important source of nutrients in lake water. Even in some lakes, more than half of the nutrients that flow into a lake through surface runoff will pass through the nutrient cycle and then enter the sediments to be buried . High inBenthic macroinvertebrates mainly live on the surfaces of sediments, and changes in the physical and chemical properties of sediments impact them . MacroinUnder climate change scenarios, global warming , wind spIn China, due to rapid economic and population growth, the water pollution caused by the discharge of pollutants has gradually increased, especially eutrophication. Subsequently, the Chinese government made many investments in water pollution control and set up the Major Science and Technology Program for Water Pollution Control and Treatment in 2006 to develop pollution control technologies. After nearly ten years of management, nutrients in major rivers and lakes have been reported to have declined ,26, and For lakes, the reduction in organic-pollutant input will improve the anoxic conditions of the water-sediment interface, and during the eruption of cyanobacteria blooms, the anoxic conditions of the water-sediment interface will be aggravated. Hypoxia is fatal to lake macroinvertebrates, and how macroinvertebrates respond to this change has not yet been studied.In this study, the northern bay area of Lake Taihu  was taken as the research object. This lake is one of the lakes that has received the most limnological research  and has 2), shallow , and eutrophic lake located in the southern Yangtze River Delta [Lake Taihu, the third largest freshwater lake in China , is a laer Delta . To bett2 sampling area, three replicates) and sieved in situ through 250-μm-aperture mesh. In the laboratory, the samples were sorted on a white tray, and the specimens were preserved in a 7% buffered formalin solution. The specimens were identified to the species or genus level and counted. Water temperature (Wtemp), depth, and pH were measured in situ by a multiparameter water-quality sonde , and transparency (SD) was measured by a Secchi disk.Macroinvertebrate samples were collected with a modified Peterson grab (0.025 mMn) concentrations were measured in the laboratory based on [During invertebrate sampling, mixed water samples from the surface layer, middle layer, and bottom layer were collected at each site. The total nitrogen (TN), total phosphorus (TP), chlorophyll (Chla), and permanganate index (CODbased on . In Lakehttp://cdc.cma.gov.cn (accessed on 10 November 2022)).High-frequency monitoring of the dissolved oxygen concentration at the bottom of Lake Taihu (10 cm above the water-sediment interface) was conducted every hour using YSI 6600 V2 multisensor sondes . The monitoring period spanned from 10 October 2007 to 15 July 2016, and the sensors were deployed in Meiliang Bay . Daily wind data from 1 January 2007 to 31 December 2020 from the WuXi weather station , located near Meiliang Bay and Zhushan Bay, were obtained from the China Meteorological Data Sharing Service System (The geom_smooth function  in ggploMn [The trophic level index (TLI) recommended by the Chinese National Environment Monitoring Center was used to assess the eutrophication level of lakes. This index was assessed using five main indicators of responses to nutrients: Chla, TP, TN, SD, and CODMn ,36. AccoMn ,38, and Mn ,21. Therp < 0.05. For the calculation of the Shannon-Wiener diversity index, Margalef’s diversity index and Pielou’s index were used; see Shannon [Regression analysis was performed to analyse the relationship between the density and diversity index of benthic macroinvertebrates and eutrophication. Before performing regression analysis, we used an empirical exponent of 0.25 to transform the macroinvertebrate density data to better approximate a normal distribution . Correla Shannon , Margale Shannon , and Pie Shannon .p values were obtained with the function envfit from the vegan library [p < 0.05) were selected. For the different classes of macroinvertebrates, a random forest regression model was used to analyse the relative importance of environmental factors to their density changes.We used nonmetric multidimensional scaling (NMDS) analysis to show the characteristics of the macroinvertebrate community changes. In the multivariate analysis, species density data were used, and the top 20 dominant species were selected. Since the sediment is sampled only in May every year, the macroinvertebrate data in May were used for analysis. NMDS analysis based on Bray–Curtis distances produced three-dimensional solutions meeting the criterion of a final stress of <0.2 . The NMD library , and sigThe random forest regression model analysis was completed using the R package ‘randomForest’. The R package ‘samba’ was used to test whether the slope and intercept difference between the regression equations were significant .−1 in 2007 to 2.48 mg·L−1 in 2019 . TP first declined from 1.53 mg·L−1 in 2007 to 1.25 mg·L−1 in 2012 and then began to rebound . The silt% maintained fluctuations of approximately 78% after 2009 but increased significantly from 65.6% in 2007 to 77% in 2009. Affected by massive stocking, the fish yield of Taihu increased year by year .The TN in North Taihu showed a significant declining trend from 4.79 mg·L rebound . From 20ound , and the density remained stable from 2013 to 2019  showed that the community structure in the northern lake area had a horseshoe shape . The sigThe high-frequency monitoring results of bottom-layer dissolved oxygen (DO%) also indicate that the occurrence of low dissolved oxygen concentrations increased in August after 2013. However, there were no significant changes observed in May. Further analysis showed that after 2013, in the autumn and winter seasons (November and February) without blooms, the diversity of macroinvertebrates in North Taihu did not show a declining trend, while in the season of cyanobacterial blooms, the diversity index showed a declining trend .2 = 0.50, p < 0.001), but during the period 2014–2019, although the two were still significantly correlated , the correlation slope was significantly lower (p < 0.001) than that in the previous period, and the intercept of the regression equation was also significantly different (p = 0.007) , but during the period 2014–2019, the linear regression results showed that the relationship between the two was not significant. The Margalef diversity index and Pielou’s index also showed the same results  . Similar results .From 2007 to the present, there was no significant increase in external nutrient loading in Taihu , but eutPrevious studies have shown that lake macroinvertebrates are sensitive to environmental changes and are strongly influenced by oxygen, predation, substratum type, and habitat complexity ,48,49,50In Taihu, under the situation of an increase in internal loading, although the eutrophication of lakes has increased, there is no significant increase in nutrient input. During the cyanobacteria outbreak season, the death and decomposition of algae can easily lead to hypoxia on the sediment surface, and many benthic macroinvertebrates will suffocate ,53; howeRegarding the use of macroinvertebrates for eutrophication assessment, our results showed that from community to population, macroinvertebrates responded differently to eutrophication changes caused by internal loading or external input. Especially for the oligochaete number and the diversity index, most of the assessment methods consider their response to eutrophication ,54,55. UWith the gradual control of external nutrient loading, the contribution of internal loading to eutrophication in recent years has gradually increased. Our results show that the community structure of macroinvertebrates responds markedly differently to this. Intensified internal loading leads to weaker (or not significant) correlations between macroinvertebrate diversity and eutrophication-tolerant species numbers with the TLI index. The main reason for this change is that during internal loading intensification, the DO at the water-sediment interface improves in seasons without blooms, whereas hypoxia occurs frequently during blooms . By comp


