Inulin had the highest elasticity index value (31.05 nm−2) and MVI value (590.17 nm−2). The instability index was the lowest in the case of pea protein, gellan gum, konjac gum, and inulin (below 0.02). The color parameters and whiteness index (WI) of each biopolymer differed significantly from one another. Based on the obtained results, pea protein, gellan gum, konjac gum, and psyllium hydrogels had similar structural and biomechanical properties, while inulin hydrogel had the most diverse properties. Wheat protein, maltodextrin, and tara gum did not form a gel structure.The aim of this study was to conduct a comparative assessment of the structural and biomechanical properties of eight selected food-grade biopolymers  as potential hydrogel building blocks. The prepared samples were investigated in terms of the volumetric gelling index, microrheological parameters, physical stability, and color parameters. Pea protein, gellan gum, konjac gum, and psyllium samples had high VGI values (100%), low solid–liquid balance (SLB < 0.5), and high macroscopic viscosity index (MVI) values (53.50, 59.98, 81.58, and 45.62 nm Hydrogels are a three-dimensional network of hydrophilic polymers with viscoelastic properties. Creating a matrix with high-water content is possible due to the formation of structural networks . HydrogeNaturally sourced hydrogel building blocks (biopolymers) have great potential in achieving the above-mentioned goals, while being biocompatible, biodegradable, and edible. These biopolymers are proteins and polysaccharides with different biomechanical and functional properties . NaturalProtein and polysaccharide hydrogels are generally induced by physical  and chemical  induction techniques, or by a mixed technique to achieve the desired properties . They arBiopolymer hydrogels have a wide range of potential applications in different sectors. They can be used in tissue engineering to mimic the extracellular matrix (ECM), providing a non-immunogenic biocompatible scaffold . Pre-gelTo summarize, it can be stated that food-grade biopolymers (protein and polysaccharides) have a great potential in the biomedical, food, pharmaceutical, and cosmetic sectors due to their renewability, sustainability, affordability, biocompatibility, biodegradability, and edibility. Nonetheless, due to the lack of publications on this topic, preliminary comparative studies of the gelling ability of different biopolymers and their potential as hydrogel building blocks are needed. For this purpose, eight food-grade biopolymers were selected to evaluate their gelling ability and potential as hydrogel building blocks.® F85F, protein content 88%, ash 10%), wheat protein , and maltodextrin  5, ash 0.5%) were obtained from Roquette Freres, . Gellan gum , konjac gum , Psyllium Husk Powder , and tara gum  were obtained from C.E. Roeper GmbH, . Inulin  was purchased from BENEO GmbH .Pea protein , wheat protein (WP), inulin (INU), and maltodextrin (MD)—concentration 20 g/100 g. Konjac gum (KG) and psyllium (PS)—concentration 1.5 g/ 100 g. Gellan gum (GG) and tara gum (TG)—concentration 0.4 g/100 g. The preparation of the samples involved dispersing the chosen biopolymers in distilled water (80 °C) using a homogenizer . Then the solutions were stored  for 24 h at a temperature of 8 °C to let them develop a gel-like structure. G—volume of the formulated gel, VT—total volume of the sample. The reported values represent the averages of three replicates. Furthermore, the samples were evaluated in terms of their appearance after the vials were inverted. It is a visual test to determine whether a sample has formed a gel structure or is still a sol , solid–liquid balance (SLB) [nm2], and macroscopic viscosity index (MVI) [nm−2]. The MSD value is the mean of several scattering trajectories of the particle movement as a function of time in the analyzed sample. EI is directly proportional to the elastic modulus (G’) and is calculated as the reciprocal of the MSD value at the plateau. SLB corresponds to the dimensionless ratio of modulus of elasticity and modulus of viscosity loss G’/G”. MVI is the equivalent of the apparent viscosity at zero shear and is calculated as the reciprocal of the MSD slop [The Rheolaser Master device  was used to investigate the microrheological properties of the samples. The device operates based on dynamic MS-DWS (Multi Speckle Diffusing Wave Spectroscopy) technique in the near-infrared (wavelength of 650 nm). The detector captures the interfering backscattered waves, and the measurement results were recorded using the Rheotest software . Based oMSD slop . The repThe physical stability of the obtained gels was assessed using LUMiSizer 6120-75 . This physical stability assessment technic involves subjecting the samples to centrifugal force while illuminating the entire sample cell with near-infrared (NIR) light. The sensor simultaneously measures the intensity of transmitted light as a function of time and position over the entire sample length, and the data is converted and recorded using the provided software . For this analysis, the following parameters were used: dispersion volume 1.8 mL; wavelength 870 nm; light factor 1; 1500 rpm; experiment period 15 h 10 min; interval time 210 s; temperature 20 °C. Based on the recorded data, the destabilization behavior (fingerprint) was obtained, and the instability index was computed ,54. The The color parameters were measured using a CR-5 stationary colorimeter  in the CIE system  with a D65 illuminant. Before each use the device was calibrated, and to exclude the mirror image of the measurement vessel  in which the sample was placed, the specular component excluded method was used. The measurements were taken five times for each of the three replicates (at a temperature of 20 ± 1 °C). The brightness of the studied sample is indicated by the L* color parameter that ranges from 0 to 100 . The a* parameter represents the share of green  and red  color. The b* color parameter values represent the share of blue  or yellow  color in the samples . The rep follows : ΔE=, the instability index, and the color parameters , and the whiteness index (WI). Tukey’s test at significant level = 0.05 was used to confirm the significant differences between the biopolymers. Additionally, the results were assessed using the principal component analysis (PCA) and hierarchal cluster analysis (HCA). All the analyses were performed using Statistica13.3 .To determine the ability to form a gel structure by the tested biopolymers the volumetric gelling index (VGI) was determined. The mean values of VGI and the images of the analyzed biopolymers are presented in The microrheological properties were determined using the MD-DWS method, which allows for the measurement to be carried out in a non-invasive way . The rectilinearity of the MSD profiles indicates that the analyzed sample is fluid, exhibiting Newtonian fluid behavior. The non-rectilinear curve path occurs at the transition from fluid to sol. When the examined samples change from sol to gel the MSD profiles achieve a plateau. This means that the particles are not able to move freely due to the formation of a network interaction.The mean square displacement MSD of each analyzed biopolymer as a function of decorrelation time is presented in −2, which means that the sol was close to getting to the gelling point where SLB = 0.5. The elasticity index (EI) is directly proportional to the storage modulus G’ and provides information about the sample’s elasticity, which is due to the solid-like characteristic. Based on the obtained EI values, only INU differed significantly from the rest of the biopolymers, with the highest EI value (31.05 × 10−2 nm−2). Although the SLB values of PP, GG, KG, and PS showed that they exhibited more solid-like behavior, they had low EI values , which can suggest that their gel structure was softer (less elastic). The MVI value of the inulin (INU) samples reached the highest value, which correlates with the elasticity index (EI). PP, GG, KG, and PS had significantly higher MVI values than those of WP, MD, and TG, which proves that although they all had comparable EI values, the WP, MD, and TG did not form a gel structure.The mean values of the microrheology parameters: solid–liquid balance (SLB), elasticity index (EI), and macroscopic viscosity index (MVI) are presented in Physical stability is an important parameter in characterizing the ability of biopolymers to form a hydrogel. To assess the physical stability of the analyzed biopolymers, the instability index was calculated. This parameter ranges from 0 for a stable sample to 1 for an unstable sample. The mean values of the instability index for each biopolymer are presented in Pea protein (PP), gellan gum (GG), konjac gum (KG), and inulin (INU) samples had the lowest value of the instability index (below 0.02). The instability index of PS was significantly higher than PP, GG, KG, and INU, but still relatively low (0.06). Higher instability indexes were recorded for TG (0.44), WP (0.54), and the most physically unstable