To address the obesity epidemic, there is a need for novel paradigms, including those that address the timing of eating and sleep in relation to circadian rhythms. Electronic health records (EHRs) are an efficient way to identify potentially eligible participants for health research studies. Mobile health  apps offer available and convenient data collection of health behaviors, such as timing of eating and sleep.The aim of this descriptive analysis was to report on recruitment, retention, and app use from a 6-month cohort study using a mobile app called Daily24.Using an EHR query, adult patients from three health care systems in the PaTH clinical research network were identified as potentially eligible, invited electronically to participate, and instructed to download and use the Daily24 mobile app, which focuses on eating and sleep timing. Online surveys were completed at baseline and 4 months. We described app use and identified predictors of app use, defined as 1 or more days of use, versus nonuse and usage categories  using multivariate regression analyses.Of 70,661 patients who were sent research invitations, 1021 (1.44%) completed electronic consent forms and online baseline surveys; 4 withdrew, leaving a total of 1017 participants in the analytic sample. A total of 53.79% (n=547) of the participants were app users and, of those, 75.3% (n=412), 50.1% (n=274), and 25.4% (n=139) were immediate, consistent, and sustained users, respectively. Median app use was 28 (IQR 7-75) days over 6 months. Younger age, White race, higher educational level, higher income, having no children younger than 18 years, and having used 1 to 5 health apps significantly predicted app use (vs nonuse) in adjusted models. Older age and lower BMI predicted early, consistent, and sustained use. About half  of the participants completed the 4-month online surveys. A total of 33.5% (183/547), 29.3% (157/536), and 27.1% (143/527) of app users were still using the app for at least 2 days per month during months 4, 5, and 6 of the study, respectively.EHR recruitment offers an efficient  approach to recruiting participants from health care settings into mHealth research. Efforts to recruit and retain less engaged subgroups are needed to collect more generalizable data. Additionally, future app iterations should include more evidence-based features to increase participant use. Obesity and its related medical comorbidities are highly prevalent public health conditions -5. The sMobile devices and mobile health  apps are ubiquitous, readily available approaches to collect real-time data on health behaviors, such as dietary intake, physical activity, and sleep -18. mHeaAlthough mHealth research has grown exponentially in the last few decades, study attrition is a major problem, and there is a need to identify successful, low-burden, and efficient recruitment and retention strategies ,27. The This study presents a secondary analysis from a 6-month, multisite, cohort study that used the EHR to identify and recruit participants to use a mobile app (Daily24), designed to assess timing of eating and sleep . The maiDescribe the EHR-based recruitment and electronic consent (e-consent) methods and response rates for enrolling in the study and downloading the mobile app.Describe engagement strategies, app use, and retention rates during the 6-month study.Evaluate demographic and behavioral predictors of Daily24 app use.We hypothesized that people who are younger, have greater education, and have higher BMIs would be more likely to use the app. This study has the potential to inform the field of behavioral health in methodology, uptake, and engagement of mHealth approaches for observational research.We recruited a cohort of adult patients from three health care systems in the PaTH Clinical Research Network, part of PCORnet . The three health care systems included the Johns Hopkins Health System, the Geisinger Health System, and the University of Pittsburgh Medical Center -37.Institutional Review Board (IRB) approval was obtained from the Johns Hopkins School of Medicine (IRB00174516), which had a reliance agreement with the other institutions’ IRBs.Potential participants were identified using EHR-based eligibility criteria  to querPotentially eligible participants were sent recruitment messages via email or the patient portal  from February to July 2019. Each partnering health care system tailored its own strategy to recruit participants from the large pool of potentially eligible patients who were identified using the computable phenotype. One site used patient portal recruitment almost exclusively, focusing on patients who had a health system visit in the last week. The other two sites sent email recruitment letters through their primary care and weight management practices, with messages signed by the clinic medical directors. We designed a web-based e-consent process in REDCap (Research Electronic Data Capture) beginning with a study description, including participant expectations and duration see . Upon coThe Daily24 mobile app was custom designed by our research team to collect information from participants about the timing of eating and sleep, including wake time, sleep time, timing of each eating occasion, and estimate of amount eaten  during a 24-hour window . The desFollowing enrollment in the cohort, participants received a text message on their mobile phones with a unique link to the Daily24 registration form. This unique link contained a token  that enabled the study team to connect participants’ data between the mobile app and their online enrollment information and surveys, while preserving privacy. Registration included an overview of how to use the app, study timeline, and incentives (see next section), followed by selection of a unique “Daily24 name” from a list of randomly generated combined nouns  that, once selected, was the participant’s Daily24 username. Participants then received a link to download the Daily24 app via iOS (Apple Store) or Android (Google Play).Although we encouraged participants to enter as much data as possible over the 6-month study, we developed and applied strategies aimed at maximizing app use during their first 4 weeks of participation  and 1 week per month for the remaining 5 months of the study, called “POWER weeks” . These hDaily24 app usage data were collected using Amazon Web Services. Self-reported online surveys were administered using REDCap at baseline and at the end of 4 months using standard measures assessing demographics, mHealth use, height, and weight, as well as eating, physical activity, and sleep habits. Technology use and health app use were assessed using the Pew Social Media Update 2016  and a suTo facilitate and encourage baseline survey completion, participants received automated reminders at 15 minutes, 24 hours, and 48 hours after consent and had up until 90 days after receiving the initial survey link to complete the survey. Personalized survey-engagement strategies included a combination of staff emails, text messages, and US $100 raffle gift cards. Participants had up until 60 days to complete the 4-month measures, but this paper only reports baseline survey descriptive results. Data collection was completed in January 2020.App users were defined as using the Daily24 app for at least one day, which was captured by having at least one meal and sleep entry, on at least one day, and pushing “done for the day” on the screen. Nonusers either did not register or download the app or did not push “done for the day” on any day. App use was further categorized into three non–mutually exclusive ways:Immediate use, defined as using the app for 7 days or more during the POWER 28.Consistent use, defined as using the app for 28 days or more during the entire 6-month study, which was based on using the app equal to or more than the median overall days of use for the entire 6-month study.Sustained use, defined as using the app for at least 2 days during the last POWER week (month 6) of the study.2 tests) for baseline characteristics for all participants and by app use versus nonuse categories. App use was also described in median days of use for the total study, median days used in targeted and nontargeted usage days, and frequency of 2 or more and 7 or more days of use during each month of the study. We selected these two categories based on the following logic:This was a secondary analysis of data from a parent cohort study. We used descriptive statistics , more likely to be college graduates , had greater annual income , and were less likely to have children younger than 18 years old . There were no differences between app users and nonusers regarding weight, height, mean BMI, and BMI category. App users were less likely to drink sugar-sweetened beverages , reported better sleep quality , and were less likely to take daily naps . They were also more likely to use health apps overall , and to use them for the purpose of tracking exercise , eating , and sleep .Out of 1017 participants, 547 (53.79%) were app users . When examining app users by use category, 412 (75.3%), 274 (50.1%), and 139 (25.4%) were categorized as immediate, consistent, and sustained users, respectively. Of the sustained users, 116 (83.5%) used the app at least one day every month of the study, and 133 (95.7%) used the app at least one day for 5 out of the 6 months. In comparison to non–app users , app users were younger  days over the 6-month study, 20 (IQR 7-35) days during the targeted 63 days of the study, and 6 (IQR 0-41) days during the 117 nontargeted days of the study. Out of 1017 enrolled participants, 328 (32.25%) completed the 4-month follow-up surveys within 72 hours of receiving the link. Of the remaining 689 participants (67.75%), study staff were able to reach out to 610 participants (88.5%) through personalized emails, text messages, and US $100 raffle invitations delivered up to one week prior to study completion. Of the 610 contacted participants, 113 (18.5%) completed their surveys after one contact, 56 (9.2%) after two contacts, and 35 (5.7%) after three contacts, increasing the overall number of 4-month survey completers to 532 (52.31%).EHRs and patient portals are readily available through most health care systems, and use of mHealth apps is fairly ubiquitous ,44. ThisOnce enrolled, 54% of participants who downloaded the app entered timing of eating or sleep data on at least one day. While the frequency criteria to classify someone as an app user in this study was fairly low , other studies have used a similarly low frequency to define usage ; howeverAlthough criteria for defining usage categories differ across studies, our immediate  and consistent  rates were higher than the “robust” cohort rates  reported in the AMHS; in the case of sustained users , our rates were fairly comparable to those in the AMHS . We attrP<.05) or African American  were related to a greater likelihood to download a health app. Inconsistencies in findings may be related to different assessment methods , recruitment methods , and racial and ethnic distribution in recruitment regions [This study’s usage data provides important information about predictors of health app use to guide the design of future observational studies using apps. Our finding that those who were younger, more formally educated, and wealthier were more likely to be app users is consistent with past research ,49. This regions ,56. Not  regions . While y regions . We also regions , influen regions ,56.There are several limitations of this study. First, this was an observational cohort study and was not designed with a comparison group to assess differences in app use among participants instructed to log for 6 months without additional guidance on targeted tracking days, compared to our approach of emphasizing tracking on POWER 28 and POWER week days. In designing the study, to optimize longitudinal tracking, we decided to preidentify targeted days to decrease participant burden and, more importantly, to increase the likelihood that we would collect data on some days across each of the 6 months rather than risk the typical pattern of heavier use up front followed by drop-off ,49. ThisHealth apps aimed at weight loss and related behaviors are among the most highly used mHealth apps . Time-re