Background and Objectives: Ulcerative Colitis (UC) subtypes defined by disease extent and shared pathophysiology are important. Analyzing the clinical characteristics of UC with different disease extent and optimizing clinical typing are conducive to the pathogenesis research, disease monitoring and precise treatment.Methods: 188 patients with active UC were divided into distal and extensive colitis. The clinical characteristics of the two groups were analyzed by propensity score. Spearman is used for correlation analysis, and receiver operating characteristic (ROC) curve was used to evaluate the ability of clinical indicators to predict Mayo endoscopic subscore (MES).Results: Compared with distal colitis, extensive colitis had more severe disease activity, younger age, higher utilization rate of corticosteroids and incidence of extra intestinal manifestations (EIMs), and clinical indicators were differentially expressed in the two groups. After using propensity score, the incidence of EIMs in the extensive colitis was still higher than that in distal colitis. Inflammation, coagulation and immune indicators like CRP, FC, IL-10, D-D and α1-MG are higher in extensive colitis, and metabolic indicators like LDL-C, HDL-C, TC, GSP and albumin are higher in distal colitis. The correlation between clinical indicators and MES is affected by disease extent. The area under curve (AUC) of CRP + D-D + α2-MG for predicting distal colitis MES3 was 0.85, and the AUC of IL-6+ GSP+ α1-MG predicted extensive colitis MES3 can reach 0.82.Conclusion: Differential clinical indicators can become potential markers for predicting disease progression and prognosis, and have significance for UC mechanism research and drug development. We can select biomarkers according to lesion site. Ulcerative colitis is a chronic intestinal inflammatory disease. Different from Crohn’s disease (CD), which is another type of inflammatory bowel disease (IBD), UC is confined to the colon, and mucosal inflammation may extend continuously from the rectum to the proximal end as the disease progresses . Severe The Lancet proposed a new classification of IBD based on different pathogenesis, providing a new idea for the mechanism research and clinical precision treatment of IBD , left-sided colitis (E2) and extensive colitis (E3). A systematic review showed that 69.5% of UC patients had distal colitis, and patients with extensive colitis accounted for 30.5%, and the 10 year colectomy rate is 19% for those with extensive colitis, 8% with left-sided colitis and 5% with proctitis . The disCurrently, some studies have focused on the potential value of clinical site phenotype in the selection of treatment regimen and pathogenesis of UC, and actively explored the predictive markers related to disease site progression . HoweverIn this retrospective study, we collected 188 UC patients who visited the Department of Gastroenterology, Jiangsu Provincial Hospital of traditional Chinese medicine from 1 January 2019, to 30 April 2022.This study was approved by the ethics committee of Jiangsu Provincial Hospital of Chinese Medicine from January.All patients were diagnosed according to the combination of UC clinical, endoscopic, and histopathological criteria. Montreal classification was used to assess the lesion site, modified Truelove and Witt were used to classify the disease severity.Inclusion criteria: 1) meet the diagnostic criteria of ulcerative colitis; 2) In the activity period of ulcerative colitis. Exclusion Criteria: 1) diseases such as shigellosis, intestinal tuberculosis, amoebiasis, Ischemic colitis and Crohn’s disease were excluded; 2) complicated with immune system diseases such as Rheumatoid Arthritis, Sjögren’s syndrome and systemic lupus erythematosus; 3) complicated with heart, brain, kidney, hematopoietic system and other important organs damage or serious infection.Clinical information on patients with UC, including age, sex, symptoms, and colonoscopy and histopathology results, was collected from the electronic medical record system.2 test is used for comparison. Spearman was used for multivariate correlation analysis. The difference is statistically significant if p < 0.05, and the difference is statistically significant if p < 0.01.R (version 4.2.1) was used for data analysis, and the normality test was carried out for the measurement data. The measurement data conforming to normal distribution or approximate normal distribution is expressed as ‾x ± s, and two independent sample T-tests were used for analysis; nonparametric rank sum test was used for data not conforming to normal distribution. The counting data are expressed as the number of cases or the rate (%), the χPropensity score was used to minimize bias and adjust for confounding factors. We used a propensity score to match the gender, age, disease duration and disease activity of the two groups. Using a greedy nearest neighbor matching approach, in which each patient in the distal colon group was matched to an extensive colon group, ultimately producing the smallest within-pair difference among all available pairs with treated patients. Patients were matched only if the Logit difference in paired propensity scores between the two groups was less than or equal to 0.5 times the pooled estimate of standard deviation.A total of 188 patients with active UC were included in this study. There were significant differences in age, disease activity, incidence of EIMs and utilization rate of corticosteroids between the two groups. Patients with distal colitis were mainly mild to moderate, and patients with extensive colitis were mostly moderate to severe. Partial Mayo scores were also statistically different between the two groups, but there was no difference in MES. .The coagulation function of UC patients is closely related to the degree of disease activity and the state of inflammation. The results in We next carried out a comparative analysis of the patient’s immunological indicators, mainly including complement(C), immunoglobulin (Ig) and immunoprotein electrophoresis. The results showed no significant difference in immunoglobulins between the two groups, and the serum level of C3 in distal ulcerative colitis was lower than that in extensive colitis, but there was no significant difference in C4. The results of immunoprotein electrophoresis showed that the ratio of α1- Micro globulin (MG), α2-MG, β1-MG in patients with distal colitis was also significantly lower than that in patients with extensive colitis .We classified and compared some metabolic related indicators in the biochemical indicators, including lipid metabolism, glucose metabolism and protein metabolism . The comFrom the above comparison results, it can be seen that the disease activity level of extensive colitis is higher than distal ulcerative colitis. In order to further clarify whether there are differences in clinical indicators between distal and extensive colitis, we use propensity score to balance the degree of disease activity of the two groups of patients .The results showed that after excluding the influence of disease activity factors, there was no difference in age, utilization rate of corticosteroids and pMayo between the two groups, but the incidence of EIMs in extensive colitis was still higher than that in distal colitis. Although some clinical objective indicators have become similar after balanced treatment with propensity score , there are still many other indicators that are differentially expressed between the two groups .Patients with distal and extensive ulcerative colitis have different disease activity, and this difference significantly affects the expression of clinical markers. We performed Spearman correlation analysis for the above clinical indicators. . There iWe selected the indicators with strong correlation with MES for group analysis. The results showed that there was no correlation between ESR and MES in both groups of patients, while IL-6 and GSP were only correlated with MES in extensive colitis and not in distal colitis. CRP, FC, D-D, FDP, a1-MG and a2-MG were correlated with MES in the two groups. Although the correlation coefficients were different, there was no statistical difference between the two groups .We further analyzed the ability of clinical indicators to predict MES 3 in both groups of patients, and the research results are presented as ROC curves in In patients with extensive colitis, the AUC of CRP, FC, IL-6, FDP, GSP and α1-MG independently predicted MES 3 is 0.70, 0.65, 0.70, 0.73, 0.76, and 0.70, respectively, and the AUC of IL-6 + GSP+ α1-MG predicted MES3 can reach 0.82, with sensitivity and specificity of 66% and 94%, respectively .The site phenotype of ulcerative colitis is dynamic and closely related to the disease activity, which suggests that we cannot judge the disease condition based on the initial lesion site, so dynamic follow-up is required during treatment. In this study, we divided the patients into two groups: distal and extensive ulcerative colitis, and compared their clinical characteristics and objective indicators.The results showed that the age, disease activity and the incidence of EIMs were in great differences between the two groups. These three are interrelated, and were listed as high-risk characteristics of ulcerative colitis in the 2019 ACG and AGA adult UC guidelines, emphasizing more active treatment in the early stage . In the Biomarkers for disease activity monitoring and treatment response have been a notable topic for research of UC in recent years. In this study, we incorporated the clinical objective indicators including cytokines as much as possible. In the first part of the study, we found that a large number of clinical indicators were differentially expressed in the two groups. Most of these clinical indicators have been confirmed to be related to the disease activity of ulcerative colitis in previous studies . In ordeThe abnormal immune response of intestinal mucosa is an important internal factor causing inflammation and tissue damage in UC . CytokinTC, LDL-C, HDL-C, Albumin, GSP and other metabolic markers were also differentially expressed in the two groups. The metabolic process of the body is regulated by many physiological and pathological links. The dysregulation of intestinal flora is related to a variety of human metabolic diseases. Studies have found that the amount and types of beneficial bacteria which has important and unique significance for the integrity of intestinal mucosal barrier are significantly reduced in the gut of IBD patients. . IntestiA large number of studies have focused on clinical markers used to predict disease activity, but few have examined whether the predictive value of different biomarkers is influenced differently by lesion site. To this end, we preliminarily explored the correlation between clinical biomarkers and MES in two groups. ESR was associated with MES overall, but after grouping ESR was not associated with MES in either distal colitis or extensive colitis. Furthermore, IL-6 and GSP were associated with MES in extensive colitis but not in distal colitis. CRP, FC, D-D, FDP, a1-MG and a2-MG were correlated with MES in the two groups. Although the correlation coefficients were different, there was no statistical difference between the two groups. In addition, the ability of biomarkers to predict MES 3 in the two groups are different. The lesion site of ulcerative colitis may affect the predictive ability of biomarkers.In conclusion, this study conducted a comparative analysis of the clinical characteristics and objective indicators of distal colitis and extensive colitis, with the aim of finding biomarkers related to disease site extension and exploring the significance of different indicators in predicting disease activity, mechanism research and drug development. However, this study is only a preliminary exploration, subsequent large-scale retrospective studies and prospective clinical studies are needed to further verify the results.The manuscript, including related data, figures and tables has not been previously published and that the manuscript is not under consideration elsewhere.


Malnutrition is strongly linked to adverse outcomes in patients with Crohn’s disease (CD). In this study, our objective was to validate the Global Leadership Initiative on Malnutrition (GLIM) criteria and develop a fast and accurate diagnostic approach for identifying malnutrition in CD patients.This study assessed 177 CD patients from four general hospitals. The efficacy of the GLIM criteria for the diagnosis of CD malnutrition was compared. By analyzing the independent factors, a nomogram model was derived and internally validated to predict the diagnosis of malnutrition in patients with CD. Model performance was assessed using discrimination and calibration, decision curves, and net benefit analyses.Compared with the SGA criteria, the GLIM criteria was consistent in sensitivity (88.89%) and specificity (78.43%) . The Harvey-Bradshaw index(HBI) score , body mass index , and mid-upper arm circumference  were independent factors associated with malnutrition. The nomogram was developed based on these indicators showing good discrimination in malnutrition diagnosis , with agreement after calibration curve and decision curve analysis.The GLIM criteria are appropriate for diagnosing malnutrition in CD patients. The HBI score may be used to diagnose malnutrition in patients with CD and become a possible selection for the GLIM etiologic criteria of inflammation. The HBM nomogram could be a simple, rapid, and efficient method for diagnosing malnutrition in CD patients. MalnutrIn the past few decades, several tools have been used in the clinical diagnosis of malnutrition in patients with CD. The World Health Organization (WHO) considers the body mass index (BMI) as an essential indicator of malnutrition ; howeverIn 2018, the GLIM criteria were proposed as the global uniform criteria for the diagnosis of malnutrition . The GLIIn addition, In the clinical application of the GLIM criteria, multiple parameters are utilized for diagnosing malnutrition based on the criteria. Due to the complexity and time-consuming nature of using multiple parameters, it would be beneficial to develop a simplified yet accurate clinical approach for diagnosing malnutrition upon admission in patients with CD.Therefore, the objective of this study was to assess the reliability of the GLIM criteria in diagnosing malnutrition in patients with CD. Furthermore, the study sought to investigate the specific etiological criteria incorporated in the GLIM criteria for diagnosing malnutrition in patients with CD. Moreover, the aim was to develop and validate a simplified, efficient, and precise diagnostic approach for identifying malnutrition in CD patients. Ultimately, this will contribute to the early detection of malnutrition in patients with CD and facilitate timely diagnosis and treatment.2.2.1.This study is a multicenter, prospective, observational study (registration number: ChiCTR2000035720). The study enrolled patients diagnosed with Crohn’s disease at four general hospitals, including the Affiliated Jinling Hospital of Nanjing University, The First Hospital of China Medical University, Sir Run Run Shaw Hospital, and The Affiliated Hospital of Qingdao University, during the period from September 2020 to May 2021. All assessments and data collection were carried out within 48 h of admission for each patient.The study’s inclusion criteria were as follows: (1) age ≥ 18 years, (2) diagnosis of Crohn’s disease based on clinical, radiologic, endoscopic, and histologic criteria, and (3) willingness to participate in the study and provide written consent. The exclusion criteria were: (1) emergency surgery for an intestinal fistula or abdominal abscess, (2) unstable vital signs or hemodynamics, (3) pregnant or lactating women, (4) admission due to other critical comorbidities or organ dysfunction, (5) patients with a life expectancy of less than 24 h, (6) immunosuppressive treatment for conditions unrelated to inflammatory bowel disease (such as organ transplantation), (7) contraindications to bioelectrical impedance analysis (BIA), making body composition analysis unsuitable, and (8) patients who had already been selected for participation in other clinical studies see .2.2.Within 48 h of admission, researchers collected baseline characteristics including sex, age, height, weight, and history of smoking and drinking. They also gathered information related to inflammatory bowel disease (IBD), recent changes in non-volitional weight loss, and food intake. The Inflammatory Bowel Disease Questionnaire (IBDQ) was used to assess the quality of life (QoL) of patients with Crohn’s disease. The IBDQ is a validated and reliable measurement tool . Several2.3.Physical function was evaluated using various measures, including body composition, mid-upper arm circumference (MUAC), muscle