were the samples prepared using MD (0.77). The “fingerprints” or transmission profiles indicate changes in the particle concentration within the analyzed samples using the STEP technology (space-time resolved extinction profiles). In the case of each biopolymer, the evolution of the transmission profiles provides the necessary information on the kinetics of concentration changes caused by phase separation. Additionally, based on the transmission level through the analyzed samples, it is possible to observe the transparency of some systems. The “fingerprints” transmission profiles for each biopolymer are presented in A structural compression was observed in the case of WP, MD, and TG. However, the destabilization of the system was the fastest for maltodextrin (MD) and wheat protein (WP). Based on the transmission profiles, the most stable samples were PP, GG, KG, INU, and PS. Gellan gum (GG), konjac gum (KG), and psyllium (PS) samples had high transparency, which was indicated by the high transmission of the near-infrared (NIR) light through the cell. The light transmission was around 40% for GG, 70% for KG, and 50% for PS. Although the KG and PS samples were stable, a movement in the particles’ concentration (including the air that might have become entrapped in the structure during the preparation process) could have caused the fluctuations observed in the fingerprints.The mean values of the color parameters  and the whiteness index for each biopolymer are presented in To comprehensively determine the difference between the studied biopolymers, the total color difference parameter (ΔE) was calculated . It was The PCA and HCA of the obtained result are presented in In the present study, eight biopolymers were analyzed in terms of their volumetric gelling index, microrheological properties, physical stability, and color parameters. Based on the volumetric gelling index , PP, GG,The physical stability results (instability index and fingerprints, The color of hydrogels is one of the main characteristics determining the quality of the products in which they are used, and it has a decisive influence on consumer acceptance or rejection in the case of food and cosmetic products . Due to Based on the achieved results, and in the investigated gelling conditions, pea protein, gellan gum, konjac gum, psyllium, and inulin had the most promising gelling ability—they were able to produce highly elastic and physically stable hydrogels. Moreover, pea protein, gellan gum, konjac gum, and psyllium hydrogels had similar structural and biomechanical properties, while inulin hydrogel had the most diverse properties. Wheat protein, maltodextrin, and tara gum were similar in terms of the analyzed properties and did not form a gel structure. Since the combination of two biopolymers might result in hydrogels characterized by a broader range of structural and biomechanical properties, and enhanced interdisciplinary, and biomedical application potential, additional studies are currently being conducted.


Geographic location and national income may influence access to innovation in healthcare. We aimed to study if geographical location and national income influenced the timelines to activate the global phase III APHINITY trial, evaluating adjuvant pertuzumab in patients with HER2-positive early breast cancer.Time from regulatory authority (RA) submission to approval (RAA), time to Ethics Committee/Institutional Review Board (EC/IRB) approval, time from study approval by EC/IRB to first randomised patient and from first to last randomised patient were collected. Analyses were conducted grouping countries by geographical region or economic income classification.p = 0.47), although there was a trend to longer time to RAA in upper middle-income economies (p = 0.07). Except for time from first to last patient randomised, there was wide variation in timelines overall and within geographical regions and economic income groups.Forty-one countries (of 42) had data available regarding all relevant timelines. No statistical difference was observed between the time to RAA and geographical region (Geographical location and income classification did not appear to be the major drivers influencing time for clinical trial activation. Wide variability in activation timelines within geographical regions and income groups exists and is worthy of further investigation. Clinical trials are essential for the development of new drugs, devices and diagnostic tests leading to patient benefit . In cancThe complexity of phase III clinical trials has, however, grown considerably and there are several administrative barriers that can contribute to increasing the length of time required to activate a clinical trial , 7–11. TA previous analysis of regional timelines to initiate the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) global phase III trial NCT00490139), which recruited patients between 2007 and 2011, suggested that geographical location and national income affect the time taken for trial initiation, being significantly longer in South American and upper middle-income economies; this potentially affects patient access to trials of innovative therapies in such locations [39, whichTo provide more recent data on this topic and to motivate a discussion around the activation process of phase III trials across the globe, we aimed to study if geographic location and income classification would influence the activation timelines of the phase III APHINITY trial (NCT01358877), which investigated the addition of pertuzumab to chemotherapy and Trastuzumab as adjuvant therapy for patients with HER2-positive early breast cancer.APHINITY was a phase III global trial, designed by the Breast International Group in collaboration with a pharmaceutical industry sponsor, and was conducted under the auspices of an independent data and safety monitoring committee. The APHINITY trial activation timelines in each participating country were recorded by the pharmaceutical industry study sponsor and transferred to the study team for the purpose of this analysis. Data were compared across geographical regions  and economic income groups  as defined by the World Bank , 15.The following time intervals were evaluated for each participating country:Time to regulatory authority (RA) approval, defined as the interval (in days) between protocol submission by the sponsor to the RA and its approval.Time to Ethics Committee or Institutional Review Board (EC/IRB) approval, defined as the interval (in days) from submission by the study sponsor to EC/IRB and its approval.Time from RA to first patient, defined as the interval (in days) between RA approval and first patient randomised into the study.Time from EC/IRB to first patient, defined as the interval (in days) from first EC/IRB approval to the first patient included in the study.Time from first to last patient, defined as the interval (in months) from the first patient randomised in the study in a particular country to the last patient randomised in the study (31 August 2013).Protocol approval was not received from the national EC/IRB for Brazil in a timely fashion; Brazil did not, therefore, participate in the APHINITY trial. Additionally, the protocol was not submitted to the national RA for Israel so the corresponding timelines for Israel could not be calculated. The missing day in a partial date of protocol submission to country EC/IRB for Argentina and for Switzerland was imputed as day 15 as the middle of the month. Each individual patient’s date of randomisation was recorded in the randomisation system and uploaded to the APHINITY database.Each site’s country was classified according to World Bank guidelines  and grouEconomic income group was derived from each site’s country and based on the World Bank’s list of economies (June 2019)  and clasp-value was <0.05.Descriptive statistics, including means, medians and ranges, were calculated for the different timelines evaluated. Differences between geographical regions and economic income classification groups were calculated using one-way analysis of variance (ANOVA), following data normalisation on square roots of the different timelines obtained. Geographical regions represented by only one participating country were not included in the ANOVA calculations. ANOVA statistics was calculated only for time to RA approval as the process of EC/IRB approval does not follow a standard procedure being highly variable and influenced by local procedures, which could led to data misinterpretation. Differences were considered statistically significant if APHINITY randomised 4,805 patients between November 2011 and August 2013 among 42 countries. Of the 42 countries, 21 (50.0%) were located in Europe and Central Asia, 9 (21.4%) in East Asia and Pacific, 8 (19.0%) in Latin America and Caribbean, 2 (4.8%) in North America, 1 in Middle East and North Africa (2.4%) and 1 (2.4%) in sub-Saharan Africa. Twenty-eight (66.7%) of the 42 countries had high, 11 (26.2%) upper-middle and 3 (7.1%) lower-middle income economies .F: 0.87; p = 0.468; Regarding the