I2 statistic and Q test. Meta-regression and subgroup analyses were conducted to investigate potential sources of heterogeneity. Influence analysis was conducted to determine the robustness of the pooled conclusions. Deeks’ funnel plot asymmetry test was performed to assess publication bias. A summary receiver operating characteristic curve (SROC) was constructed. Results: Twenty-three studies involving 2749 breast lesions were included in our meta-analysis. The pooled sensitivity and specificity were 0.80  and 0.84 , respectively. The pooled diagnostic odds ratio was 19.95 . The area under the SROC (AUC) was 0.85 . Conclusion: SMI has a relatively high sensitivity, specificity, and accuracy for differentiating between benign and malignant breast lesions. It represents a promising supplementary technique for the diagnosis of breast neoplasms.Purpose: We performed a systematic review and meta-analysis of studies that investigated the diagnostic performance of Superb Microvascular Imaging (SMI) in differentiating between benign and malignant breast tumors. Methods: Studies published between January 2010 and March 2022 were retrieved by online literature search conducted in PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Disc, China National Knowledge Infrastructure, Wanfang, and Vip databases. Pooled sensitivity, specificity, and diagnostic odd ratios were calculated using Stata software 15.0. Heterogeneity among the included studies was assessed using  Breast cancer, the most common neoplasm in women, is the leading cause of cancer-related female deaths worldwide. According to the Global Cancer Statistics 2020), breast cancer accounted for 11.7% of all new cancer diagnoses and 6.9% of all cancer-related deaths 020, brea. TherefoAs a noninvasive, cost-effective, and radiation-free option, conventional ultrasound is an important screening modality for the early detection of breast lesions . In addiWith the rapid development of computer techniques in clinical ultrasonography , Superb A meta-analysis addressing this topic was published, which included 15 studies with 2071 breast lesions examined using SMI . HoweverGiven these limitations, there was insufficient data to assess the accuracy of SMI for differentiation of breast lesions. It is necessary to reappraise the diagnostic value of SMI in differentiating benign and malignant breast tumors. In addition, there are four major diagnostic criteria of breast tumors in SMI, namely: Alder classification (AC), the presence of penetrating vessel (PV), microvascular distribution pattern (MVDP), and vascular index (VI). However, the diagnostic performance of SMI in previous studies showed variability due to the use of different diagnostic criteria. Therefore, the aim of our systematic review was to evaluate the diagnostic accuracy of SMI in differentiating benign and malignant breast tumors and to identify the diagnostic criteria associated with the best diagnostic performance.Generally, this systematic review is structured as follows: “Introduction”, “Materials and Methods”, “Results”, “Discussion”, and” Conclusions”.https://www.crd.york.ac.uk/prospero/ (accessed on 1 February 2022)) (*registration number: CRD42021262596). In addition, the organization of the article is inspired by some high-quality studies [The guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) of Diagnostic Test Accuracy (DTA) were followed in this systematic review . which w studies ,20.Relevant studies published between January 2010 and March 2022 were identified by online literature search conducted in PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Disc, China National Knowledge Infrastructure, Wanfang, and Vip databases. Medical Subject Headings (MeSH) terms as well as free words were adopted. The following search terms were used in our search strategy: “breast neoplasm ”, “superb microvascular imaging ,” “ultrasonography ”, and “sensitivity and specificity ”. In addition, the reference lists of relevant articles were manually screened to identify additional studies. The EndNote software 20.0  was used to manage the literature retrieved from electronic databases. Two reviewers independently screened the retrieved studies for eligibility. The inclusion criteria were: (1) original research articles in which patients with suspected breast lesions were screened using SMI ; (2) at least one of the four diagnostic criteria mentioned above was used; (3) true-positive (TP), false-positive (FP), false-negative (FN), and true negative (TN) rates could be extracted directly or indirectly; (4) 50 or more lesions were included in the study; (5) language of publication: English and Chinese; and (6) the nature of breast tumors was confirmed by surgery or aspiration biopsy. The exclusion criteria were: (1) review articles, case reports, meta-analyses, letters, or conference abstracts; (2) duplicated publications; (3) the studies restricted to specific breast neoplasms, such as intraductal papilloma or small breast malignant tumor (less than 10 mm in diameter); and (4) the outcome indicator  cannot be directly or indirectly extracted from the article. Conflicts between individual judgments were resolved by discussion or consultation with a third author. The 2 reviewers independently extracted data pertaining to the following variables using Microsoft Excel spreadsheets: (1) general study characteristics including the first author’s name, country, publication year, number of lesions, mean age of patients, mean size of lesions, instrument used for SMI, scale, study design, diagnostic criteria; and (2) The TP, FP, FN, and TN were obtained directly or calculated based on the reported sensitivity and specificity values. In case of any missing information, the original authors were contacted for the relevant information. All the included studies were independently assessed by 2 reviewers using the Quality Assessment of Diagnostic Accuracy Studies checklist version 2 (QUADAS-2). QUADAS-2 includes 4 items in the bias risk domain and 3 items in the applicability domain. The 4 items in the bias risk domain are: (1) patient selection; (2) index test; (3) reference standard; and (4) flow and timing. The 3 items in the applicability domain are: (1) patient selection; (2) index test; and (3) reference standard. Each item within the domains of QUADAS-2 was classified as low, high, and unclear risk. If any of the items in the domain were judged as no, it was judged as high risk. Only if all items in the domain were judged as yes, it was judged as low risk. If one or more of the items in the domain were judged to be uncertain, it was judged as uncertain risk. The quality assessment graphs were prepared using RevMan software 5.3 .This study was conducted based on the guidelines for systematic reviews and meta-analyses ,22. TPs,I2 statistic were used to assess the heterogeneity of sensitivity and specificity among studies. p values < 0.1 for Q test or I2 values > 0.5 were considered indicative of significant heterogeneity [The Q test and the ogeneity . By sequogeneity . All staSome studies have shown that the epidemiology, risk factors, and tumor characteristics of breast cancer in China differ from those in Korea and other Asian countries ,28,29. IA total of 404 articles were identified after the initial search; of these, 184 duplicated studies were removed. After reviewing the titles and abstracts, another 82 articles were excluded. After full-text assessment of the literature, 26 articles were considered eligible based on the inclusion and exclusion criteria. It is worth mentioning that two types of diagnostic basis were respectively used in two eligible studies. Ultimately, 28 studies were included in the qualitative review. In addition, a further five studies were excluded due to incomplete data. Hence, 23 studies involving 2749 lesions were included in the meta-analysis. A schematic illustration of the literature screening and selection process is presented in The included studies were published between 2015 and 2021. Overall, 3732 lesions in 3579 patients were analyzed. The average age of the patients was 48.7 range, 43.7–54.2) and the mean number of lesions per study was 133 range, 50–300). Majority of the included studies were conducted in China .7–54.2 a,46,47,48–300. MajThe results of quality assessment are presented in As for “flow and timing” domain, the analysis for all included patients was not performed in one study, leading to a high risk of bias. In addition, 22 studies were judged to have unclear risk of bias since an appropriate interval between index test and reference standard was not elaborated. With respect to concerns regarding applicability, there were five studies with unclear concerns regarding patient selection, 14 studies with unclear concerns regarding index tests, and six with unclear concerns regarding references standard. In general, the quality of the included studies was relatively satisfactory.I2 = 28.32%, p = 0.10) and significant heterogeneity in specificity . SROC for the diagnostic value of SMI using VI for differentiation of benign and malignant breast lesions is shown in I2 = 17.87%, p = 0.22) and in terms of PLR, there was a significant heterogeneity . The pooled diagnostic odds ratio was 19.95  (As shown in 4–26.82) . Moreove4–26.82) .Publication bias was assessed using the Deeks’ funnel plot asymmetry test. The results indicated no significant influence of publication bias of eligible studies .p < 0.001). In addition, there are significant difference in both sensitivity and specificity for prospective study design and VI diagnostic (p < 0.001). A summary of the sensitivities, specificities, PLRs, NLRs and DORs of studies is presented in We conducted meta-regression and subgroup analysis to investigate the potential source of heterogeneity. According to In our current study, we evaluated the diagnostic performance of SMI in differentiating between benign and malignant breast lesions. In the 23 included studies, the sensitivity ranged from 0.77 to 0.82 and specificity ranged from 0.79 to 0.88. The pooled sensitivity and specificity values were 0.80 and 0.83, respectively. The pooled DOR was 19.95 and overall diagnostic accuracy, represented by AUC, was 85%. In addition, the pooled PLR and NLR of all eligible studies were 4.88 and 0.24, respectively, which indicated that SMI can be used to distinguish between benign and malignant breast tumors. However, due to the significant heterogeneity of specificity and PLR, we conducted a meta-regression and subgroup analysis. Meta-regression of the included studies indicated that region, study design, and diagnostic criteria might be potential sources of heterogeneity. However, these results require verification with follow-up studies due to the limited sample in this study. Subgroup analysis was also carried out for the diagnostic performance of SMI to differentiate benign and malignant breast lesions. There were higher pooled specificity, PLRs, and DORs in the China group compared to non-China group. It is worth mentioning that the pooled specificity, PLRs values, and DORs of the MVDP were higher than those of the other diagnostic criteria groups. Moreover, VI was roughly as effective as AC when used as the diagnostic basis for breast lesions on SMI. It is possible that the plane outlined by the sonographer with the richest blood flow signals is not the plane with the most obvious malignant characteristics, which may lead to missing important diagnostic information of breast lesions .A similar study was published, and the results supported the effectiveness of SMI in diagnosing breast lesions . HoweverSMI was shown to be superior to CDFI and PDI in detecting microvascular blood flow signals owing to its intelligent adaptive algorithm and powerful multidimensional wall filtering system . At presAC and VI are used to evaluate blood flow abundance of breast lesions. AC can be classified as grade 0, I, II, and III based on the number of blood vessels in the tumor . HoweverSMI enables visualization of breast tumor microvascular architecture. SMI mainly evaluates the microvascular structure from two perspectives: PVs and MVDP. In the subgroup analyses, the pooled diagnostic accuracy of the MVDP was higher than that of PV. Hence, the combination of VI and MVDP may unlock the potential of SMI for differentiating breast lesions. However, there is a paucity of relevant studies, and this requires validation in the future.Some limitations of our study should be acknowledged. First, all eligible studies were conducted only in Asia, which may limit the generalizability of our results to patient populations in other parts of the world. Second, the parameter setting, and image acquisition details were not available for all studies, such as frame rate, dynamic range, and image acquisition section. It is possible that these factors contributed to heterogeneity of our study. Lastly, there were 23 eligible studies, however, only 2 of these studies used PVs as a diagnostic criterion, so a larger sample size may provide more convincing evidence. Further comprehensive studies are required to resolve these issues. Our systematic review suggests that SMI has an encouraging diagnostic value to differentiate between benign and malignant breast tumors. Moreover, according to the subgroup analyses, MVDP may be more effective among the four main diagnostic criteria, and it may benefit sonographers in selecting appropriate diagnostic criteria. In addition, study design, region, and the selection of diagnostic criteria may be potential sources of heterogeneity. In spite of its current limitations, such as a restricted region and a relatively small sample size, SMI remains a promising supplementary tool for sonographers to distinguish between breast lesions in clinical practice.