strength, the five-repetition sit-to-stand test (5STS), and the 6-meter walk test. The patient’s left arm was in a state of natural sagging when the MUAC was measured. The circumference of the left upper arm was measured at the midpoint twice, and the average value was calculated . Other s2.4.The Crohn’s Disease Activity Index (CDAI)  and HBI 2.5.p values < 0.05 were considered as independent predictors. Random forest plots were drawn to demonstrate the precision and importance of the predictors, and incorporated into nomograms for the individualized predictions of malnutrition. To evaluate the performance of the nomogram, the area under the curve (AUC) was calculated to assess discrimination. Additionally, calibration curve analysis was performed with 1,000 bootstrap repetitions to evaluate calibration. Decision curve analysis was conducted to evaluate the clinical utility of the nomogram by calculating the standardized net benefits at different threshold probabilities. Several recommended malnutrition diagnostic tools were set as comparators to the nomogram model, including the WHO-related BMI, ESPEN, and SGA criteria.Multivariate logistic regression analysis was performed using the stepwise selection method based on Akaike’s information criterion to identify independent risk factors for malnutrition in patients with CD. Variables with 2.6.p < 0.05) were included in the logistic multivariate regression analysis model (backward selection) to determine independent risk factors for malnutrition. For all analyses, statistical significance was determined using a significance level of p < 0.05. The statistical software packages SPSS  and MedCalc  were utilized for conducting the statistical analyses.Categorical variables were presented as frequencies or percentages. For continuous variables, normal distribution was assessed, and the results were reported as mean and standard deviation (SD) if normally distributed, or median and interquartile range (IQR) if not normally distributed. Univariate analysis was performed by Pearson Chi-square test or Fisher exact probability method, and factors with statistical difference . Prior to the commencement of the study, all patients provided informed consent by signing a consent form.3.3.1.2, mean age, 36.4 ± 13.5 years) were enrolled in the analysis, as shown in p < 0.05). The IBDQ score of patients with malnutrition was significantly lower than that of well-nourished patients . No statistically significant differences were observed between the two groups in terms of age, sex, and duration of disease .A total of 177 hospitalized patients with CD  with the SGA criteria. When compared to the SGA criteria, the ESPEN criteria were superior to the WHO criteria in all aspects of data on malnutrition diagnosis in patients with CD，while the GLIM criteria were superior to the ESPEN criteria in sensitivity (88.89% vs. 70.64%) and negative predictive value (78.43% vs. 54.88%), and the specificity (78.43% vs. 88.24%) and positive predictive value (91.06% vs. 93.68%) were not far behind those of the ESPEN criteria. According to the ROC curve analysis results . These variables were included in the multivariate logistic regression analysis. After stepwise variable screening, three variables were screened as independent factors related to malnutrition in CD patients , including BMI , MUAC , and HBI score . A random forest plot was constructed to show the precision and importance of these predictors  was conducted as indicated in 4.In the present study, we investigated the validity of the GLIM criteria for the diagnosis of malnutrition in patients with CD and observed higher HBI scores in patients with malnutrition compared with those with normal nutritional status. For the first time, we used the HBI score as an independent diagnostic parameter for identifying malnutrition in patients with CD. Additionally, we integrated BMI and MUAC to develop and validate a simple, efficient, and precise diagnostic method for malnutrition in CD patients.Our study found that the prevalence of malnutrition in CD patients was 69.5%, according to the GLIM criteria, in line with previous findings of studies that employed the GLIM criteria as a standard , 19, 21.Owing to the use of the GLIM criteria, current research has gradually recognized the important role of etiological criteria for the diagnosis of malnutrition; however, they still focus more on the phenotypic criteria, ignoring the specific selection of the etiological criteria for the GLIM criteria, resulting in diversity. In three studies investigating inflammatory bowel disease (IBD), the plasma C-reactive protein (CRP) level was examined as a specific marker for the GLIM etiological criteria of inflammation , 18, 21,However, Huang et al.  showed tDuring the analysis of the inflammatory etiology criteria for the GLIM criteria, our results showed that HBI score was independently associated with GLIM-defined malnutrition . HBI is associated with nutrient deficiencies in malnourished patients, which further supports our results , 29. In To simplify the diagnostic process, we developed the HBM nomogram model. Although there are many nomogram models for the prediction of postoperative complications in CD , 33, no Significantly, compared to other forecasting models , the HBMWe acknowledge some limitations in the study. First, our nomogram model can only diagnose malnutrition in patients with CD and cannot distinguish the severity of malnutrition. Second, there is a lack of external validation cohorts due to the limitation of the sample size; therefore, it is necessary to further expand the sample size and conduct further research to improve the evaluation model. Nevertheless, we are cautiously optimistic that the HBM nomogram may be useful once externally validated.5.In summary, the GLIM criteria are appropriate for diagnosing malnutrition in patients with CD. In addition, we developed and validated a simple, rapid, and efficient nomogram model for malnutrition diagnosis in patients with CD, and external validation in independent cohorts is recommended. This is the first study to use the HBI score as a diagnostic indicator of malnutrition, thus suggesting that the HBI score may be a possible selection for the GLIM etiological criteria of inflammation.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by The Affiliated Jingling Hospital of Nanjing University . The patients/participants provided their written informed consent to participate in this study.The study was conceived and designed by XW and WZhu. The trial protocol was designed and drafted by XW, YZ, and LZ. The statistical analysis plan was contributed by LH and YS, who also performed the statistical analysis. LH, FN, and YS were involved in drafting and critically revising the manuscript. The research was conducted by YZ, CD, YH, YW, WZho, QC, XJ, and HJ, who were responsible for the data collection and hands-on work. Data curation and quality checking were carried out by LH, YZ, CD, YW, and XJ. All authors critically revised and approved the final version of the manuscript, and share responsibility for its content.This work was funded by the 13th Five-Year Plan Foundation of Jiangsu Province for Medical Key Talents (ZDRCA2016091) and the Science Foundation of Outstanding Youth in Jiangsu Province (BK20170009).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fnut.2023.1236036/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