time interval between EC/IRB approval to first patient randomised, Latin America and Caribbean had a longer time interval  compared to other regions  . FurtherF: 2.85, p = 0.07; The different time intervals for study activation across economic income groups are reported in Similar to the findings for geographical regions, there was a wide variation in the timelines for study activation overall and within the economic income groups. For example, the median time for EC/IRB approval to first randomised patient across overall was 56 days, but again the range was wide  were recorded for all participating countries and across the defined economic and geographic regions. This timeline was relatively homogenous between geographic regions , the Voluntary Harmonisation Procedure (VHP) is an initiative developed by the ‘Clinical Trials Facilitation Group’, a working group of the ‘Heads of Medicines Agencies’ . The VHPWe should, however, remember that study activation is only one of the facets where bureaucracy might hinder clinical cancer research. According to a survey of 940 clinical investigators, the number of administrative tasks related to clinical trials and their complexity have grown markedly during recent years, which they consider an obstacle to the development of clinical research . FurtherSome limitations of our research need to be acknowledged. First, the results from this analysis should be considered as exploratory, as they were not pre-planned; nevertheless, they warrant further evaluation in other phase III trials. In addition, although the geographic and or economic region were not identical in the two reports, 87.8% of the countries participating in APHINITY also participated in ALTTO, so there was considerable overlap. In our report, however, geographic and economic regions were classified according to the current World Bank Criteria (June 2019), while the prior ALTTO analysis only used World Bank Criteria to classify income groups and not geographic groups. In addition, as the results were presented by country (and region), there would have been wide variation in income of the populations of hospital sites, although these should not have affected nationwide procedures. Also, the rather small number of countries in some geographic regions, such as North America and Middle East and North Africa, as well as in the lower-middle income subgroup should be noted. Lastly, our findings may not apply to academic trials as they differ from industry sponsored trials in several aspects such as the resources available to address the regulatory, as well as financial and operational, obligations of international clinical trials.per se appear to be the major drivers behind a delay on activating a clinical trial. The causes of such delays should, therefore, be further investigated on a country and site-basis with a common interest in the safe and efficient delivery of clinical trials across the most diverse and representative patient populations possible.In conclusion, although general improvement in the timelines to activate a clinical trial was observed in the APHINITY trial compared to the previous ALTTO report, there was wide variability in the timelines within geographic and economic regions. Our results suggest that geographical regions and national income levels do not The APHINITY trial  is a randomised, multicenter, open-label, phase III study. The Ethics Committee and relevant health authorities at each participating institution approved the study protocol. All participants gave written informed consent before study entry.This manuscript does not contain any individual person’s data in any form. Therefore, consent for publication is not applicable.Partial results of this work have been presented as a poster at the 2020 San Antonio Breast Cancer Symposium (PS7-21).Due to the Informed Consent Form, data privacy and Intellectual Property Rights-related restrictions, the clinical data cannot be made public, i.e., accessible for anyone, for any purpose without a review process and without putting an agreement in place. Nevertheless, raw data are available upon request and any request can be directed to the central APHINITY team.MAF, OE, DP, SG and LR: none. CT: Travel grant, Roche; advisory board: AstraZeneca, Eisai, Daiichi Sankyo, MSD. Speaker: Pfizer and Eisai. MP: MP’s institution received funding from Roche in respect of the APHINITY trial. NP: advisory board: Lilly; contracted research: Novartis, AstraZeneca, Daichii Sankyo, Roche and Pfizer; speaker: Novartis, Lilly, AstraZeneca and Roche. DE: funding for his research fellowship (2018–2019): Novartis; speaker fee: Janssen; salary paid by Roche. EA: honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac and Libbs; travel grants from Roche/GNE and GSK/Novartis; research grant to my institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier. JB: travel expenses: AstraZeneca and Roche; consultant: AstraZeneca, Daiichi Sankyo, Genomic Health, Libbs, Lilly MSD, Novartis, Pfizer and Roche. EC: employee of Roche Products Ltd; issued patent: Uses for and article of manufacture including HER2 dimerisation inhibitor pertuzumab, 13/649591.This sub-analysis has received no funding.


The most common presentation of decompensated HF is dyspnea, and arterial blood gas analysis is an excellent tool for the decision-making process for most dyspneic patients. However, data on the prognostic value of ABG in HF patients are limited. Herein, a retrospective cohort study was conducted to investigate whether the utilization of arterial blood gas analysis was independently associated with re-hospitalization in patients with heart failure.As a retrospective cohort study, the relevant clinical data of hospitalized patients admitted to Zigong Fourth People's Hospital, Sichuan, China from December 2016 to June 2019 with a diagnosis of HF were analyzed. The re-hospitalization within 6 months and the use of intravenous diuretic, nitrates, inotropes, or vasopressors were compared between patients with and without arterial blood gas analysis. We used a multivariable logistic regression model, propensity score analysis, and an inverse probability-weighting model to ensure the robustness of our findings.We included 1,605 patients with heart failure. The overall re-hospitalization rate within 6 months was 38.2%; it was 34.8% and 41.8% for heart failure patients with or without arterial blood gas analysis, respectively. In the inverse probability-weighting model, the use of arterial blood gas analysis was associated with a 26% lower re-hospitalization rate within 6 months.The performance of arterial blood gas analysis is associated with a 6-month rehospitalization rate benefit in a general population of heart failure patients. This association warrants further investigation. Many tests and procedures utilized in the treatment of heart failure patients are unverified clinically. When the results are extremely likely to affect patient therapy, an arterial blood gas (ABG) sample should ideally be collected. The need to evaluate the adequacy of patient ventilation, measure the response to therapeutic or diagnostic treatments, monitor the severity and course of a documented disease process, and examine acid-base status are all common indications for an ABG analysis . IndicatRoutine ABG analysis is not recommended in individuals with heart failure in clinical practice. When a precise measurement of O2 and CO2 partial pressure is required, an ABG analysis should be conducted . Patients with cardiogenic shock should have their lactate and pH levels checked. However, there is a lack of evidence on the prognostic significance of ABG in HF patients. The purpose of this study was to investigate if there was an association between ABG analysis and the rehospitalization rate of heart failure patients.The STROBE  statement was followed in the reporting of this study . We retrThe primary outcome was rehospitalization within 6 months. Rehospitalization was defined as the first rehospitalization within 6-month time period after discharge from the index hospitalization. Unfortunately, the reason of rehospitalization was not clarifed in this public database. The secondary outcomes included offering intravenous diuretic, nitrates, inotropes, or vasopressors therapy.All of the participants were subjected to descriptive analysis. Numbers and percentages were used to represent categorical variables. For normal distributions, continuous variables were reported as mean and standard deviation (SD), and for skewed distributions, median and interquartile range. For categorical, regularly distributed, and non-normally distributed continuous variables, we employed the chi-square test, one-way ANOVA, and Kruskal-Wallis tests, respectively.Propensity score matching (PSM)  was usedhttp://www.R-project.org, The R Foundation) and Free Statistics software versions 1.3. A threshold of p < 0.05 (two-sided) was considered statistically significant.All the analyses were performed with the statistical software packages R (9/L), Troponin (0.43 ± 2.72 pg/ml), BNP , CCI