Adalimumab is the only biologic agent approved for the treatment of moderate-to-severe hidradenitis suppurativa (HS) patients , which is recommended in two different maintenance doses . We conducted a prospective multicentric study to measure outcomes related to the severity of disease and quality of life (QoL) of patients affected by moderate-to-severe HS, treated with adalimumab at a maintenance dosing of 40 mg or 80 mg. Assessments were performed at baseline (T0) and after 32 weeks of treatment (T32). We enrolled 85 moderate-to-severe HS Italian patients, 43 men (50.6%) and 42 women, aged between 16 and 62 years . Statistically significant improvements were observed for clinical status ), pain levels (3.1 mean decrease in VAS), and QoL (3.4 mean improvement in DLQI score). Patients with no comorbidities, and those with higher levels of perceived pain showed significantly greater improvement in QoL than their counterpart from T0 to T32. As for the proportion of patients who at follow-up reached the minimal clinical important difference (MCID) in QoL, significantly higher proportions of success were observed for age (patients in the 29–39 category), pain (patients with higher reported pain), and Hurley stage III. While both treatment regimen groups  improved significantly, no statistical differences were observed when comparing the two treatment dosages. Hidradenitis Suppurativa (HS) is a chronic, recurrent, and debilitating skin condition of the hair follicle ,2 characThe aim of this study was to compare the clinical severity, quality of life (QoL), and the perceived pain due to HS, at baseline and after 32 weeks, in Italian patients affected by moderate-to-severe HS (Hurley II and III) and treated with two different adalimumab regimens .This is a prospective multicentric study, in which we measured specific outcome values related to the severity of disease and QoL of patients affected by HS treated as maintenance therapy with adalimumab in two different dosages, i.e., 40 mg weekly or 80 mg each two weeks. Scores were registered at baseline (T0) and at follow-up, after 32 weeks of treatment (T32). The study was approved by the Institutional Ethical Committee of IDI-IRCCS, Rome, with the number 607/1, approved on 17 September 2019.Consecutive patients with a diagnosis of HS were recruited from October 2019 to October 2020, from five different centers . The inclusion criteria were: (1) age 16 years or more; (2) female or male sex; (3) patients under treatment with adalimumab (40 mg or 80 mg dosage) and treated with topical therapy; (4) diagnosis of moderate-to-severe HS (Hurley II and III); (5) written informed consent, signed by the patient.The exclusion criteria were: (1) presence of nodular acne associated with macro-comedones, single pilonidal cysts, and recurrent necrotic folliculitis of the scalp in absence of other criteria to fulfil the diagnosis of HS ; (2); HSAt baseline, each patient filled out a standardized sociodemographic data collection form concerning: age; sex; weight and height, BMI; age at HS onset and age at diagnosis; comorbidity ; and smoking habit (number of cigarettes per day). Complete socio-demographic information is included in The physician assessment was conducted through the IHS4 ; the HuIn order to assess the patient’s QoL, the following tools were used: VAS ; the DLAll analyses were performed using SPSS 25.0. The convergence and dispersion trends for quantitative variables were expressed as mean ± standard deviation, and qualitative variables were expressed as frequencies and percentages. Differences among DLQI scores were obtained through the comparison between baseline and T32, and results have been identified with ΔDLQI and used as the first QoL outcome measure, as well as the percentage of patients who reached the MCID (%MCID). The percentage of HS patients who achieved the HiSCR at week 32 has been reported in p < 0.150 , we included in the model sex and gender by default; furthermore, the variables that in univariate analysis had p = 0.488); the PGA was 4.09 in both groups (p = 0.988); the DLQI scores were 15.27 and 15.14 in the two groups, respectively (p = 0.940); and the VAS scores were 5.45 in the non-compliant group and 6.22 in the compliant group (p = 0.185). The study population therefore included 85 patients with HS. Among them, 43 were men (50.6%) and 42 women, aged between 16 and 62 years . The sociodemographic features of the sample, QoL and clinical differences at T32 are reported in There were 107 patients enrolled at baseline, and 22 (20.6%) did not reach week 32. At baseline, there were no differences between the patients who completed the follow-up and those who did not. The IHS4 was 19.77 in the “lost to follow-up” group and 22.16 in the “compliant” group  had a BMI > 25, and 61/85 (71.8%) were smokers or ex-smokers. Sixteen of 85 (18.8%) patients presented n IHS4 between 5 and 10 (moderate HS) while 69 had a IHS4 > 11 (severe HS). Sixty-two patients (72.9%) were treated with adalimumab 40 mg while 23 (27.1%) with adalimumab 80 mg. p = 0.021) and in those with higher pain VAS scores at baseline . Patients with no comorbidities (vs. patients who had at least one) also had a higher level of improvement, but it did not reach statistical significance (p = 0.063).In the main variables of interest, when looking at the mean differences of DLQI scores between T0 and T32 , we obseAs for the proportion of patients who at follow-up reached the MCID in QoL, higher proportions of success were observed for age (patients in the 29–39 category), pain (patients with higher reported pain), and Hurley stage III. A difference was also observed for BMI, with a greater proportion of MCID achievement for normal weight patients, though it did not reach statistical significance. However, no significant differences in HiSCR were observed in any of the variables of interest.HS is a debilitating disease characterized by significant chronic inflammation and compromised QoL . So far,In our sample, regarding the differences of DLQI scores considering T0 and T32, a higher level of improvement was reported in patients with no comorbidities and in those with higher pain score. This could be because patients with comorbidities could present other diseases that did not respond to anti-TNF therapy. Otherwise, patients with a higher pain score could improve with biologic therapy due to the immunomodulation of the immune system and to the anti-inflammatory effects of this therapy that, consecutively, lead to an improvement of DLQI. Furthermore, one center showed a significantly higher QoL improvement, probably due to selection of patients with higher severity and pain.Regarding patients who, at follow-up, reached the MCID in QoL, a significant higher proportion of success was reported for age in the “29–39 group”, patients with higher reported pain, and those affected by Hurley stage III. Our data diverge from a recent multicenter cohort study that analyzed the clinical and QoL parameters predicting response in 389 patients with HS treated with adalimumab 40 mg weekly as maintenance. In this study, none of the parameters of sex, BMI, age at onset, age at diagnosis, age at baseline, HS phenotypes, or smoking correlated with response to adalimumab; otherwise, the therapeutic delay was identified as a significant risk factor for nonresponse to adalimumab. Furthermore, in our study, a large difference was also observed for BMI, with a greater proportion of response for normal weight patients, even if it did not reach statistical significance. Moreover, no significant statistical differences in HiSCR were reported in the considered variables of interest. This could depend on the sample size and, therefore, did not reveal a significant difference in the efficacy of the treatment with the two different dosages assessed with the HiSCR outcome.Considering IHS4, DLQI, VAS, and PGA, all these outcomes presented a statistically significant improvement from baseline to T32 in the two main group of our study ; however, no statistical differences were reported subsequently to the stratification by treatment dosage. Specifically, there was a mild higher improvement in IHS4 for the group treated with 40 mg compared to 80 mg. Regarding the logistic regression analysis, the odds of reaching the MCID were significantly higher for patients in the 29–39-year-old group, for those with normal BMI, and those with more severe pain. Furthermore, males had a higher odds of reaching MCID compared to females, but this difference did not reach statistical significance.n = 3207) found that an anxiety disorder was diagnosed in 3.9% of those with HS, compared to 2.4% of those without HS [Depression is a well-established and common comorbidity in patients with HS and is generally associated with a worse clinical outcome ,29. The thout HS . In addithout HS . Even ifthout HS .The main finding of our multicenter prospective study, conducted within a cohort of 85 patients with moderate-to-severe HS treated with adalimumab 40 mg and 80 mg as maintenance, is that both regimens showed comparable levels of clinical efficacy and QoL enhancement, with a significant improvement of the HS clinical manifestations, but no statistical differences were observed when comparing the two treatment dosages. Therefore, the choice between the two treatment regimens should take into particular account patient preferences (such as a reduced number of injections), as well as the doctor’s perception of the patient’s ability to adhere to treatment prescriptions.