Background: Cancer, also known as a malignant tumor, is caused by the activation of oncogenes, which leads to the uncontrolled proliferation of cells that results in swelling. According to the World Health Organization (WHO), cancer is one of the main causes of death worldwide. The main variables limiting the efficacy of anti-tumor treatments are side effects and drug resistance. The search for natural, safe, low toxicity, and efficient chemical compounds in tumor research is essential. Berberine is a pentacyclic isoquinoline quaternary ammonium alkaloid isolated from Berberis and Coptis that has long been used in clinical settings. Studies in recent years have reported the use of berberine in cancer treatment. In this study, we performed a bibliometric analysis of berberine- and tumor-related research.Materials and methods: Relevant articles from January 1, 2002, to December 31, 2021, were identified from the Web of Science Core Collection (WOSCC) of Clarivate Analytics. Microsoft Excel, CiteSpace, VOSviewer, and an online platform were used for the literary metrology analysis.Results: A total of 1368 publications had unique characteristics. Publications from China were the most common (783 articles), and Y. B. Feng (from China) was the most productive author, with the highest total citations. China Medical University (Taiwan) and Sun Yat-sen University (China) were the two organizations with the largest numbers of publications (36 each). Frontiers in Pharmacology was the most commonly occurring journal (29 articles). The present body of research is focused on the mechanism, molecular docking, and oxidative stress of berberine in tumors.Conclusion: Research on berberine and tumors was thoroughly reviewed using knowledge map and bibliometric methods. The results of this study reveal the dynamic evolution of berberine and tumor research and provide a basis for strategic planning in cancer research. In every nation worldwide, cancer ranks as a primary cause of mortality and a significant roadblock to increasing life expectancy . The morCoptis chinensis and other Berberis species  publications in a language other than English. A total of 1,368 papers were obtained.Published studies from January 1, 2002, to December 31, 2021, related to BBR and tumors were collected from the Science Citation Index Expanded (SCI-E) of the Web of Science (WoS) Core Collection (WOSCC) of Clarivate Analytics. To guarantee the reliability and accuracy of the findings, we performed pertinent pretests and improved the retrieval method. The retrieval method is illustrated in All retrieved documents were used for the bibliometric analysis. We extracted information including titles, annual publications, countries and institutes, authors, references, keywords, and scientific cooperation analysis. Data were independently extracted from a set of articles by TY and YRZ. SP-H mediated the outcomes if a disagreement arose.We used CiteSpace (version 6.3. R3), VOSviewer (version 1.6.18), Bibliometrix (version 3.1.4), R language (version 3.6.3), and Microsoft Excel 365 for data analysis and presentation.CiteSpace, developed by Prof. Chao-mei Chen, is a bibliometric mapping analytical tool used worldwide, most predominantly in China . It is aVOSviewer, developed by van Eck and Waltman, creates visual network maps of scientific information, including bibliometric network analysis . We usedhttps://www.bibliometrix.org) is an open-source instrument for quantitative scient-metric research. Machine-learning software was used to evaluate the distribution of each component examined in the bibliometric investigation. The variables were annual scientific production, average citations per year, most impactful journals by H-index or total citations (TC), top journals’ production over time, most relevant authors, most globally and locally cited documents, most pertinent affiliations, country-level scientific output, international collaboration network, country of origin of the corresponding author, top producing nations over time, historical direct citation network, most widely cited publications, most pertinent keywords, and keyword cluster analysis. Impact factor (IF) and partition information for the journals referred to the “Journal Citation Report (JCR) 2022.” These analytical methods offer unbiased and varied viewpoints on the function of berberine in tumor formation. The variables are presented as numbers and percentages in the descriptive study. p-values were not reported because no comparisons were made.Visualization of the annual publication numbers; country, institute, author, and journal rankings; cited reference bursts; and most globally and locally cited Local Cited Documents, was performed using Microsoft Excel 365. Additionally, we performed a descriptive study of writer output over time and keyword evolution in Bibliometrix . BibliomWe assessed the historical development process, current research conditions, and forecasted future trends in development by statistically analyzing the general usage of BBR pharmacological functions in the number of publications over time.0.2604x, which conforms to Price’s law. The simulation curve had a relatively strong coefficient of determination (R2 = 0.9543), which fitted the annual literature growth trend well. Based on this curve, we predicted that the number of annual articles will steadily increase, indicating increased interest in research on BBR and tumors.We counted the number of papers related to “berberine and tumors” from 1972 to 2021 and collected 1,587 articles for bibliographic records from the WOSCC. Ultimately, 1,368 articles were eligible for the next stage of analysis based on the exclusion criteria of publication time, document type, and language. n = 97), Italy (n = 61), Iran (n = 60), Japan (n = 42), Egypt (n = 30), Germany (n = 26), and Poland (n = 24).Statistics on the research countries reporting on publications related to “berberine and tumors” showed the stages of BBR pharmacology development in each country and made comparisons easier. According to WoS, many countries have participated in research in the last 20 years. Publications from China ranked first in total number of citations, but the average number of citation per paper was very low, only 30.14%, compared to the top 10 countries. Although the number of articles published by Germany was limited compared to China, the average citation per article ranked second among the top 10 countries. This finding suggested that the publications were of very high quality and had certain reference values. The H-index is a mixed quantitative indicator that considers both the number of posts and the required number of citations and can be used to identify influential researchers . China’s). As shown in Using an online bibliometric analysis platform, we evaluated the significance of nations in the visualization of cooperative networks. Katz and Martin, two scientists, defined scientific cooperation as the study of academics collaborating to create new scientific knowledge, known as scientific collaboration . Figure The top 10 productive institutes are listed in The top 10 authors in terms of the number of articles in the past 20 years are listed in Frontiers in Pharmacology (IF = 5.9879) was the most popular journal with 29 articles, followed by Molecules (IF = 4.9269) with 28 articles. PLOS One (IF = 3.7521) was the most frequently cited journal . The distribution of journals across fields, evolution of citation trajectories, and drift of scientific research centers can be displayed using the dual-map overlay of journals . Moreover, current cancer treatments are inefficient, and the surgical prognosis is poor because tumor cells can invade and spread after treatment with a variety of chemical medications . NaturalFrontiers in Pharmacology (29 articles), followed by Molecules (28 articles). We also analyzed the reference with the strongest citation burst; the latest literature of the co-cited reference was “Berberine, an epiphany against cancer,” which was published in Molecules in 2014. This article summarizes the molecular targets of BBR, several mechanisms by which BBR inhibits cancer, and the potential discovery of BBR derivatives for anti-cancer drugs  published the most studies related to BBR and tumors worldwide. However, the University of Hong Kong ranked first in terms of average citations per article. Y. B. Feng, an author based in China, was the most productive and had the highest total citations. The journal that published the most articles was er drugs . Our anaAs shown in In clinical practice, most patients experience the invasion and migration of cancer cells from a single focus to other distant tissues. In 2015, research on migration and invasion became a hot topic . A wide Apoptosis was the main keyword in BBR-related research  and the Research on the effect of BBR on cell cycle arrest started around 2012 but was mainly concentrated in 2017 . To someNumerous studies have reported that BBR regulates cell signal transduction by inhibiting tumor cell proliferation. As shown in in vitro and in vivo  signaling, which in turn reduces colon cancer growth  in vivo . This re and Sun Yat-sen University. The terms “mechanism,” “molecular docking,” and “oxidative stress” are now popular study topics related to BBR in tumors.