score, consisted of more Peripheral vascular disease (6.4%), Chronic obstructive pulmonary disease (COPD) (16.3%), Diabetes (26.5%) and Chronic kidney disease (25.3%) than no ABG group. The opposite patterns were observed in Albumin and Sodium.We included 1,605 patients in our study cohort . Blood gThe 30 variables were initially used to create a propensity score model. P = 0.004). The propensity score-matched rehospitalization rates for the no ABG group and ABG group were 41.4 and 34.9%, respectively. In multivariable logistics regression, the OR was 0.76   and 34.8% (286/ 823) for the no ABG group and ABG group in the original cohort, respectively. IPW demonstrated a significantly lower rehospitalization rate in the ABG group. The OR was 0.74  .p = 0.003). Second, ABG patients were significantly more likely to take intravenous nitrates . Finally, there was no significant difference in the use of intravenous inotropes or vasopressors in the two groups.We evaluated several secondary outcomes to investigate what factors could have contributed to the ABG analysis's advantages following PSM. There were several significant changes in secondary outcomes. In the beginning, ABG patients were considerably more likely to utilize intravenous diuretics , and insufficient cardiac output causes decreased tissue perfusion, leading to metabolic acidosis in HF patients with cardiogenic pulmonary edema. Thus, in high-risk HF patients, arterial blood gas analysis may be utilized as a comprehensive marker for backward and forward failure, and acid-base balance can be used to determine the general condition of heart function . However2, PCO2, and pH upon admission were not associated with all-cause long-term mortality, discouraging the use of ABG for prognosis evaluation , Minana et al. demonstrated that arterial POaluation . Kato etaluation . Meanwhialuation . These fPatients with ABG had a higher severity of illness score, more concomitant illnesses, and a higher BNP level in our study. Despite these indicators indicating a worse group of patients, we observed that after adjusting for confounding, patients who received ABG analysis had a substantially decreased rehospitalization rate after 6 months. There was an obvious selection bias in the study population since the criteria for ABG were not previously specified, and more “critical-looking” individuals were more likely to undergo ABG analysis.Clinicians may choose to perform ABG tests early in the stay for patients with heart failure, considering the factors shown in The findings should not be interpreted as the final and conclusive word on the value of ABG in the management of heart failure. The potential issues of residual confounding by variables not captured in the electronic health record, as well as the generalizability of the findings to other institutions, require further investigation as an observational single-center study retrospectively performed on electronic health record data. Because practice patterns may have changed over the study period, the outcomes were not adjusted for the year of admission, which is a limitation of the analysis. For several analyses, prospective randomized trials will be required for confirmation.In a broad population of heart failure patients, ABG analysis performance is associated with a 6-month rehospitalization rate benefit. The cause of this advantage is unknown; however, it might be related to the increasing use of intravenous diuretics and nitrates as suggested by ABG values. This relationship needs further investigation.https://doi.org/10.13026/8a9e-w734.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving human participants were reviewed and approved by the Ethics Committee of Zigong Fourth People's Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.XZ: methodology and writing. YS and HZ: data curation and validation. HL and XJ: writing—review and editing. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China , the Clinical Research Center of Shandong University (2020SDUCRCA009), the National Key Research and Development Program of China (2017YFC1308303 and 2021YFF0501403), Z-2019-42-1908-2 and Z-2016-23-2101 project of China International Medical Foundation, and the Natural Science Foundation of Shandong Province . The funders had no role in the 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. 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.


Given the descending trend of menarche age and the effect of social determinants of health on menarche, the present study was conducted to examine the relationship model of social determinants of health with menarche age of girls.The present cross-sectional study enrolled 840 mothers and their 6-17 year-old daughters in the city of Kashan, Iran (2020). Questionnaires used included: demographic-family questionnaire for mothers and daughters, question about age at menarche, Perceived Social Support, Physical Activity, Socioeconomic Status, Spiritual Health, General Health Questionnaire, the quality of couple's relationship and the family communication pattern. The statistical analysis was performed in SPSS-16, and the relationship model was examined using path analysis method in LISREL-8.8.The girls' menarche age was directly affected by sister's (b = 0.83) and mother's menarche age (b = 0.05), BMI (b = 0.01), physical activity (b = -0.06), conversation orientation (b = -0.002), socioeconomic status (b = -0.01) and maternal general health (b = 0.009). It was also indirectly affected by mother's menarche age, social support, socioeconomic status, and maternal spiritual health and parents relationships.The results showed that the numerous factors affect the girls’ age at menarche directly and indirectly. Considering mutual interaction of factors revealed in the proposed model, it is recommended this model be used as an appropriate framework in research, design and implementation of programs relating to adolescent girls. Menarche; Puberty; Menstruation; Social determinants of health. The studies published in 67 countries between 1960 and 1990 reported the mean age of menarche 13.53 years, which corresponds to a declining rate of 3–4 months per decade. Some studies report that this reducing trend is slowing down or stopping, but others report this trend still continues in some European and Asian countries . In IranChanges at age of puberty predispose adolescents to risks including: unsafe sexual activity, failed marriages, unwanted pregnancy and sexually transmitted diseases, obesity, metabolic syndrome, hypertension, type II diabetes, coronary heart disease, and premature death , 5, 6. GAccording to the world health organization (WHO), general health is the result of interactions among Social Determinants of Health (SDH), and a detailed comprehensive picture of the complex interaction of these factors on one another is required for an effective control and prevention. Social determinants of health describe circumstances in which people are born, grow up, live, work, and grow old . The socThe WHO model was selected because most studies conducted so far have focused on the effect of social factors on childhood and the individual's health in adulthood. Adolescence as a major development stage of life and puberty as a turning point and a critical stage in this period have been overlooked in SDH research , 10 becaAccording to the WHO model, puberty and its stages can be regarded as a health outcome in adolescence affected by structural and intermediary factors that require a comprehensive investigation. Not much information exists regarding the relationship of social determinants of health with stages of puberty and their interaction. Therefore, the present study was designed to examine the relationship model of SDH and stages of puberty using the WHO approach. In this study, it was assumed that the menarche age can decrease by environmental factors more than genetic factors and structural factors such as socio-economic status indirectly affect the age of menarche.22.1A descriptive cross-sectional study was conducted in the 2021 in Iran. The population of this study was the mothers-daughters in community health Centers. These places were selected because schools were closed during COVID-19 pandemic. All centers were sorted by district in terms of socioeconomic status and five centers were randomly selected. Then, the participants were selected by convenience sampling from these centers based on inclusion criteria. Inclusion criteria were healthy Iranian girls, 6–17 years, resident of Kashan city, no history of taking drugs such as hormone therapy, use of exogenous estrogen and special diet, Iranian mothers with literacy, no history of mental illness, no age restrictions. The age range of 6–17 years was selected according to the age range of puberty from early to late in girls. Exclusion criteria were reluctance to participate in the study and completing questionnaires inappropriately. The sample size per age group (6–17 years) was determined 63 subjects using Equation Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper.