Keloids are skin fibroproliferative disorders, resulting from abnormal healing of deep cutaneous injuries. Cryosurgery, the most common treatment for keloids, causes skin traumas. Even though the clinical practice of cryosurgery has increased, effective wound healing therapy is still lacking. In this investigation, nonwoven nanofibrous patches composed of ulvan, a marine sulfated polysaccharide exhibiting anti-inflammatory and antioxidant activities, and polyethylene oxide (PEO) were fabricated through electrospinning and characterized. Their wound healing efficacy on skin traumas resulting from cryosurgical treatment of keloids was clinically tested and evaluated in comparison to a reference product. Twenty-four volunteer patients undergoing cryosurgery as a treatment of keloids were selected to apply either the ulvan/PEO patch or the reference product for 21 days. The ulvan/PEO patch, 21 days after cryosurgery, showed significant wound healing, elimination of skin inflammation, restoration of biophysical parameters similar to normal values and significant decrease in haemoglobin concentration, skin texture and volume, while no discomfort or adverse reaction was observed. In contrast, the reference product showed inferior performance in all evaluated parameters. The designed ulvan/PEO patch represents the first wound dressing to effectively heal skin trauma after cryosurgical treatment of keloids. Keloids, from the clinical perspective, appear as elevated, firm, bosselated papules associated with skin color variations, including erythematous or brown pigmentation ,2. In coCryosurgery is an effective and quick treatment of keloids that is performed by topically applying liquid nitrogen in order to freeze the targeted tissue . It induClinical practice guidelines for the treatment of skin trauma resulting from cryosurgery include the application of a variety of topical agents ,9, with Efficient wound treatment could be addressed by the application of innovative, effective wound dressings that can accelerate wound healing with minimum scar marks . RecentlUlva [Marine polysaccharides are highly biocompatible, biodegradable, non-toxic and abundant biopolymers, with diverse structures and bioactivities, representing valuable biomaterials for the development of novel biomedical systems ,32,33,34Ulva ,36, is aUlva ,45,46,47Ulva ,49 and iUlva  that canUlva ,51,52,53The aim of the present study was to prepare ulvan-based nanofibrous patches and clinically evaluate their wound healing efficacy, in comparison to a reference product, for the treatment of skin trauma in patients receiving cryosurgery for the removal of keloids.The promising results observed in our recent study for the treatment of burn wounds using ulvan/gelatin-based nanofibrous patches  promptedNonwoven nanofibrous patches were fabricated by electrospinning of a single spinning solution composed of ulvan and polyethylene oxide (PEO) under optimized electrospinning conditions and parameters A. The an−1, respectively, whereas the sulfate ester groups showed characteristic absorption bands at 1207 and 845 cm−1. In the FTIR spectrum of PEO, the characteristic peak attributed to the −CH2 stretching vibration was recorded at 2874 cm−1, whereas the characteristic peaks attributed to the C–O–C stretching vibrations were observed at 1092, 959 and 842 cm−1. The FTIR spectrum of the ulvan/PEO fibers displayed the characteristic bands of its components. The characteristic signals were observed at slightly shifted bands compared to the raw materials, indicating their interaction into the hybrid polymer matrix. The successful incorporation of ulvan in the fiber mats was evident by its characteristic absorption bands at 3375 and 1615 cm−1 assigned to the stretching vibrations of −OH and −C=O groups, respectively, while the presence of PEO was verified by the characteristic peak at 2878 cm−1 [The FTIR spectra of ulvan powder, PEO powder and the fabricated ulvan/PEO patch are shown in 878 cm−1 ,45,54,55The fabricated ulvan/PEO nanofibrous patches, as well as the utilized ulvan and PEO raw materials, were physicochemically characterized by TGA and DSC analyses E–G. As sDemographic information, including age, body-mass index (BMI), phototype (Fitzpatrick skin type), medical conditions, family history, sun exposure, and smoking, and full medical history, as recorded for all patients, are presented in p = 0.024; day 21, p = 0.001).The clinical assessment of skin trauma using the POSAS scar scale ,58 is prPhoto-documentation confirmed the initial evaluation based on the POSAS criteria. In contrast to the reference product, the ulvan/PEO patch significantly contributed to wound healing and soothed the injured skin sites .p < 0.05). In contrast to patients treated with the reference product, almost no pain and no itching was reported from patients using the ulvan/PEO patch . On day 21, volume, volume conforming and skin texture were significantly decreased in the patients using the ulvan/PEO patch in comparison to those using the reference product .The patients treated with the ulvan/PEO patch, as compared to those using the reference product, showed lower haemoglobin concentrations that returned close-to-normal values on day 21 (p < 0.05).The hydration, transepidermal water loss (TEWL), and erythema levels on days 7 and 21, as well as melanin levels on day 21 were significantly lower for the patients using the ulvan/PEO patch, as compared to those using the reference product (p = 0.001).All patients filled out a questionnaire in which they were asked to comment on their experience using either the ulvan/PEO patch or the reference product. In the overall evaluation, patients using the ulvan/PEO patch reported significantly higher satisfaction (4/5) in comparison to those using the reference product  strongly supported these findings. In addition, no adverse reaction or patient discomfort was observed. In contrast, treatment with the reference product showed inferior performance in all evaluated parameters.Even though the main limitation of this clinical study is the relatively small sample size, it is obvious that the ulvan/PEO nanofibrous patch, due to the antioxidant, anti-inflammatory and wound healing properties of ulvan ,49,59,60Ulva rigida were collected in Parga bay, Greece. The algal specimens were cleaned from foreign materials, washed with seawater and fresh water, and air-dried. For the isolation of ulvan, 0.6 kg of the air-dried algal biomass, grounded to small pieces, was soaked in 12 L of distilled H2O and heated in an autoclave at 121 °C for 20 min. The resulting hot aqueous solution was filtrated through cotton cloth; the filtrate was left to cool at room temperature and 48 L of ethanol (96% v/v) was added to the filtrate for the precipitation of the polysaccharide. Subsequently, the suspension was left at 4 °C overnight and the resulting precipitate was filtered through cotton cloth, washed thoroughly with ethanol, sonicated in an ultrasonic bath for 1 h, vacuum-filtered, and finally lyophilized overnight to afford ulvan as an off-white powder. The characterization of ulvan  was performed as previously described [Polyethylene oxide (PEO)  was purchased from Sigma-Aldrich . Specimens of the green alga w/v in deionized H2O followed by the addition of PEO at 2% w/v, resulting in a 2:1 (w/w) ratio of ulvan to PEO. Electrospinning was performed using a γ-High Voltage Research DC power supply generator  with a maximum voltage of 50 kV. The polymer solution was electrospun from 10-mL disposable syringe fitted with 23G stainless-steel blunt needle, with the syringe mounted on a horizontally positioned Harvard PHD 2000 programmable syringe pump . The produced nanofibers were deposited on sterile gauge wrapped on a RC-6000 rotating drum collector at a rotation speed of 500 rpm . The temperature and relative humidity were 22 ± 2 °C and 60 ± 5%, respectively. The solution feeding rate, applied voltage and tip-to-collector distance were fixed at 1 mL/h, 25 kV and 30 cm, respectively. The prepared nanofibrous patches were sterilized under UV light for 1 h prior to their use.The ulvan/PEO spinning solution was prepared under stirring for 24 h at room temperature to ensure its homogeneity by dissolving ulvan at a concentration of 4% A PhenomWorld desktop scanning electron microscope (SEM) with tungsten filament (10 kV) and charge reduction sample holder  was used for the morphological characterization of the nanofibers of the ulvan/PEO patch. The samples were sputter-coated with gold. Using the embedded image analysis software , the diameters of 100 fibers from each SEM image were measured and the average fiber diameter was determined. The chemical composition of the fibers was analyzed by Fourier transform infrared spectroscopy using the attenuated total reflection (ATR) method on a FTIR Bruker Alpha II . Thermogravimetric (TGA) analysis was performed using a TA Thermogravimetric Analyzer  at a 10 °C/min heating rate from 40 to 600 °C under a 25 mL/min nitrogen flow. The sample weight, sample temperature, and heat flow were recorded continuously. Differential scanning calorimetry (DSC) analysis was conducted using a TA Thermal Analyzer . Samples of 6–7 mg sealed in aluminum pans were heated from 40 to 350 °C at a constant rate of 10 °C/min under a 50 mL/min nitrogen flow.All procedures performed were in accordance with the guidelines of good clinical practice (GCP) as defined in Directive 2001/20/EC, the US Federal Code of Users (21 CFR Part 312), and the International Conference on Harmonization (ICH). The study was conducted in accordance with the principles of the Declaration of Helsinki  R1; 21 CFR Part 312; WHO 2008). The volunteers were selected among the patients of the First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Syggros Hospital, from October 2021 to January 2022. The protocol of the study was approved by the Institutional Scientific Review Board of the University Hospital “Andreas Syggros”, National and Kapodistrian University of Athens, Medical School (Protocol. Nr. 3693/14-10-2021). Eligible patients were adults diagnosed with confirmed keloids before receiving cryosurgery therapy. The lesions were located on the shoulders, chest, forearm, back or arms. The exclusion criteria were pregnancy, breastfeeding, concomitant chemotherapy, immunosuppressive treatment, previous radiotherapy to the treated area, as well as patients with other autoimmune skin diseases, including atopic dermatitis, psoriasis, and ichthyosis. This was an open-label, two-treatment clinical research trial comparing the efficacy of the ulvan/PEO patch versus a reference product. Twelve patients were randomly selected to apply the ulvan/PEO patch and twelve patients were randomly selected to apply the reference product in different cryosurgery treated areas.w/w) twice daily to the skin trauma at different sites [The patients received two cycles of local conventional cryosurgery (liquid nitrogen at −196 °C) between 20–30 s. They were instructed to apply for 21 days either the ulvan/PEO patch daily for 24 h or a thin layer of the reference product . The scale ranges from 1  to 10 (worst scar imaginable) and assesses scar color, elasticity, hypopigmentation, volume, pain, itching, overall opinion and skin type of the patient ,58. All The skin was examined with an Antera 3D camera  to the symmetric healthy anatomical sites to keloids (day 0) and on days 0, 7, and 21 after cryosurgery to the keloids’ anatomical sites. Haemoglobin concentration, skin texture, and skin volume were assessed using Antera 3D software .2/h) obtained 1 min after the start of the measurement. Erythema and melanin were calculated using a Mexameter MX 18  by measuring absorption/reflection at three different light wavelengths. The data were recorded in arbitrary units. Before each measurement, the treated area was cleaned with 0.9% sodium chloride solution and wiped with sterile gauze.Skin parameters, including hydration, TEWL, erythema and melanin, were assessed by non-invasive biophysical methods to the symmetric healthy anatomical sites to keloids (day 0) and on days 0, 7, and 21, and after cryosurgery to the keloids’ anatomical sites. Hydration was measured by changes in dielectric constant using a corneometer CM 820 . Data were recorded in arbitrary units. The skin barrier function (TEWL) was assessed with a Tewameter TM 210  by measuring the density gradient of water evaporation from the skin. The estimation was based on the mean value of the flux density of water  to 5 (maximum positive effect).p) was less than the significance level, the result was considered significant, p-values of 0.05 were considered statistically significant and are indicated by the symbols (*) for p ≤ 0.05, (**) for p ≤ 0.01, (***) for p ≤ 0.001, and (****) for p < 0.0001. SPSS®  was used for all statistical analyses.The statistical analysis began with the estimation of descriptive criteria. Before statistical comparisons were made between two or more groups, a normality test was performed. To determine the normality of the data distribution, the Shapiro–Wilk test was used because of the small number of participants. If the nominal normality hypothesis is rejected, the data are considered to deviate from the normal distribution. Because the data in this study were not normally distributed in all situations, non-parametric approaches were used. The Mann–Whitney U test was used to compare two independent groups, while the Wilcoxon signed-rank test was used for group comparison between two time points. Values at subsequent time points were compared using the Friedman non-parametric test. Once a significant result was obtained, a post hoc analysis using Dunn’s test was performed. In this study, the type I error (significance threshold) was set at 5% in all situations. If the estimated p-value (Cryosurgery is an effective and quick intervention for treating keloids, skin fibroproliferative disorders that result from abnormal healing of deep cutaneous injuries. Skin trauma, often encountered as a side effect of cryosurgery, is, to date, treated with topical products, such as sprays and gels, to promote tissue repair. The main drawback of the application of such products is the uncontrolled dosage, which is frequently associated with incomplete or delayed healing and even infections. This clinical study aimed to present the evaluation of a new ulvan-based nanofibrous wound dressing as an effective treatment of wounds resulting from cryosurgical removal of keloids. Treatment of skin trauma resulting from cryosurgical removal of keloids with the designed ulvan/PEO nanofibrous patch effected remarkable wound healing with concomitant elimination of skin inflammation. These findings were supported by the significant decrease in the POSAS score and the restoration of various parameters related to the skin’s condition, coupled with the lack of adverse reaction or patient discomfort. In contrast, treatment with the reference product showed inferior performance in all evaluated parameters.