Objectives: This study aimed to assess the prevalence of trimester-specific dietary supplements (DS)s use and their possible correlates during pregnancy.Method: Pregnant women were convenience sampled and recruited from a comprehensive obstetric care center in Shanghai, China. Data relating to the use of DS during pregnancy, social support and other social-demographic and obstetric data were collected. Trimester-specific DS use and factors related DS were explored.Results: Of the 2803 women participating in this study, 94.8%, 96.2%, 93.8%, and 94.4% reported the use of at least one DS during pregnancy  and in the first, second, and third trimesters of pregnancy, respectively. Significant differences were noted in the use of DS containing folic acid, calcium, iron, vitamins, and docosahexaenoic acid (DHA), during the three trimesters of pregnancy. A higher proportion of DS use was negatively associated with certain categories of pregnant woman, including unemployed/housewife, low education level, obese, and low social support. A positive association was identified with gestational age.Conclusion for practice: Considering the high prevalence of DS use during pregnancy, future studies are needed to evaluate the accuracy and suitability of DS usage during pregnancy. Maternal nutritional status during pregnancy is essential for both maternal and fetal health. Of particular importance are micronutrients such as folate acid, iron, calcium, and zinc, all of which are considered to be positively related to fetal brain development . HoweverVariations on the prevalence of DS use during pregnancy are evident across different countries. The reported prevalence of at least one DS use during pregnancy was 75.3% in Japan (the majority of participants were in mid-to-late pregnancy) , 77.6% iFurthermore, the use of DS has been reported to relate to a variety of factors at both the individual and national levels. Studies have shown that socioeconomic status, such as age, gender, educational level, employment status, income, marital status, residence, and medical insurance status, are all factors that could affect the use of DS in a general population . HoweverIt is vital that we understand the specific use of DS during pregnancy, consider important implications for the formulation of appropriate and effective interventions for the appropriate use of DS, and produce public health policies relating to maternal nutrition in pregnancy. Under this perspective, the objectives of the present study were to: (a) measure the prevalence of the trimester-specific use of DS, and (b) investigate the factors related to the use of DS by women. We hypothesized that the prevalence of DS use will vary across the different periods of pregnancy and that the use of DS might be related to sociodemographic and obstetric characteristics in pregnant women.This was a cross-sectional survey that was conducted to investigate the trimester-specific use of DS by pregnant women in Shanghai, China. We also investigated the factors associated with the use of DS. The paper was written in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.A convenience sampling method was used to recruit pregnant women who registered their pregnancy in the study hospital and attended their routine antenatal visits. Given the utilization of multivariate analysis in the present study, a sample size of 150–300 participants is recommended to ensure a stable test, with 10–20 participants per independent variable being deemed appropriate, and given the estimated number of independent variables that potentially relate to the use of DS in this study, which is 15. And from epidemiological point of view, considering that 300,000 deliveries are reported in the study setting each year, we selected a 10% (n = 3000) sample for our survey. The inclusion criteria were (1) ≥ 18 years of age, (2) pregnancy confirmed by B ultrasound, (3) competent in Mandarin, (4) able to use a mobile phone, and (5) agreed to participate in the study. The exclusion criteria were as follows: (1) cognitive or mental disorders and (2) severe pregnancy complications. Of the 3000 women approached, 124 refused to participate, while 2803 completed the questionnaires (a response rate of 93.4%). This study was reviewed and approved by the Ethics Committee of the Shanghai First Maternity and Infant Hospital (Reference: KS19101).etc., but ruled out folic acid supplementation alone. Although folic acid is also a vitamin, we have listed this agent separately because it plays a vital role during pregnancy. We also provide an “other” response for women to record the brand name of the DS they used if they did not know the ingredients. The “other” response was categorized into seven items by the researcher based on ingredients. A panel of experts  examined the DS use checklist for validity. A pilot survey of 40 pregnant women showed that the test-retest reliability over 2 weeks of all DS items was 0.75–0.86.To the best of our knowledge, there are no widely recognized tools available to investigate the use of DS by women during pregnancy. Referring to a series of related studies , we deveSocial-demographic characteristics included age, ethnicity (Han Chinese or ethnic minority), educational level , occupation (employed or unemployed/housewife), marital status (married or single/divorced), local residence (Shanghai or non-Shanghai), medical insurance , and social support. Except for social support, all social-demographic characteristics were extracted from electronic medical records. Social support was evaluated by the social supported rating scale. This scale was designed by Xiao in 1986 and was revised in 1994 . This is2); normal weight (18.5 kg/m2 ≤ BMI <24.0 kg/m2); overweight (24.0 kg/m2 ≤ BMI <28.0 kg/m2); and obese (BMI ≥28.0 kg/m2) , mode of conception , gestational age, pregnancy risk grading , pre-pregnancy body mass index (PPBMI), and history of adverse pregnancy. The pregnancy risk grading was routinely evaluated for all Chinese pregnant women who registered their pregnancy in a hospital l. The severity of pregnancy risk was classified into five colors: green (low risk), yellow , orange (high risk), red (very high risk) and purple (infectious disease). PPBMI was categorized into four groups according to the WHO recommendation on adult body mass index (BMI) classification for the Asian population: underweight (BMI <18.5 kg/m0 kg/m2) . HistoriThis study was conducted over 1 year (May 2020–May 2021). The study involved a paper-free survey; this was due to the forced restriction of unnecessary contact during the COVID-19 pandemic. The research staff approached pregnant women who were waiting for their routine antenatal visits and explained the basic details of the study to eligible participants. After informed consent was obtained, a quick response code (QR code) for the electronic questionnaire was presented. This allowed the study participants to scan the QR code using their smartphones to complete the survey online. To ensure the uniqueness of each participant, each pregnant woman’s medical card number would only be allowed to participate once in this study. The questionnaire was completed in approximately 3–5 min during pilot testing. The research staff were nearby to provide assistance with the questionnaire if necessary; these staff allowed an adequate time for the patients to rest and ask questions.p < 0.05) were then re-evaluated by multiple regression analysis with a stepwise procedure . For all analyses, the alpha level of significance was set to 0.05.Data were analyzed using the Statistical Package for Social Sciences version 20.0 for Windows . Social-demographic characteristics, obstetric characteristics, and the use of DS during pregnancy, were reported using descriptive statistics. Trimester-specific DS use was tested by the Chi-squared test and advanced pairwise comparisons were adjusted by the Bonferroni correction. Group differences in the overall use of DS were tested by t-tests or by one-way analysis of variance. And chi-square tests were used to analyze group differences in each DS based on sociodemographic and obstetric data. Multiple linear regression analysis was also performed to explore factors related to the use of DS. Social-demographic and obstetric characteristics that were related to DS use in univariate analysis  and in the first, second, and third trimester of pregnancy was 94.8%, 96.2%, 93.8%, and 94.4%, respectively. 