Leptospirosis is a zoonosis with a worldwide spread that leads to clinical manifestations ranging from asymptomatic infection to a life-threatening disease. The immune response is predominantly humoral mediated limited to the infecting serovar. Individuals living in an area endemic for leptospirosis are often exposed to an environment contaminated with leptospires and there is a paucity of information on naturally acquired immunity. In the present study, we evaluated the kinetics of agglutinating antibodies in individuals from an endemic area for leptospirosis in Salvador, Brazil comparing two different intersample collection times.Between 2017–2018, we carried out a biannual prospective cohort with 2,086 individuals living in an endemic area for leptospirosis in Salvador, Brazil. To compare agglutinating antibody kinetics using microscopic agglutination test (MAT) with different collection times, a subcohort of 72 individuals with quarterly follow-up was carried out in parallel.The results revealed that using a shorter time for intersample collection led to the detection of a higher number of infections and reinfection events. Furthermore, we observed a higher rate of titer decay indicating partial and short protection. However, there was no indication of major changes in risk factors for the disease.We evaluated antibody kinetics among residents of an endemic area for leptospirosis comparing two sample collection times. The constant exposure to the contaminated environment increases the risk for leptospirosis infection with reinfection events being more common than expected. This indicates that the burden of leptospirosis might be underestimated by serological surveys, and further studies are necessary to better characterize the humoral response after infection. Leptospira  as the main carrier  estimates the occurrence of more than one million human cases of leptospirosis worldwide, with more than 50,000 deaths each year, most of which occurs in developing countries and tropical and subtropical climate regions , 10. In he world . In Braz carrier , 15.Leptospira and there are reports of the presence of anti-Leptospira antibodies in patients recovering from severe disease and in individuals with no previous history of the disease, most likely resulting from asymptomatic infection  and limited to the infecting serovar . Individnfection . Howevernfection . In the This project was approved by the Research Ethics Committee of the Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), the National Research Ethics Council (CONEP) through the Certificate of Presentation for Ethical Appreciation (CAAE) #45217415.4.0000.0040 and the Yale University Institutional Review Board #1006006956. All participants received guidance on the objectives, procedures, and risks associated with participation during informed consent. Minors gave verbal consent and we obtained written consent by their parents or legal guardian. Collegiality of participation was assured. Laboratory results were made available to the cohort participants.2 made up of three valleys, with open sewage close to the residences, places of garbage accumulation, and risk of flooding mainly in the bottom areas of the valleys , an urban slum community of Salvador, Bahia, Brazil . This co valleys . Due to  valleys , 18. Pre valleys , 19. TheBetween September 2017 to December 2018, residents of Pau da Lima with ≥5 years and who slept at least three nights a week at home were enrolled in the biannual analysis study. During all visits (every 6 months), blood samples were collected for evaluation of anti-leptospire antibodies using the microscopic agglutination test (MAT). Previously validated epidemiological, exposure and sociodemographic questionnaires were applied annually for field data collection. At the moment of enrollment for the biannual study, individuals with a previous history of leptospirosis infection determined by MAT were enrolled for our subcohort, together with controls that had no history of infection. For this subcohort, a quarterly analysis follow-up was performed (every 3 months) for blood collection, with a total of five home visits to assess antibody kinetics. For the entire study, we considered as exclusion criteria the following: participant not found at the time of the team visit, refusal to participate in the study and inability to locate the participants after three attempts.Leptospira using the microscopic agglutination test (MAT). The MAT was performed with L. interrogans serovar Copenhageni strain Fiocruz L1-130, the most prevalent serovar in the region   to assess whether MAT titers protect against reinfection.Statistical analyses were performed using the RStudio package, version 1.2.5033. Descriptive analysis was performed to obtain absolute frequencies or means and medians for categorical variables and univariate analysis through Welch's two-sample During a cohort study for leptospirosis conducted from 2017–2018, a total of 2,086 individuals were enrolled for a biannual collection of blood for MAT assay and analysis of epidemiological data. Among them, 339 (16%) were serologically confirmed for leptospirosis infection. We enrolled 110 participants for a subcohort performing a quarterly analysis follow-up. Among those, 52 confirmed cases and 20 negative cases that had ≥4 blood samples at the end of the study were analyzed .The demographic, socioeconomic and exposure information of all the cohort participants and the subcohort are shown in The kappa statistics for leptospirosis case classification at the different collection times was 0.48 (95% CI: 0.32–0.63), achieving moderate agreement . In thisThe distribution of MAT titers of samples positive for the Fiocruz L1-130 strain and their frequencies are listed in p < 0.001 and p = 0.005) and cleaning sewage (p = 0.003 and p = 0.033) were associated with a higher chance of infection for both groups with different collection times. Furthermore, informal employment (p = 0.013) for the quarterly analysis collection group and being married or having a stable union (p = 0.032) for the biannual were also associated with a higher chance of infection when compared to the non-infection group (p = 0.04) on the quarterly analysis group (p = 0.03) and informal employment (p = 0.01) were both associated with a higher risk (p = 0.047) showed as a risk for infection on the biannual analysis  . The varon group . A more is group . For reiher risk . A similher risk . Interesanalysis . There wLeptospira infection will help to better understand the duration of the immune response after infection, the course of infection, and the dynamics of protective immunity. In this study, we had the opportunity to evaluate the kinetics of the antibody response and the factors associated with exposure to leptospirosis in naturally infected individuals with asymptomatic infection comparing a biannual and a quarterly serological analysis. Among the 72 individuals who participated in the subcohort with ≥4 quarterly collections, we found that 65% had circulating anti-Leptospira antibodies. The variables age (p < 0.001 and p = 0.005) and cleaning sewage (p = 0.003 and p = 0.033) were associated with a higher chance of infection in both analyses.The immunity against leptospirosis is based on a short-term humoral response for humans and animals . HoweverThe time of blood collection between samples can affect the number of infection and reinfection of leptospirosis. A recent study applied a titer decay rate on the serological data of the same population in Salvador, Brazil and identified a higher number of mean infection rate on the biannual analysis and even higher when applying the decay to annual analysis . In agreLeptospira serovar or by related serovars for a short period . Written informed consent to participate in this study was provided by the participants or their legal guardian/next of kin.JC: conception, methodology, and writing of the original draft. NN: data curation, data analysis, and review. GS, RV, AM, and JS: investigation and review. FC, AK, and MR: funding acquisition, investigation, methodology, and review. EW: funding acquisition, investigation, methodology, proofreading, supervision, writing-proofreading, and editing in English. All authors contributed to the revision and editing of the manuscript, and approved the submitted version.This research was funded by grants from the National Institutes of Health , Well-come Trust (218987/Z/19/Z), Coordination for the Improvement of Higher Education (CAPES), from Brazil, and National Council for Scientific and Technological Development (CNPq) (307319/2016-4). 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. 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.