L*, a*, and b* values, whereas BMP formulated with MD had significantly higher water activity, solubility index, tapped density, bulk density, and flowability. The highest retention of bioactive compounds was reported in freeze-dried mushroom powder compared to cabinet dried powder using SPI as a carrier agent. Fourier transform infrared (FTIR) analysis confirmed that certain additional peaks were produced in the mushroom button powder-containing SPI  and MD . Thus, the results revealed that SPI showed promising results for formulating the BMP using the freeze-drying technique.In this investigation, the effect of different drying techniques, such as freeze-drying and cabinet drying, with two different carrier agents, such as maltodextrin (MD) and soy protein isolate (SPI), at different levels  on button mushrooms has been revealed. The results showed that the button mushroom powders (BMPs) formulated with SPI as a carrier agent had significantly higher powder yield, hygroscopicity,  Mushrooms are edible fungi, and their production and consumption have substantially increased due to their nutritive value, flavor, and high delicacy , 2. In IMushrooms are used in noodle products because of their unique flavors and health-promoting characteristics. Incorporating mushrooms into noodles would support the development of key organoleptic features, including the appearance, texture, and flavor of the developed product. Based on this, the objective of this research is to formulate a mushroom-based noodle, and the impact of mushrooms was assessed in terms of their physicochemical characteristics and textural aspects.Fresh button mushrooms were procured from the Division of Plant Pathology, SKUAST-Jammu. Button mushrooms were considered mature when the caps are well-rounded and the partial veil is totally intact. The length-to-thickness ratio of the stipe  should be small. The length of the drape should be long enough to allow minor trimming without cutting flush with the veil. Button mushroom caps have an average diameter of 4.51 ± 0.87 cm and are linked to short truncated stems with a height of 7.21 ± 1.23 cm. Raw materials were collected, washed, and cut into thin slices followed by drying.Agaricus bisporus) were selected, washed, and cut into thin slices to provide uniform mixing with carrier agents. The samples were mixed with different carrier agents at different concentrations by adding 25 ml of distilled water to formulate the paste for proper mixing for drying purposes. In freeze-drying, mushroom slices were frozen at a temperature of −80°C in a conventional freezer and then subjected to freeze-drying in a freeze-dryer  at a pressure of 5 mTorr (0.666 Pa) for a period of 38 h. The obtained flakes were ground using a Mixer Grinder   in a similar way as in the case of a freeze dryer  into a cup of water activity meter . The instrument was calibrated as per the instruction manual calibration. The sample was kept in a cup until a constant reading was obtained.2CO3, and then, weighing was carried out after 1 week. Hygroscopicity was calculated as 1 g of adsorbed moisture per 100 g of the sample  and tapped density  of the mushroom powder were determined using the methods given by Santhalakshmy et al.  of samples was calculated using the formula given in Equations (6) and (7):The color parameter of the mushroom dried by different methods was measured with a Hunter Lab color analyzer  and expressed in terms of The total phenolic content (TPC) in the mushroom powder was calculated using the spectrophotometric method given by Sawczuk et al. . The Fol−1) and each dilution of the standard rutin solution (10–100 g ml−1) were used in test tubes. Each test tube was filled with 1.50 ml of methanol, 0.10 ml of aluminum chloride solution, 0.10 ml of potassium acetate solution, and 2.80 ml of distilled water and then shaken. Sample blanks for all extracts and standard rutin dilutions were produced in the same method but with distilled water rather than the aluminum chloride solution. All generated solutions were filtered using Whatmann filter paper No. 1 before being measured for absorbance. The absorbance was measured at 510 nm against a suitable blank. A rutin calibration curve was used to determine the TFC. The results were represented as milligrams of rutin equivalents (RE)/g of the extract.The total flavonoid content (TFC) in the mushroom powder was evaluated using the procedure described by Ravanfar et al. . To deteThe free radical scavenging capacity of the sample was calculated with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and DPPH radical scavenging activity using the procedure given by Kiselova-Kaneva et al.  and was Ac = absorbance of the control and A = absorbance of the sample at 517 nm. The graph plotting each concentration and percentage inhibition yielded the IC50 value (the concentration of the sample extract required to inhibit 50% DPPH activity).where 3+ to Fe2+. The reducing power of the sample was calculated using the procedure given by Oyaizu (50 (concentration exhibiting 50% absorbance) and compared to that of butylated hydroxytoluene (BHT) and ascorbic acid.The reducing power assay is used to determine the ability of an extract to reduce Fey Oyaizu . The red−1, representing an average of 32 scans. All spectrums were measured under ambient conditions.Infrared (IR) spectra were measured using a Nicolet 360 Fourier transform IR (FTIR) spectrometer (USA) by mixing 0.1 g of the powdered sample with 0.5 g of potassium bromide for pellet preparation to attain the IR spectrum. The IR region was observed between the range of 650 and 4,000 cmpost-hoc analysis of variance (ANOVA). All statistical analyses were conducted using SPSS software.All samples were prepared at various carrier agent concentrations and analyzed three times. The results were presented in the form of means and standard deviations (SDs). Significant differences between samples were analyzed by Process yield (powder yield) is an important parameter of the drying process because it influences cost and efficiency. It accounts for the total mass losses, including the extraction and drying processes. However, at a higher dosage of SPI, the moisture content of the button mushroom powder (BMP) also showed a significant increase, which may be due to the higher water holding capacity of proteins than polysaccharides, i.e., MD . The dataw) of the samples decreased from 0.62 to 0.36 for MD-treated powder and from 0.58 to 0.37 for SPI-treated powder in both cabinet dried and freeze-dried BMPs, which was less than that of untreated powder, which had 0.67 and 0.53 in cabinet dried and freeze-dried powders, respectively. The drying technique also significantly influenced the water activity of the samples. Water activity may directly affect the shelf life of the powder. The results depicted that the BMP prepared using MD as a carrier agent possessed significantly lower water activity than the powder produced using SPI. The variation in water activity may be attributed to the high hydrophilic attraction of SPI as compared to MD. The water activity value of 0.20–0.40 for dried foods is regarded as microbiologically safe, increasing the shelf stability of the products  and HR are important in giving information regarding the flowability of the powder . FlowabiL*, a*, and b*). The data presented in L* value increased, which can be due to the inherent whitish color of the carrier agent, while a* and b* decreased. The L* value increased in both MD- (65.16–85.26) and SPI-treated powders (63.87–76.23) in both cabinet dried and freeze-dried BMPs, which was higher than that of the untreated powder having 60.32 and 73.39 for the cabinet dried and freeze-dried powders, respectively. The addition of different carrier agents significantly reduced a* and b* in both drying procedures. The a* value decreased in both MD- (3.12–0.66) and SPI-treated powders (3.96–0.73) in both cabinet dried and freeze-dried BMPs, respectively, which were less than that of the untreated powder having 3.04 and 0.89 for the cabinet dried and freeze-dried powders, respectively. The b* value decreased in both MD- (11.37–7.87) and SPI-treated powders (12.01–10.37) in both cabinet dried and freeze-dried BMPs, respectively, which was less than that of the untreated powder having 12.26 and 10.22 for the cabinet dried and freeze-dried powders, respectively. Meanwhile, the WI value increased in both MD- (63.21–83.27) and SPI-treated (61.70–74.05) powders in both cabinet dried and freeze-dried BMPs, respectively, which was less than that of the untreated powder having 58.35 and 71.48 for the cabinet dried and freeze-dried powders, respectively. The changes in color parameters largely depend on the type and concentration of carrier agents in the feed solutions, which can be related to polyphenolic changes during drying , whereas the redness (+a*) of the treated purple sweet potato extract was significantly decreased as the concentration of MD increased. The increase in lightness and a reduction in chroma (color saturation) could be attributed to the dilution effect (a* (redness) and an increase in L* (lightness) with the incorporation of carrier agents  and positive association with antioxidant activity under different drying conditions.The influence of drying conditions on the antioxidant activity of the dried products was investigated by examining the relationship between TPC, TFC, DPPH and reducing power activity of the samples obtained under various drying conditions. −1 to study the chemical bond structures and identify the functional groups of the products. The IR spectrum of the developed products is shown in −1. The cabinet dried powder product of the mushroom paste–MD showed characteristic peaks at 930, 994, 1,077, 1,148, 1,305–1,458, 1,628, 2,925, and 3,265 cm−1. Major peaks of the cabinet dried powder product of the mushroom paste–SPI were observed at 1,035, 1,394, 1,525, 1,626, 2,927, and 3,271 cm−1. For the freeze-dried mushroom paste–SPI, significant peaks were observed at 884, 927, 952, 1,019, 1,078, 1,388, 1,524, 1,625, 2,939, and 3,277 cm−1.Fourier transform IR analysis of the formulated powder products was carried out in the wavenumber range 650–4,000 cm−1 has been considered the “carbohydrate region” and is characterized by sharp overlapping peaks resulting from glycosidic linkages consisting of CO stretching, CC stretching, and COH bending vibrations (−1 could be ascribed to the N–H bending and C–N stretching of the “amide III group” of tertiary aromatic amines. The peak wavenumber in the range of 1,625–1,635 cm−1 could be C=O stretching of the “amide I group” of the antiparallel β-pleated sheet protein structures present in mushrooms (−1 could be assigned due to the CH stretching and denotes the presence of carbohydrates. The peak at 3,188–3,277 cm−1 could be assigned to the O–H stretching vibrations or N–H stretching groups (The wavenumber absorption band in the range of 800–1,300 cmbrations –70. The ushrooms . A charag groups , 80–82.−1 and a slight absorption peak shift from 1,080 to 1,077 cm−1 were observed. The reduction of peak intensities and the absorption peak shift from higher to lower wavenumbers indicates that the freeze-dried powder product has a weaker bonding structure than the cabinet-dried powder product. Deformation and weakening of the bonding structure could make the powder product less stable, resulting in a shortened shelf life. Absorption peaks of the mushroom–SPI powder at wavenumbers of 1,524–1,525 cm−1 could be assigned to the amide II region in proteins (−1 is very stable under different conditions (−1 in cabinet dried mushroom paste and SPI powder, confirming the formation of undesirable different complex compounds. The formation of different complex compounds was undesirable for our target powder product. Hence, due to the presence of SPI without the formation of additional complex compounds, the freeze-dried powder product of the mushroom paste incorporated with SPI could be considered the best product because it is relatively more stable in addition to its higher protein content compared to others.The reduction in the peak intensity of the freeze-dried mushroom–MD sample at wavenumbers of 930 and 1,077 cmproteins , 84. Thinditions . The N–HThe present study investigated the performance of different carrier agents, such as MD and SPI, and button mushrooms during both freeze-drying and cabinet drying. The influence of incorporation of carrier agents at different concentrations on functional, flow, bioactive, and chemical parameters was investigated. SPI showed a positive increase in powder recovery. MD showed better solubility, and SPI displayed higher hygroscopicity. The results of this study also confirmed the efficacy of the addition of carrier agents to retain bioactive compounds. The highest recovery of phenolic compounds, calculated using FTIR of treated samples, depicted that the incorporation of carrier agents was proven to be effective, and freeze-drying was the most appropriate drying technique. It was concluded that SPI had higher potential as a carrier agent to produce BMPs during drying when compared with MD. BMPs are high in bioactive components that have antioxidant characteristics, such as phenolic and flavonoid compounds. Mushroom powders can be used as a supplement for a variety of staple foods because of their capacity to boost protein content and also to provide valuable health benefits from bioactive compounds.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.RS, JS, KD, and AD contributed to the conception, design of the study, and wrote the first draft of this manuscript. GN and AD proposed the title of this manuscript. RS, JS, and KD wrote the sections of this manuscript. BK, AS, AA, HH, and MA have critically revised this manuscript. All authors collated papers, read, and approved the final version of this manuscript.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.