278 (9.9%) of the women chose an “other” option. The “other” responses mainly include some brand names of DS which could be categorized into folic acid, multi-vitamins, and DHA. But also include some traditional Chinese medicine, such as bird’s-nest, donkey-hide gelatin, p < 0.001) during the three trimesters, as determined by the Chi-squired test. Pairwise comparisons further showed that the use of folic acid supplements decreased as the pregnancy progressed. Peak use (93.1%) was noted in the first trimester; this rate decreased dramatically (by 49.4%) in the second trimester and reduced even further during the third trimester. In contrast, the use of iron supplements increased as the pregnancy progressed; the use of these supplements was. relatively low (7.9%) in the first trimester but then increased during the second trimester and reached a peak (61.7%) during the third trimester. The use of calcium, vitamins, and DHA supplements, all increased during the second trimester and remained stable in the third trimester. The use of iodine and zinc supplements was extremely low throughout pregnancy .Univariate analysis showed that employment, educational level, marital status, local residence, medical insurance, social support, gestational age, and PPBMI, were all factors that were significantly related to the number of DS types used by pregnant women ; Table 2p = 0.010), low educational level , obese  and low social support , but was positively associated with gestational age   . FactorsIn the present study, we investigated the use of DS by women during pregnancy as well as the social-demographic and obstetric factors related to the use of DS. This is the first contemporary study to describe the trimester-specific prevalence of DS use in a population of Chinese pregnant women. In this study, the utilization rate of DS among pregnant women in Shanghai, China, was much higher than that reported in other counties , thus suWe also identified a relatively higher proportion of women taking folic acid supplements during pregnancy  when compared to the study of a Swedish cohort (74.4% used folic acid in the first trimester compared to 43.2% in the third trimester). However, our results were similar to those reported by a previous study conducted in four cities in China, which found that 95.1% of pregnant women took folic acid supplements during pregnancy or 3 months prior to pregnancy . The repBut it is indicated that socioeconomic disparities in the utilization of folic acid during pregnancy still exist . FurtherIn addition, the demand for additional calcium during pregnancy has been well-established . An adeqAlong with folate acid and calcium, iron is one of the nutrients for which dietary intake alone cannot realistically meet the increased demands of pregnancy. In addition, due to the low bioavailability of dietary iron, iron supplementation is usually recommended for women during pregnancy to prevent and treat maternal iron deficiency anemia (IDA), but must be used with caution . In factIn this study, vitamin supplements were used by 30.9%, 40.6%, and 43.7% of women in the first, second, and third trimesters; these figures are relatively lower than those reported by Savard et al.  . This fiThis study considered the use of dietary supplements (DS) during pregnancy under both medical guidance and self-administration by pregnant women. Folic acid supplementation during the first trimester is generally a self-initiated practice among expectant mothers for prenatal care. In cases where early prenatal consultations reveal a lack of folic acid intake, physicians may prescribe the supplement accordingly. Clinical assessments are typically used to detect calcium and iron deficiencies, and if such deficiencies are diagnosed, supplementation or prescription may be recommended. However, some pregnant women may choose to take these supplements for preventive purposes. Vitamins and DHA, on the other hand, are typically self-administered by pregnant women.We also investigated the sociodemographic and obstetric factors related to the use of DS among pregnant women. We found that being unemployed, being a housewife, having a low educational level, low levels of social support, and being obese, were all negatively associated with the number of DS types used by pregnant women. These results are supported by a previous study carried out in Sweden which showed that education level and employment were associated with the use of DS during early pregnancy . A previIn addition, we observed an increase in the use of DS in married women, those living in Shanghai, and those that had medical insurance. However, these associations did not retain significance in the multivariable model. Although parity was also reported as a factor related to the use of DS during pregnancy in Sweden  and NorwThere are some limitations associated with the present study that we need to consider. First, this study was conducted in one hospital in Shanghai; most participants were highly educated. Second, the use of DS in this study was only evaluated by yes or no questions, the advantage of this instrument is that it provides a time-effective means of providing dietary surveys in a busy clinical setting. A disadvantage, however, is the limited accuracy of the dietary data. Furthermore, we were unable to calculate the actual intake of supplements and food sources. Therefore, it was impossible to compare the actual intake with dietary recommendations in the current study. Future studies should involve a larger and more representative sample and include more detailed dietary investigations. In addition, the use of DS prior to conceptional was not investigated in this study. Finally, the cross-sectional study design precludes the investigation of any specific causal relationships.In summary, we demonstrated a high prevalence of DS use in women during pregnancy and the use of DS was associated with employment status, educational level, perceived social support, PPBMI, and gestational age. The findings of the current study emphasized the crucial need for future studies to evaluate the accuracy and suitability of DS usage during pregnancy. Due to the high prevalence of DS use during pregnancy, synergistic efforts between policymakers, maternal and child nutrition experts, and obstetric health workers, are highly recommended to guide the appropriate use of DS during pregnancy, such as education, monitoring, and taking necessary actions.