Identifying the risk factors leading to hypertension can help explain why some populations are at a greater risk for developing hypertension than others. The present study seeks to identify the association between the risk factors of hypertension in 35- to 65-year-old participants in western Iran.This cross-sectional study was conducted on 9705 adults from baseline data of Ravansar Non-Communicable Disease (RaNCD) cohort study, in the west region of Iran. Each of the latent variables were confirmed by confirmatory factor analysis. Using Structural Equation Modeling (SEM), we assessed the direct and indirect effects of factors associated with blood pressure.Socioeconomic status (SES), physical activity, mean of serum lipids, obesity, diabetes and family history of hypertension had a diverse impact on the blood pressure, directly and (or) indirectly. The standardized total effect of SES, physical activity, mean of serum lipids, and obesity were -0.09 vs. -0.14, -0.04 vs. -0.04, 0.13 vs. 0.13 and 0.24 vs. 0.15 in men and women, respectively. Diabetes had a direct relationship with the blood pressure in women (0.03).With regard to control of high blood pressure, public health interventions must target obesity, lifestyle and other risk related to nutritional status such as hyperlipidemia and hyperglycemia in Iranian population and among those with higher SES. Hypertension is one of the most important risk factors for chronic heart diseases , 2. The Hypertension has a wide range of risk factors including, genetic, behavioral and environmental risks , 9. IdenBy assessing the effect of the latent variables, SEM is the most useful method for the concurrent testing of complex relationships between variables .SEM reduces measurement errors by involving several overt variables for each latent variable. Unlike traditional regression models that treat each covariate in the model as an independent direct effect, SEM allows to test the model with several dependent variables and assess the concurrent direct and indirect effects of several independent variables on the dependent variable.Available research allows us to hypothesize a model that depicts the relationships between independent factors and blood pressure in terms of direct and indirect  effects. The present research which is the first of its kind in Kurdish people, was conducted to use SEM to identify the (direct and indirect) effect of the risk factors associated with of BP in the Ravansar Non-Communicable Disease (RaNCD) cohort study.We used data from baseline phase for Ravansar Non Communicable Disease (RaNCD) cohort study, in the west region of Iran. This study started in 2014. RaNCD is a part of Prospective Epidemiological Research Studies in Iran (PERSIAN), conducted in different Iranian ethnicities, in coordination with the Ministry of Health and Medical Education. In fact, 10,000 adults have been recruited for RaNCD cohort study. Ravansar is one of the cities of Kermanshah province. The city of Kermanshah , is the center of the province and the largest and most important Kurdish settlement in the western region of Iran. The Ravansar district population is about 50,000 people, mainly from Iranian Kurdish ethnicity. All included participants, have provided oral and written informed consent. Eligibility criteria in the cohort study comprised of being in the age range of 35–65 years, permanent inhabitants of the Ravansar region, and having Iranian nationality .The data used in this study pertained to more than 10,000 participants aged 35 to 65 who had voluntarily entered the study. For the purpose of this study, we excluded those with a clinical history of stroke (50 subjects), myocardial infarction (65 subjects), and renal failure (53 subjects).Anthropometric indices including body weight, height, waist to hip ratio and body mass index, waist circumference (WC), were measured according to standard methods. Body weight was measured using Bio-Impedance Analyzer BIA  with a precision of 0.5 kg. Height was measured by BSM370  with the precision of 0.1 cm. BMI was measured by dividing weight (kg) by the square of height (m). The Waist to Hip Ratio (WHR) was calculated by dividing the waist circumference over the hip circumference. WC was measured with a flexible measuring tape at a level midway between the lower rib margin and the iliac crest to the nearest 0.5 cm . The statitioner . Self-retitioner .P-value less than 0.05 was considered as statistically significant.After a comprehensive review of available evidence and consultation with the experts in this field, the conceptual model was developed. Our conceptual model, in fact, represent the hypothesized relationships between different latent and observed variables and their association with our outcome of interest (BP). In SEM, while single-headed arrow represents causal relationship, double-headed arrow represents correlation. Finally, we translate the conceptual model into the statistical model. Accordingly, we first conducted an exploratory factor analysis (EFA) to identify the latent variables underlying the observation variables. The principal component analysis (PCA) and varimax rotation was conducted to estimate the latent variables. The number of the extracted factors was chosen based on the factor eigenvalue  and 47% (2908) of women and men had waist-to-hip ratio >  = 90, respectively. The general characteristics of the study participants are shown in Table Exploratory factor analysis was conducted and the Kaiser-Meyer-Olk statistic was determined to be 0.697, which indicated that the data were suitable for factor analysis. The four latent factors included SES, blood pressure, obesity, lipid profile were extracted with eigenvalue greater than 1. The extraction results of the latent variables are shown in Table 81 Table .Table 2RThe conceptual model of the study included the variables extracted from the results of previous studies and a review of literature plus consultation with experts. The final model was constructed of the different models Fig.  and was Hypertension is a major public health problem globally . AlthougThis study has demonstrated that individual with a higher level of SES had a direct negative, and indirect positive effect  on BP with positive effects on increasing the risk of dyslipidemia and obesity in both sexes. In addition, SES had total negative effect on BP. Increased awareness, accessibility of medical treatment and opportunities to prevent and diagnosis of hypertension have been indicated as protective effect of higher SES on of BP. However, unfavorable living habits, unhealthy diet including the consumption of high-calorie foods , obesity and physical inactivity have been indicated as indirect positive effect of higher SES on raised blood pressure. This finding is consistent whit previous research that found that individual with a higher level of SES had a direct and indirect effect on hypertension with structural equation model , 16. IndObesity was the most important risk factor that directly affected the of BP in our study in both sexes which is consistent with the results of previous studies , 30. OveIn the present study, dyslipidemia was directly associated with of BP in both sexes, and was also associated directly with obesity in both men and women with direct association with diabetes in women, resulting in total positive effect (ß = 0.13 in both sexes). Many clinical studies have shown that the dyslipidemia is a strong marker for predicting the risk of atherosclerosis and heart diseases , 33. In The association between DM and serum lipids has been much debated over the past decades , 37. TypThis study has strengths and weaknesses. The most important strength of the present study was the sample size which was large enough to investigate the association between all the above mentioned variables with hypertension. Our study reveals advantages of SEM application for of BP compared with the traditional analysis methods. In fact, SEM includes causal modeling, analysis of covariance structures, latent variable and robust model. SEM reduces measurement errors by involvement of several overt variables for each latent variable instead of single-measurement particularly with variables that are measured by multiple indicators, e.g. . HoweverOur study showed that although there are other factors associated with of BP, among the modifiable risk factors, obesity and antihypertensive drugs had the strongest direct effect on the outcome. For future works, we suggest investigation of relationship between different factors with incidence of hypertension which is more valuable than prevalence.The present study demonstrated that BP was related to SES, physical activity, mean serum lipids, obesity and diabetes directly and (or) indirectly.In accordance with other reports, the public health interventions to prevent and control hypertension, should focus on obesity, increasing physical activity and improving the life style specifically among those with higher SES.