Despite advancements in early detection and treatment, cancer continues to pose a threat to human health and is the leading cause of death worldwide. According to recent research, the fibronectin type-III domain-containing (FNDC) protein family has been implicated in several different human disorders. However, little is known regarding their expression and prognostic significance in most human malignancies. We carried out a thorough cancer vs. normal expression study using the Oncomine and Tumor Immune Estimation Resource (TIMER) databases, as well as a prognostic evaluation using the Kaplan-Meier (KM) plotter and PrognoScan databases. Oncomine revealed that the mRNA expression levels of FNDC1, FNDC3A, and FNDC3B were higher in most malignancies than in normal tissues, but the mRNA expression levels of FNDC4, FNDC5, FNDC7, and FNDC8 were downregulated in most cancers when compared with normal tissues. In survival analyses based on KM Plotter and PrognoScan, all members of the FNDC family displayed significant correlations with survival outcomes in breast, gastric, and ovarian cancers. Furthermore, the whole FNDC family, except for FNDC7 and FNDC8, was found to have substantial predictive effects in lung adenocarcinoma, but not in squamous cell lung cancer. In addition, potential connections between several FNDC family members and survival results in liver and colorectal malignancies were discovered in this study. One or more members of the FNDC family demonstrated statistically significant differences in expression between cancer and normal tissues, suggesting that they could be used as prognostic biomarkers for specific cancers. Due to the aging population, the trend toward environmental deterioration, and the appearance of some undesirable behaviors and habits, the burden of cancer has increased considerably worldwide, even with advancements in cancer diagnosis and treatment. Therefore, there is a pressing need to investigate the fundamental causes of cancer and develop possible biomarkers to enhance the diagnosis, treatment, and prognosis of patients with cancer.Cancer is the second most common cause of death and is a serious public health concern worldwide. It is predicted that there will increase of 27.5 million new cancer diagnoses each year by 2040 worldwide, from 17 million in 2018. From the UniProt Knowledgebase, the FNDC protein family contains 11 proteins in humans, namely FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, FNDC6 interleukin-20 receptor subunit beta (IL20RB), FNDC7, FNDC8, FNDC9, FNDC10, and FNDC11. Tissue development, cell adhesion, migration, and proliferation are among the many roles they perform.,5 Some studies have also shown that FNDCs are regulated by microRNAs–8 and circRNA. Other processes, such as the regulation of adipogenesis and osteoblast differentiation by FNDC3B, regulation of FNDC4 by TGF-β, and involvement of the corticoid receptor in the regulation of FNDC5 expression, have also been discovered. General expression analyses and functional findings are available for the genes FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, and FNDC6. FNDC1 was discovered to be a regulator of cardiovascular function and to play a role in the death of cardiomyocytes triggered by hypoxia in 1 study.,14 Moreover, FNDC1 has been linked to an increased risk of arterial hypertension according to a quantitative trait loci study. In contrast, the expression of FNDC1 was correlated with tumorigenesis in gastric, breast, and prostate cancers. Expression analyses showed that FNDC3A was upregulated in CRC, and downregulation of FNDC3A expression reduced the ability of cervical cancer cells to proliferate, migrate, and colonize their environment. Epithelial-to-mesenchymal transition is accelerated by FNDC3B, which activates various pathways in various cancer cells, including hepatocellular carcinoma, acute promyelocytic leukemia, and tongue squamous cell carcinoma cells. FNDC4 is an anti-inflammatory factor that is upregulated in patients with inflammatory bowel disease. Furthermore, FNDC4 operates as an extracellular factor that increases the invasiveness of HCC, in part by activating the PI3K/Akt signaling pathway, as previously described. To date, FNDC5 has been the most extensively researched FNDC primarily because it transports the peptide hormone irisin, which has been postulated to stimulate adipose tissue conversion. Interleukin-20 receptor subunit beta (IL20RB/FNDC6) is a type II cytokine receptor with a single-pass type I membrane protein, which plays a role in the pathophysiology of chronic inflammation and autoimmune disorders. However, little is known about FNDC6’s role in cancer. For example, in papillary renal cell cancer, FNDC6 overexpression is linked to increased migration and poor prognosis.Fibronectin type III domain-containing (FNDC) proteins are distinguished by the presence of at least 1 conserved fibronectin type III domain of fibronectin, an important type of extracellular matrix protein and a well-known tumorigenesis regulator.st examined the changes in mRNA expression of FNDC family members between cancer and normal tissues in common human tumors using the Oncomine and tumor immune estimation resource (TIMER) databases to determine if there were any differences. Second, we examined the prognostic value using the Kaplan-Meier (KM) plotter and PrognoScan databases.In brief, these findings suggest that some cancers can choose members of the FNDC family as prognostic biomarkers or potential therapeutic targets. However, a comprehensive analysis of the transcriptional expression and prognostic relevance of FNDC family members in human malignancies is currently lacking. In this investigation, we 1https://www.oncomine.org/resource/login.html), an online microarray database that offers the most complete spectrum of mutations, gene expression data, and clinical information, can be used to identify novel biomarkers or new treatment targets. Discrepancies in FNDC family mRNA expression in common human malignancies were examined using the Oncomine database. The thresholds for each malignancy and gene were as follows: the fold change was 2, the P value was 0.01, the gene rank was in the top 10%, and the data type was mRNA. The cancers, datasets, genes, sample sizes, t test, fold change, and P value were derived from studies that indicated statistical differences. Thus, the Oncomine data platform was terminated on January 17, 2022. Therefore, we also studied the transcriptional expression of FNDC family members in the TIMER database.Oncomine (http://timer.cistrome.org/), which is an excellent online tool. Using a novel statistical method, TIMER calculates the number of immune cells in the tumor microenvironment: B cells, CD4 T lymphocytes, CD8 T lymphocytes, neutrophils, macrophages, and dendritic cells. These findings were confirmed through pathological examinations. Gene expression and survival analyses were performed using TIMER. The current version of TIMER is available at TIMER2.0, and it contains 10009 samples from TCGA representing 23 different cancer types.It is possible to determine the clinical relevance between distinct immune cells and different cancer types using TIMER , an online prognostic assessment database that can assess the effect of 54k genes  on survival in 21 forms of cancer, including 7830 breast cancers, 2190 ovarian cancers, 1440 gastric cancers, and 3452 lung cancers. Based on the intermediate levels of mRNA expression, cancer patients were separated into 2 groups: those with high expression and those with low expression. For each gene, the required probe ID was placed in the database separately for each high-and low-expression group. Statistical significance was be reached P value < .01. It was possible to summarize the information from the KM plotter homepage in terms of cancer type, Affymetrix ID, genes, survival results , HRs, and P value; some typical plots were also provided.To assess the prognostic roles of the FNDC family in these cancers, we used the KM plotter (http://www.abren.net/PrognoScan/) looks through a large number of publicly available cancer microarray datasets for correlations between gene expression and patient prognoses, such as overall survival (OS), relapse free survival (RFS), and disease free survival (DFS). The criterion was raised to a P value of < .05 for Cox regression. We chose datasets with a Cox P value of < .01 for research.The following qualities describe the PrognoScan database: a large-scale collection of data, a systematic analytic method for gene prognostic value, and tumor markers and proto-oncogenes that can be evaluated using this strong analytical framework. The PrognoScan database , and IDC epithelia. In the other 6 databases, we reached the same conclusion. According to the Radvanyi and Finak databases, FNDC3A expression is elevated in both invasive mixed and invasive breast carcinomas. Regarding FNDC3B, only 1 out of 34 analyses showed significantly increased expression between the cancer and non-cancerous groups. FNDC3B was shown to be overexpressed in invasive breast cancer, which was identified by the Finak dataset, whereas we obtained the opposite conclusion from other databases, including TCGA, Radvanyi, and Gluck. It was found that the level of FNDC4 expression in IDC and mixed lobular and ductal breast carcinoma was low, and this was also found in databases such as TCGA. According to TCGA database, FNDC6 was downregulated in intraductal cribriform breast adenocarcinoma. FNDC8 was decreased in ductal breast cancer in situ, invasive ductal and lobular breast cancer, and invasive mixed breast carcinoma in studies from TCGA database. For FNDC5, cancer tissues were not significantly different from the normal tissues. Table http://links.lww.com/MD/I34 of the supplementary file.Next, we investigated whether the FNDC family is associated with the prognosis of breast cancer patients using the KM plotter and PrognoScan software programs. The OS, RFS, distant metastasis-free survival (DMFS), and post-progression survival (PPS) for each gene in the KM plotter database were investigated. All the significant results are shown in Figure http://links.lww.com/MD/I31, which demonstrates the mRNA expression levels of the FNDC family in human cancers from TIMER).Similarly, taking advantage of the Oncomine database, we obtained relationships between FNDC family expression and lung