To determine the efficacy of hyperbaric oxygen therapy (HBO) in the treatment of necrotizing soft tissue infections (NSTI), we conducted a meta-analysis of the available evidence.Data sources were PubMed, Embase, Web of Science, Cochrane Library, and reference lists. The study included observational trials that compared HBO with non-HBO, or standard care. The primary outcome was the mortality rate. Secondary outcomes were the number of debridement, amputation rate and complication rate. Relative risks or standardized mean differences with 95% confidence intervals were calculated for dichotomous and continuous outcomes, respectively.p < 0.05]. However, the number of debridements performed in the HBO group was higher than in the non-HBO group . There was no significant difference in amputation rates between the two groups . In terms of complications, the incidence of MODS was lower in the HBO group than in the non-HBO group . There was no significant difference in the incidence of other complications, such as sepsis, shock, myocardial infarction, pulmonary embolism, and pneumonia, between the two groups (p > 0.05).A total of retrospective cohort and case-control studies were included, including 49,152 patients, 1448 who received HBO and 47,704 in control. The mortality rate in the HBO group was significantly lower than that in the non-HBO group [RR = 0.522, 95% CI , The current evidence suggests that the use of HBO in the treatment of NSTI can significantly reduce the mortality rates and the incidence rates of complications. However, due to the retrospective nature of the studies, the evidence is weak, and further research is needed to establish its efficacy. It is also important to note that HBO is not available in all hospitals, and its use should be carefully considered based on the patient's individual circumstances. Additionally, it is still worthwhile to stress the significance of promptly evaluating surgical risks to prevent missing the optimal treatment time.The online version contains supplementary material available at 10.1186/s13017-023-00490-y. Necrotizing soft tissue infections (NSTI), also known as necrotizing fasciitis (NF), are a rare but serious type of infection that can rapidly progress and lead to life-threatening consequences if not promptly and aggressively treated –4. NSTI HBO has been used to treat various conditions for over 50 years, starting with Brummelkamp's finding that hyperbaric oxygen conditions can suppress anaerobic infections . HBO hasGiven the rarity and seriousness of NSTI, and the absence of evidence-based guidance on using HBO in its treatment, we carried out a systematic review and meta-analysis to assess the impact of HBO on the clinical outcomes of NSTI and provide evidence-based guidance for its use in this condition.This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines  The PRI, 2. The A literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews from their inception to November 28, 2022 to identify relevant studies on the use of HBO in the treatment of NSTI, including NF and Fournier gangrene (FG). The search terms used were "necrotizing soft tissue infection," "necrotizing fasciitis," "Fournier gangrene," and "hyperbaric oxygen therapy." The language of the studies included in the review were restricted to English. The literature search strategy and full search string can be found in Additional file The following criteria were used to determine eligibility for inclusion in this study: (1) Clinical trials and observational studies published before November 28, 2022; (2) Participants diagnosed with NSTI (or NF or FG); (3) Studies that compared the use of HBO with no use of HBO; (4) Studies that reported at least one outcome of interest. The following types of studies were excluded: (1) Conference abstracts, reviews, animal studies, case reports, editorials, letters, etc.; (2) Duplicate studies; (2) Full text unavailable; (3) Studies from which data could not be extracted; (4) Studies with inappropriate outcomes; (5) Studies with low sample sizes . Two reviewers (CH and YZ) independently reviewed candidate studies by screening title and abstract, and identified the studies which met the inclusion criteria. In the event of uncertainty, the eligibility of a study was discussed between the two reviewers (CH and YZ), and any disagreements were resolved depending on the third independent reviewer (BH).The following data were extracted from included studies, if available: first author, year of publication, study design, country or region of the study, sample size, mean or median age, sex, body regions affected, confounders and the outcome of interest.Two reviewers independently evaluated the characteristics and quality of the included studies using the Newcastle Ottawa Scale . Any disRelative risks (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for dichotomous and continuous outcomes, respectively. As clinical heterogeneity and methodological heterogeneity are inevitable at any time, we performed a meta-analysis using a random effect model.Publication bias was evaluated by visual inspection of funnel plots.Subgroup analyses were conducted based on pathological entity.p value ≤ 0.05 was considered statistically significant.All statistical analyses were carried out using R software (version 4.0.2). A The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to access the overall certainty of evidence. By GRADE system, the certainty of evidence derived from cohort studies receive an initial grade of low quality. The quality of evidence from cohort studies can be improved at larger effect sizes (RR ≥ 2 or ≤ 0. 5), dose–response gradients, or attenuation by plausible confounding after excluding various factors that could lead to downgrading. Finally, the evidence of outcomes can be graded as being of high, moderate, low, or very low.A literature search identified a total of 2349 studies, of which 1508 were removed due to duplication or overlap. An additional 750 studies were excluded after screening titles and abstracts, leaving 91 full-text studies. Of these, 68 studies that did not meet the inclusion criteria were excluded, leaving 23 studies that were eligible for inclusion in the review. Figure The Newcastle–Ottawa quality assessment scale was used to evaluate the quality of the evidence. According to this scale, all of the selected studies received at least 5 stars, indicating a low to moderate risk of bias Table .Table 1NAll 23 studies , 19–39 ip < 0.05] ] and the mean mortality rate in the non-HBO group was 25.6% [95% CI ]. The study found that the mortality rate in the HBO group was significantly lower than that in the non-HBO group   , p < 0.05]. The number of debridements in the HBO group was higher than in the non-HBO group  in the non-FG subgroup, while there was no statistical significance of the number of debridements between the HBO group and non-HBO group  in the FG subgroup. There was no statistical significance in the incidence rate of sepsis between the HBO group and non-HBO group  in the non-FG subgroup, as well as in the FG subgroup . . The funnel plot is shown in Fig. The funnel plot did not show significant publication bias for the mortality rate p = 0.08. The funThe GRADE level of evidence is very low for mortality rate, amputation rate, very low for number of debridement. GRADE evidence certainty for the outcomes is shown in Table NSTI are a type of rapidly progressing infection that can be highly destructive to the skin, subcutaneous tissue, and superficial fascia . These ip = 0.01). Some studies even reported that no patients in the HBO group died [In this study, 23 eligible retrospective studies were identified, with 65.2% of the patients being male. Previous research has shown that NSTI is more common among elderly males, with a mean age of over 50 years, which is consistent with the findings of this study . The litoup died . Accordioup died , 23. Addoup died  also obsoup died . HoweverThere are several limitations to be considered in this systematic review and meta-analysis of the effectiveness of HBO in patients with NSTI. Firstly, the retrospective study design may result in inconsistent data quality and availability of certain clinical and laboratory parameters. While this is a limitation, it is worth noting that it would not be ethical to deprive patients of HBO treatment in many cases, and therefore it would not be feasible to conduct a prospective randomized controlled trial , 27. SecThe current evidence suggests that the use of HBO in the treatment of NSTI can significantly reduce the mortality rates and the incidence rates of complications. However, due to the retrospective nature of the studies, the evidence is weak, and further research is needed to establish its efficacy. It is also important to note that HBO is not available in all hospitals, and its use should be carefully considered based on the patient's individual circumstances. Additionally, it is still worthwhile to stress the significance of promptly evaluating surgical risks to prevent missing the optimal treatment time. Given the rarity of the disease, it is essential to continue producing high-quality research to provide guidance to clinicians.Additional file 1. PRISMA 2020 Checklist.Additional file 2. PRISMA 2020 for Abstracts Checklist.Additional file 3. The literature search strategy.Additional file 4. Forest plots of subgroup analyses.