At present, nano-carrier materials with antibacterial activity are of great significance. Due to the widespread resistance of many pathogenic microorganisms, it has seriously threatened human health. The natural antimicrobial substances extracted from fruits and vegetables can significantly improve their stability combined with nano-carrier materials. The resistance of pathogenic microorganisms will be substantially reduced, greatly enhancing the effect of active antimicrobial substances. Nanotechnology has excellent research prospects in the food industry, antibacterial preservation, food additives, food packaging, and other fields. This paper introduces nano-carrier materials and preparation techniques for loading and encapsulating active antibacterial substances in detail by constructing a nano-release system for active antibacterial substances. The antibacterial effect can be achieved by protecting them from adverse external conditions and destroying the membrane of pathogenic microorganisms. The mechanism of the slow release of the bacteriostatic active substance is also described. The mechanism of carrier loading and release is mainly through non-covalent forces between the bacteriostatic active substance and the carrier material, such as hydrogen bonding, π-π stacking, van der Waals forces, electrostatic interactions, etc., as well as the loading and adsorption of the bacteriostatic active substance by the chemical assembly. Finally, its wide application in food and medicine is introduced. It is hoped to provide a theoretical basis and technical support for the efficient utilization and product development of bacteriostatic active substances. TherefoAntibacterial active substances  extracted from vegetables generally have good antibacterial, fresh-keeping, anti-oxidation, anti-cancer, anti-inflammatory, and other active functions, and are widely used in food and pharmaceutical industries , 10. AmoMeanwhile, with growing interest in nanotechnology, researchers are eager to use nanotechnology to design drug-release delivery systems that limit, protect, and specifically release functional bioactive substances, thereby synergistically improving the antibacterial effect of active substances . In part2.Stability is critical to ensuring bioactive compounds, but most bioactive compounds exhibit poor stability. In this case, bioactive compounds can be loaded by selecting a suitable nanocarrier slow-release system that allows them to be transported to specific receptors to exert their efficacy . In addi2.1.Nano-encapsulated materials for the antibacterial active substances can be divided into three main categories: inorganic nanocarrier materials, organic nanocarrier materials, and hybridized nanomaterials. Inorganic nanomaterials mostly refer to metallic materials, such as carbon nanomaterials, gold and silver nanoparticles, quantum dots, and other materials. Organic nanomaterials refer to various proteins and polysaccharides, such as wheat alcohol-soluble protein, corn alcohol-soluble protein, modified starch, pectin, and other substances. In contrast, a hybrid nanomaterial is a mixture of two nano-or molecular-level components. In nature, it is usually a mixture of an inorganic and an organic substance. So, they differ from the usual sense of a mixture in that the usual mixture is of macroscopic magnitude (microns or millimeters). Mixing at the microscopic level can result in a homogeneous mixture of substances that will exhibit properties intermediate to the two components or even some new properties. Therefore, the choice of each type of nanocarrier is limited by its bioavailability, ease of application, biodistribution, food matrix compatibility, biodegradability, and biocompatibility . Thus, t2.1.1.Inorganic nanomaterials are a class of nanoparticles with various morphologies and particle sizes ranging from 1 to 100 nm that can be synthesized by physical or chemical methods. Inorganic nanomaterials are not only easy for surface modification but also can be bound to drug molecules in different ways. For example, electrostatic interactions, hydrophobic interactions, covalent bonding of enzyme-sensitive groups, etc. This leads to responsive release, making them ideal for drug delivery. Compared with other nanomaterials, inorganic nanomaterials have the advantages of easy preparation, high drug loading rate, controllable shape and size, good biocompatibility, and easy surface modification for drug delivery , 16. The2.1.1.1.The unique biological and physicochemical properties of carbon nanotubes (CNT) make them an ideal nanocarrier material for the biologically antibacterial active substance. It is a tubular hollow structure containing sheets of graphene rolled together at discrete and specific angles. Depending on the number of graphene sheets rolled together, carbon nanotubes are classified as single-walled and multi-walled carbon nanotubes. These tubes can have a cross-sectional diameter of 0.4–100 nm, while the length of the tube extends thousands of times the diameter. In nano-delivery systems, such carbon nanotubes have a high aspect ratio, ultra-light specific surface area, nano-needle-like structure, and a wide range of application prospects . The str2+ were found to be successfully modified on the oxidized multi-walled carbon nanotube (OMWCNT) surface employing characterization. The material was incorporated into an epoxy coating to form a nanocomposite that exhibited superior barrier capabilities and provided stable corrosion inhibition for nearly 9 weeks.Hence Ghahremani was inspired by mussels to design a novel nanocarrier consisting of polydopamine (PDA), chitosan (CH) and zinc cations modified on the surface of multi-walled carbon nanotubes (MWCNT) . PDA, CH2.1.1.2.Au nanoparticle (AuNP) carriers construct an effective delivery medium that can be applied in different fields, and gold nanoparticles have different anisotropic properties such as nanostars, nanorods, nanocages, nanoshells, and nano prisms –23. AmonAu nanoparticles revealed a noteworthy antimicrobial effect against Gram-positive and Gram-negative bacterial strains. Usually, the negatively charged surface of the bacterial cell wall is attracted to the positively charged nanoparticles due to the electrostatic force of the interaction . In contThe advantages of synthesizing gold nanoparticles from active substances extracted from vegetables are not limited to the reduction of environmental toxicity, the production of nanoparticles in large quantities, the simplicity of reducing metal salts, the rapidity, the economic efficiency, the safety of clinical studies, and the nanoparticles are other advantages associated with this synthetic method. Aderonke used active substances extracted from vegetables in combination with gold nanoparticles to prepare a nanoparticle with good antibacterial effect. The percentage inhibition zones of the synthesized gold nanoparticles against the tested fungi and bacteria ranged from 30 to 66% and 40 to 54%, respectively .2.1.1.3.Quantum dots (QD) include atoms in the II-VI  or III-V  elemental groups of the periodic table. They are colloidal nanocrystals and energy donors. The size of the quantum dots changes the luminescence between the UV–NIR region, i.e., smaller quantum dots (2 nm) fluoresce blue and larger ones (5 nm) fluoresce red . This op2.1.2.2.1.2.1.Chitosan is a polycationic polymer derivative of chitin, prepared by alkaline deacetylation of chitin. Besides cellulose, chitosan is the most abundant biopolymer existing in nature, and its structure consists of-d-glucosamine deacetylation unit and n -acetyl- d -glucosamine acetylation unit linked by β- , 4 glyco2.1.2.2.Starch has been widely used in food, textile and pharmaceutical fields under its wide source, low cost and high biocompatibility , 32. How2.1.2.3.Protein is a biological macromolecule with multiple moieties and is characterized by a variety of chemical and physical spatial structures that can interact with a variety of food functional factors. Therefore, proteins are excellent carriers for the delivery of food active ingredients. Therefore, proteins are excellent carriers for the delivery of food active ingredients (such as curcumin), and they are also hot materials for the research of food colloidal delivery systems in recent years. The most widely used protein nano-delivery systems are animal proteins, plant proteins, and protein peptides.2.1.3.A hybridized nanocarrier is a nanocarrier that combines two or more organic nanocarriers and inorganic nanocarriers together or separately. It includes organic–inorganic, inorganic–inorganic, and multi-component. For example, lipid-polymer hybridization, ceramic-polymer hybridization, etc. combine two nanoparticles and the nanocarrier will have the dual properties of both nanoparticles, thus improving its performance many times.2.1.3.1.Metal–organic framework materials (MOFs) are crystalline materials with a three-dimensional mesh structure formed by inorganic substituents  and organic ligands, through coordination bonds. MOFs are an important component of hybrid nanomaterials. The most commonly used MOFs material sofistitute Lavoisier frameworks (MILs series), isoreticular metal–organic frameworks (IRMOFs series), zeolite imidazole frameworks (ZIFs series), etc. As For example, Zeinab combined curcumin with MOF materials to construct cyclodextrin-metal organic backbone nanomaterials (CD-MOFs). The stability of curcumin was improved by three orders of magnitude and exhibited superior active functions . Xiao li2.1.3.2.Hydrogels are three-dimensional solid networks made of physically or chemically cross-linked hydrophilic polymeric structures that can entangle large amounts of water or other biological fluids within their networks . The forNano-hydrogels have an extremely important role in the field of drug slow release, specifically in reducing the concentration fluctuation of drug solution and releasing the loaded drug smoothly. Adila prepared a carvacrol-containing hydrogel (GG-Carv), the combination of which promotes bioavailability and delivery while maximizing the antibacterial properties of carvacrol . Table 12.2.2.2.1.2.2.1.1.Emulsification is the process of uniformly dispersing one liquid in very small droplets in another liquid that is immiscible  with each other. The organic polymer solution is homogenized with the aqueous phase and the solvent is then evaporated, leading to the precipitation of polymer molecules and the formation of nanospheres. This process of emulsification leads to nano emulsions loaded with active substances.The polymer solution containing biological compounds is emulsified in the aqueous phase and then the solvent that previously dissolved the polymer is vaporized to produce nanospheres of precipitated polymer. The advantage of this method is that it is suitable for both hydrophilic and hydrophobic compounds with good solubilization ability, while the disadvantage is that this process requires a large amount of surfactant , 63. It 2.2.1.2.Squeeze