cancer, which mainly includes lung adenocarcinoma and squamous cell lung carcinoma, but only FNDC1 and FNDC6 displayed significant results under the set thresholds. In light of Hou’s analysis, both FNDC1 and FNDC6 were upregulated in squamous cell lung carcinoma, and FNDC6 was significantly increased in lung adenocarcinoma. Details are presented in Table http://links.lww.com/MD/I35 in the supplementary file contains all specific prognostic analyses.The predictive relevance of the FNDC family in lung cancer was later demonstrated using the KM plotter and PrognoScan databases. Regarding lung cancer survival, the KM plotter examined the influence of the FNDC family on first progression (FP), OS, and PPS. Furthermore, RFS and OS were assessed for every gene using PrognoScan. Except for FNDC7 and FNDC8, each member of the FNDC family was correlated with statistically significant survival curves Fig. . Unfortuhttp://links.lww.com/MD/I31, which demonstrates the mRNA expression levels of the FNDC family in human cancers from TIMER).On the 1 hand, there’re 3 different datasets for the FNDC family in gastric cancer in Oncomine. FNDC1 was shown to be significantly elevated in diffuse gastric adenocarcinoma, gastric intestinal type adenocarcinoma, gastric mixed adenocarcinoma, gastric adenocarcinoma and gastric cancer from Cho, Wang and DErrico datasets. However, the expression of FNDC3A, FNDC5, and FNDC8 was significantly reduced in gastric using the same 3 datasets. As shown in Table http://links.lww.com/MD/I36 in the supplementary file.Next, we examined the relationships between members of the FNDC family and the survival results of patients with gastric cancer in the KM registry. This database provides OS, FP, and PPS data for the prognostic analyses of gastric cancer. Each gene of the FNDC family was closely related to OS, FP, and PPS, except for FNDC6, which was only associated with OS in patients with gastric cancer. Lower FNDC3A levels Fig. b indicathttp://links.lww.com/MD/I31, which demonstrates the mRNA expression levels of the FNDC family in human cancers from TIMER). Additionally, compared to normal liver tissues, FNDC3A and FNDC4 showed lower expression, while FNDC3B and FNDC8 displayed higher expression in liver cancer. Significant statistical differences in the prognostic results of the FNDC family in liver cancer were observed only in the KM plotter. OS, RFS, progression-free survival (PFS), and disease-specific survival (DSS) were analyzed in patients with liver cancer using a KM plotter. With respect to liver cancer, high expression of FNDC1  which demonstrates the mRNA expression levels of the FNDC family in human cancers from TIMER). We then took advantage of the PrognoScan database to study the prognostic value of the FNDC family in colorectal cancer. As shown in Figure http://links.lww.com/MD/I39 in the supplementary file.In comparison to normal tissues, FNDC1 and FNDC3B were highly expressed in colorectal cancer using the Oncomine database. Moreover, low expression of FNDC5 and high expression of FNDC8 were observed in colon adenocarcinoma according to the TIMER database . Table In the Oncomine database, there are only 3 datasets for FNDC3A, FNDC4, and FNDC5, which indicate statistically notable distinctions between prostate tumors and normal tissues. In accordance with Bonome analysis, FNDC3A was downregulated in ovarian carcinoma. Meanwhile, the expression levels of FNDC4 and FNDC5 were lower in ovarian serous adenocarcinoma in the Yoshihara dataset. In addition, we observed the expression of the FNDC family members, except FNDC7, in ovarian serous cystadenocarcinoma, the most frequent type of ovarian cancer, using TIMER .It is worth mentioning that the transcriptional expression levels in certain additional solid tumors, such as esophageal, kidney, leukemia, lymphoma, brain, and central nervous system malignancies, exhibited substantial differences Fig. . To that,17,31 and FNDC3B is increased in liver, lung, and colorectal cancers.,32,33 Our expression analyses revealed that the mRNA levels of FNDC1 and FNDC3B were significantly higher in most malignancies than in normal tissues, which is consistent with previous studies. In terms of FNDC3A, there are only a few recent studies on its significance to cancer, however, it has been discovered to be strongly expressed in colorectal and cervical cancers, among other malignancies.,19 In our study, we found that FNDC3A was more common in most types of cancers. For FNDC4, differential expression was not detected in colorectal cancer tissues but increased in inflammatory bowel disease samples. Similar to previously reported results in other studies, the majority of malignancies in our analysis had decreased mRNA expression. Contrarily, FNDC5 has been found to be highly expressed in a variety of cancerous tissues and cells, including breast and kidney cancers.,35 Different detection methods, sample sources, and histological types may have led to contradictory results. Besides, we noticed that the transcriptional expression levels of FNDC6 varied depending on the tumor type, with lower levels in esophageal, breast, and prostate cancers and higher levels in lung and pancreatic cancers being found in some cases. There were few datasets for FNDC7 and FNDC8 in our analyses, and they have rarely been reported so far.Patients with stomach, breast, and prostate malignancies have frequently been found to have FNDC1 upregulation in clinical samples, Thus, we used the KM Plotter to examine prognostic outcomes based on the 4 intrinsic categories of disease. All data are shown in Table S8, Supplemental Digital Content, http://links.lww.com/MD/I41 in the supplementary file, and all statistically significant survival curves are displayed in Figure S3, Supplemental Digital Content, http://links.lww.com/MD/I33. Furthermore, decreased FNDC3Awas found to be related with a poor RFS or OS in all subtypes of patients apart from luminal B. It’s worth noting that high FNDC3B expression was probably tied to completely opposite survival outcomes in different breast cancer subtypes and survival analysis methods. For example, in patients with luminal A classification, lower FNDC3B levels were accompanied by worse RFS, while better OS and PPS were related to decreased FNDC3B levels in patients with the same subtype. In addition, only 1 significant prognostic analysis of FNDC4 was found in the 4 intrinsic subtypes of breast cancer. Additionally, higher FNDC5 levels predicted better RFS and DMFS in basal patients. Moreover, increased FNDC6 was associated with good RFS in luminal B and basal patients, but poor PPS with high FNDC6 was detected in basal patients. Analyses of the FNDC family in breast cancer have already shown that increased FNDC3A or FNDC5 indicated good survival results . As a result, we propose that FNDC3A could be used as a predictive biomarker in the treatment of breast cancer, particularly in basal and luminal A subtypes. Additionally, FNDC5 may serve as a prognostic biomarker for basal breast cancer.Four distinct biochemical subgroups of breast cancer have emerged in recent years through comprehensive transcriptional profiling research: luminal A (ER+/HER2-/grade 1 or 2), luminal B (ER+/HER2-/grade 3), HER2 (HER2 + tumor) enriched, and basal-like (ER-/PR-/HER2-). These subgroups have been demonstrated to be consistent in their ability to predict therapy sensitivity and survival results. Lung cancer includes 2 subtypes: squamous cell lung carcinoma and lung adenocarcinoma. Our prognostic studies revealed that no gene was linked with OS or PPS in patients with squamous cell lung cancer, nor was any gene associated with PPS in patients with lung adenocarcinoma. However, in lung adenocarcinoma, all members of the FNDC family, except FNDC7 and FNDC8, are interrelated to RFS/OS and FP. This leads us to believe that, for lung adenocarcinoma, this set of genes can be used as a biomarker to predict prognosis, rather than squamous cell lung cancer, as previously thought.Lung cancer is the main cause of cancer-related death in China and around the globe.,40 What’s more, we had a few other new findings that upregulated FNDC3A mRNA expression signified better OS in gastric and liver cancer patients. FNDC1 High expression was tightly correlated with poor prognosis in ovarian cancer but with good RFS and PFS in liver cancer. A potential interaction between FNDC3B and survival outcomes has also been observed in ovarian and gastric cancer. FNDC4 and FNDC6 are relevant to survival curves in colorectal and breast cancer. Regretfully, it seems that no significant survival results were related to the FNDC family in brain cancer.Furthermore, we found that members of the FNDC family could be potential therapeutic targets or prognostic markers in several cancers, in line with earlier reports.Our research will help us to gain a better understanding of the FNDC family’s expression levels and prognostic usefulness in a few solid cancers. Moreover, our findings provide evidence that members of this family can be used as new prognostic biomarkers or prospective targets for cancer therapy in humans. However, we only focused on the mRNA expression level of FNDCs and its prognostic value and did not analyze its protein expression levels and some probable signal routings. Sample cohort studies are required to confirm the prognostic value of this family, and additional studies are required to identify the molecular pathways that underlie the development of malignant malignancies. In summary, we conducted a systematic analysis of not only the mRNA expression levels but also the prognostic value of the FNDC family in a spectrum of typical malignancies, including breast, lung, gastric, ovarian, liver, and colorectal cancers. Multiple members, including FNDC1, FNDC3A, and FNDC3B, demonstrated significant expression changes between cancer and surrounding normal tissue groups in the malignancies studied in this study. Furthermore, we developed a new biomarker, FNDC3A, for the prognosis of breast cancer, and lung adenocarcinoma might be able to choose the FNDC family as a prognostic biomarker.We are grateful to the contributors of the data to Oncomine, TIMER, Kaplan–Meier plotter, and PrognScan.Conceptualization: Hui Jiang.Data curation: Hui Jiang.Resources: Zhi Liu.Validation: Bo Ling Chu.Writing – original draft: Bo Ling Chu, Jiao He.Writing – review & editing: Ling Yang.


APOE gene are the leading cause of LPG. APOE mutations are an important determinant of lipid profiles and cardiovascular health in the population and can precipitate dysbetalipoproteinemia and glomerulopathy. Apolipoprotein E-related glomerular disorders include APOE2 homozygote glomerulopathy and LPG with heterozygous APOE mutations. In recent years, there has been a rapid increase in the number of LPG case reports and some progress in research into the mechanism and animal models of LPG. We consequently need to update recent epidemiological studies and the molecular mechanisms of LPG. This endeavor may help us not only to diagnose and treat LPG in a more personized manner but also to better understand the potential relationship between lipids and the kidney.More than 200 cases of lipoprotein glomerulopathy (LPG) have been reported since it was first discovered 30 years ago. Although relatively rare, LPG is clinically an important cause of nephrotic syndrome and end-stage renal disease. Mutations in the  LPG is round it . As a “M disease . Trendine review . The purAPOE mutants accumulate within the glomeruli. This finding was supported by observations of mutations named APOE Sendai (Arg145Cys) in 1997 and APOE Kyoto (Arg25Cys) in 1998. A total of 17 APOE variants associated with LPG have been identified to date, highlighting DNA analysis of the APOE gene as one of the most important tools for identifying LPG. These 17 mutations were retrieved from published case reports by manually literature searches, among which 13 have been included in the HGMD database .The total number of patients was estimated to be <80 in 2011 . Due to APOE Sendai (Arg145Pro) was mainly observed in north-central Japan, particularly in Yamagata and Miyagi (APOE Kyoto (Arg25Cys) was reported as the most frequent mutation in LPG throughout the world, including in southwestern China, Japan, France and the USA. However, a report in 2014 showed that 35 patients within 31 unrelated Han families with biopsy-proven LPG resided in a small county of Sichuan Basin in southwest China, indicating regional clustering with the same genetic background. It was thus suggested that the descendants of APOE Kyoto in this area were derived from a single founder. In contrast, APOE Guangzhou and Tokyo-Maebashi were reported to be dominant in cases from the southeast area of China  spontaneously developed LPG-like disease. This was the first time that LPG-like disease was observed in an organism other than humans. The kidney pathology of squirrels is similar to that of human LPG, but genetic mutations have not been determined .As the majority of the reports on the epidemiology of LPG were based on case reports, to systemically update this information, we conducted a literature review using the search item “lipoprotein glomerulopathy” from various databases  from 1988 to January 2022. A total of 274 LPG cases were identified, and the epidemiological details can be found in According to updated statistics, China and Japan have a comparatively higher prevalence of LPG, with 207 and 47 patients, respectively. There is still lack of precise epidemiological studies in LPG. Based on the current meta data from literature review, it was estimated that the prevalence of LPG is about 3.74 per 10 million in Japan and 1.43 per 10 million in China. Surely, it may be underestimated. As mentioned above, the areas most affected by LPG were located in southwestern and southeastern China and central and northeastern Japan. A total of 20 cases have been reported in other countries and territories. Among all the cases, there were 137 males and 137 females, with an average age of diagnosis of 35 years old (from 7 to 72 years). In terms of age of onset, a total of 188 patients had documented information. There were 8, 23, 112, 42 and 3 cases with age of onset ≤ 10, 11–17, 18–45, 46–65, and >65. It suggested that about 60% of the cases were diagnosed in young adults (18–45 years old) , a lipid insertion sequence (244–272) and a homo-oligomerization region (248–299) , the hinge region (AA 200–215), and the C-terminal AA 216–299). There are two important binding regions in the N-terminal sequence that have overlapping gene sequences, the low density lipoprotein receptor (LDLR) binding region , 28 (1429. There 248–299) –34, whicAs the ligand for the LDL receptor family and heparan sulfate proteoglycans (HSPG), apoE associates with triglyceride-rich lipoproteins in mediating clearance of their remnants . When exApoE is also important in endogenous lipid metabolism. Hepatocytes secrete VLDL containing apoE, and these VLDL are converted into IDL. The subsequent metabolism of IDL can be divided into two pathways, through interactions between apoE and LRP or metabolism into LDL –37. The APOE gene, rs429358 (Cys130Arg) and rs7412 (Arg176Cys), define the apoE protein as three isoforms  (Two coding variants in the human  and E4) , among w and E4) . The aff and E4) , 40–42. APOE Sendai in 1997. Further APOE mutation has been suggested to be the most important etiologic factor in the pathogenesis of LPG , among which 5 reside in the HSPG binding region (144–147 sites). Another hot spot is located in the region spanning AA 150–180, where 5 mutations have been reported (APOE gene inherited from his mother (p.Arg50His) and father (APOE Kyoto). Each his parents with a heterogeneous mutation had normal kidney function without proteinuria  mutations (APOE Chicago (Arg147Pro) and APOE5 (Glu3Lys) inherited from her mother. But her mother did not have any phenotypes , APOE Sendai (Arg145Pro), APOE Osaka or Kurashiki (Arg158Pro)] showed different protein structural stabilities (APOE Kyoto (Arg25Cys), APOE Tsukuba (Arg114Cys), and APOE Las Vegas (Ala152Asp)] ] . In vitr fibrils .APOE Sendai mutation decreased the binding ability of apoE with LDLR to <5%, it decreased its binding ability with HSPG to 66%  was associated with LPG-like lesions in atherosclerotic mice, the severity of which can be alleviated using probucol .Factors affecting CKD progression, such as fibrosis, apoptosis, local tissue injury, and infiltration of immune cells, may also be involved in LPG.These data support a complex etiology of LPG, and additional pathogenic factors warrant further elucidation.In 2006, a single set of diagnostic criteria for LPG was proposed by Japanese nephrologists , but sometimes with an uncommon type, e.g., E1/3 or others.It was suggested that although genetic testing was not necessary for definitive diagnosis, it should be performed in patients with suspected LPG whenever possible to confirm the diagnosis.Initially, LPG may cause no symptoms. Symptoms and signs are due to the buildup of waste products and fluid retention in the body , 89, 90.One of the most characteristic laboratory indicators of LPG is elevated serum apoE levels. It was reported that patients with LPG had a mean serum apoE concentration of 11.14–17.1 mg/dL (3.9–71.0 mg/dL), approximately twice the upper level of the normal population , 97, 98.APOE gene, LPG and type III HLP show obvious differences. In type III HLP, atherosclerotic cardiovascular disease and xanthomatosis are common . Of these patients, 38.7% had CKD1, 35.5% had CKD2, 18.7% had CKD3, 3.2% had CKD4, and 3.9% had CKD5. In terms of blood lipids, the average triglyceride level of these patients was 3.4 mmol/L  (reference range 0.6–1.7 mmol/L), which is approximately twice the normal upper limit. Total cholesterol was 6.8 mmol/L  (reference range 2.8–5.2 mmol/L), LDL was 3.6 mmol/L  (reference range 2.1–3.1 mmol/L), and HDL was 1.4 mmol/L  (reference range 0.9–1.6 mmol/L). Most of the patients had significantly elevated serum apoE, with a mean of 12.1 mg/dL . Great fluctuations of standard deviations suggested great clinical heterogeneity of LPG.We further checked the clinical manifestations of LPG by systematic literature review. An additional file shows this in more detail see . The meaAPOE genotypes   . The ageand E3/3 , 105–107Other complications rarely have been reported. Known comorbidities included splenomegaly, thalassemia, psoriasis, abdominal aortic aneurysm, pleural effusion, and neurofibromatosis type I , 109. HoThe most typical pathological appearance of LPG under light microscopy is the dilatation of the glomerular capillary lumen filled with eosinophilic granular and vacuolar thrombosis . The thrThe most common deposits are apoE and apoB in immunofluorescence, which might be taken as supporting evidence for the diagnosis of LPG. In the previous literature, however, immunoglobulin and complement, such as IgM, IgA, and C3 depositions, may be observed in mesangial and capillary walls in many cases, and scattered C1q deposits were also reported , 115. HoUnder electron microscopy, lipoprotein thrombosis is characterized by a fingerprint-like concentric lamellar structure, sometimes referred to as a sand stone structure . Some otBecause the main pathological feature of LPG is lipoprotein thrombosis, it should be differentiated from other diseases with thrombotic substances, such as macroglobulinemia nephropathy and cryoglobulinemia nephropathy.There is still a lack of specific or targeted therapies for LPG. Most of the regimens available were based on lowering proteinuria and hyperlipidemia. In the absence of clinical trials, current data are mostly from case reports or observational studies.Early in the history of LPG, the patient was often treated with glucocorticoids with or without immunosuppressants, similar to other nephrotic syndromes. However, it was soon proven ineffective , 118. AdRegimens have achieved some success in supporting the pathologically causal role of lipoprotein and hyperlipidemia in LPG. The first drug was probucol, which reduces total TC and LDL levels and is widely used in the treatment of hypercholesterolemia . ProbucoFenofibrate and benzafibrate can significantly reduce blood VLDL levels by acting on peroxisomal proliferator-activated receptor (PPAR) and activating lipoprotein lipase (LPL) and thus reducing TG and LDL. A small clinical contrast study based on 35 patients supported the efficacy of fibrates in LPG. After 12 months of treatment, their lipid profiles, proteinuria, and serum albumin improved, and their serum apoE decreased significantly with stable renal function , 122.Niceritrol is a nicotinic acid derivative that has been used to lower lipoprotein levels and reduce proteinuria in patients with chronic kidney disease associated with hyperlipidemia , 124. ItThe other drugs that are still in clinical use today are statins. As a potent inhibitor of 'β-hydroxy β-methylglutaryl-CoA' ('HMG-CoA') reductase, statins can increase the expression of the LDL receptor in the hepatocytes' cell membranes. In addition, statins also have multiple effects, such as reducing TG, improving endothelial function, and anti-oxidation . StatinsRenin-angiotensin-aldosterone system inhibitor (RAASi) therapy shows reno-protective effects in various forms of proteinuric CKD. Therefore, although there is no evidence that ACEIs and ARBs are effective in LPG, their administration can be considered suitable both for blood pressure control and to reduce proteinuria among LPG patients. Some case reports have suggested that antilipidemic drugs combined with ACEIs and ARBs are an effective treatment for LPG . Recentlin vitro and then use heparin to form a polymer with LDL-cholesterol, LP (a), fibrinogen, and triglyceride to precipitate them out  showed that intraglomerular lipoprotein thrombi almost disappeared. The proteinuria of six patients returned to baseline levels within 12 months. Four recurrent patients received repeat immunoadsorption treatment and showed repeated efficacy  was discovered. Patients with this gene mutation presented with kidney pathology that resembled membranous nephropathy (MN) rather than LPG , MN-like APOE disease, and LPG ; Academy of Medical Sciences—Newton Advanced Fellowship (NAFR13_1033); Beijing Natural Science Foundation (Z190023); Fok Ying Tung Education Foundation (171030); and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-046). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.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. 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