gelation is a process in which a biopolymer solution is passed through a nozzle into a gelling environment. On a small scale, the biopolymer solution is loaded into a syringe and passed through a needle into the gel state to form a gel. The technique is also suitable for industrial scale and is a gentle and convenient method for the encapsulation of hydrophilic and hydrophobic compounds .Zeng introduced catechins (CC) and proanthocyanidins (PC) into rice starch gels by extrusion gelation to explore the effects of polyphenol molecules on the structure of starch gel systems in hot extrusion 3D printing . Owing t2.2.1.3.Spray drying is one of the most popular embedding techniques for a variety of health food products. It can be used directly for hydrophilic ingredients or indirectly for oleophilic ingredients. This technique is beneficial for many applications because it converts the liquid feed into a dry powder, which usually has higher storage stability and is also easier to transport and store . In brie2.2.2.2.2.2.1.2). SC-CO2 is a new solvent with broad industrial application prospects  50% lower than that of free curcumin solution.Curcumin is an excellent antibacterial active substance and its antibacterial effect can be improved by combining it with different nanoparticles. Xie  prepared2.2.2.2.via a food-grade protein (sodium caseinate). FNP showed significant advantages in controlling NP size and increasing β-carotene loading and stability. The internal structure of NPs can be tuned by the flow rate. The loose structure is accompanied by a high release of β-carotene, while the compact structure is accompanied by a slight release.Nanoprecipitation (FNP) relies on the spontaneous emulsification of the organic internal phase of the polymer or bioactive compound and organic solvent, accommodating the external phase that then enters the aqueous phase . The nan2.2.2.3.Sequential Deposition is the sequential processing of the donor and acceptor layers, thus allowing, on the one hand, the two active components to be individually regulated and optimized; on the other hand, weakening the interactions between the two components and reducing the complexity of the film formation kinetics, thus providing new opportunities for reducing production requirements. Widely used in the development of multilayer nanocarriers, with low cost, easy adoption, simple assembly techniques and better protection of lipophilic compounds .Multilayer coconut oil–water emulsions containing curcumin were prepared and stabilized using a layer-by-layer technique assembled using multilayer gelatin, gum Arabic and tannic acid. Thus, the ability to control interfacial film properties by combining electrostatic, hydrophobic and hydrogen-bonding interactions may be able to control the physical stability, payload retention and accessibility of multilayer emulsions.3.The nano slow-release system can be used as a carrier to load antibacterial active substances. After reaching the corresponding target environment, there can be different release rates depending on the type or ratio of the carrier material. By adjusting the carrier material’s type or ratio, the bioactive substances’ release rate can be controlled, thus producing a nano slow-release system with targeting and slow-release characteristics.There are two main purposes for carrier loading of the antibacterial active substance: one is to improve the situation of poor water solubility and low bioavailability of functional and active substances, and the other is to achieve a slow-release effect and improve the therapeutic effect of functional and active substances. The slow-release refers to the slow release of the drug at a predetermined rate by maintaining a constant drug concentration level for a specific time and system, reducing fluctuations in the drug concentration in the body to reduce the side effects of the drug. This slow-release system ensures that the antibacterial active substance is maintained in the effective concentration range for extended periods. The loading and release mechanism of the carrier is mainly through non-covalent forces between the antibacterial active substance and the carrier material, such as hydrogen bonding, π-π stacking, van der Waals forces, electrostatic interactions, etc., as well as the loading and adsorption of the antibacterial active substance by the chemical assembly.3.1.Nano slow-release systems can incorporate high concentrations of therapeutic agents through the presence of appropriate functional groups on their surfaces. The drug is covalently coupled to the nanocarrier due to the presence of a large number of functional groups on the surface of the nanocarrier. The release of the drug after binding occurs through enzymatic cleavage or chemical breakage of readily hydrolyzable bonds. The nanocarrier-drug coupling slowly diffuses into the cell membrane, resulting in a specific and controlled release of the drug to the target site. This covalent coupling allows stable nanocarrier systems to be used for targeted drug delivery. For instance, cross-linking and reduction of ab-binding activity can be minimized by reacting with dimethyl maleic anhydride (DMMA) and preventing them from participating in aminolysis coupling reactions. At the end of the conjugation reaction, the protecting group can be removed from the final conjugate by simply lightly acidifying the solution. By using a polymer carrier with only one reactive group at the end of the polymer chain, branching during the conjugation reaction can be avoided .3.2.Encapsulation is a strategy for loading therapeutic drugs into nanocarrier systems. The hollow space within the nanocarrier is capable of adequately encapsulating the drug molecules. Nanocarriers such as polymeric nanocarriers, β-cyclodextrins, nanocapsules, dendrimers, etc. can effectively encapsulate drugs within their hollow cavities , 79. The3.3.Electrostatic interactions are the most direct loading strategy, while the adsorption of active substance molecules depends mainly on the surface potential of the nanocarrier material and the type of active substance structure. In general, the adsorption behavior of common nanocarriers is mainly influenced by the pH value. When the solution pH is low, i.e., the solution is acidic, a large number of hydrated hydrogen ions in the solution will compete with the metal ions on the surface of the material for available adsorption sites, and the positively charged surface of the nanocarrier material at this time does not have the electrostatic gravitational force and cannot load the functional active substance well into the pore structure of the nanocarrier material. On the contrary, when the solution pH is high, electrostatic attraction exists between the active substance and the metal ions in the pores of the carrier material .Nanocarriers with functional groups such as carboxyl and amine groups increase the solubility of hydrophobic drugs, and these high-density functional groups enable electrostatic interactions between antibacterial active substance and nanocarrier materials, which in turn encapsulate them in the nanomaterials to form a nano-delivery system. Certain NSAIDs, such as indomethacin, ciprofloxacin, diflunisal, and ibuprofen, are effectively integrated within the nanocarriers through electrostatic interactions, which greatly improves the therapeutic efficacy of these drugs .Furthermore, nanocarriers with functional groups such as carboxyl and amine groups can increase the solubility of bioactive substances in solvents. These high-density functional groups can be efficiently integrated within the nanocarriers through electrostatic interactions. For example, polymeric nanoparticles with a bilayer load representative flavonoids into deblock polymeric nanoparticle carriers (NPC) DDS with a cationic corona and hydrophobic core. It can improve the problems of poor water solubility and low bioavailability of flavonoids for clinical applications  83)..83).3.4.Hydrogen bonding is a special type of inter- or intra-molecular interaction force. A hydrogen atom is bonded covalently to an atom X, which has a large electronegativity. If it is close to an atom Y with a large electronegativity and small radius , a special intermolecular or intramolecular interaction in the form of X-H.Y is generated between X and Y using hydrogen as a medium, called hydrogen bonding. Hydrogen bonding can combine antibacterial active substance with poor water solubility with macromolecular nanocarriers. β-carotene (Car) has a wide range of physiological effects, but its insolubility in water leads to low bioavailability. Therefore, hydroxyl and carboxyl groups on the surface of carotene can be used to combine with organic functional groups on the surface of oleanolic acid (OA) to form hydrogen bonds . As show4.Various bioactive compounds are usually poorly stable, water-soluble, and have toxic effects that make it difficult to perform their potential active functions. These drawbacks can be addressed by nano-release systems  to improve stability and water solubility and mitigate toxicity. Loading and transporting antibacterial active substances through nano-delivery systems can be applied to antibacterial preservation, food packaging, the food industry, etc., greatly expanding the range of applications of the antibacterial active substance  86)..86).4.1.A natural antibacterial active substances such as curcumin, quercetin, and sulforaphane have superior antibacterial properties and can be applied to food preservation for both antiseptic purposes and without any toxic side effects to the human body. However, the most urgent problem in the field of food preservation is that these antibacterial active substances react with food components, resulting in a decrease in the efficiency of their application in food matrices. Therefore, an antibacterial active substance with antibacterial properties can be encapsulated into nanomaterials to achieve sustained release, prevent undesirable interactions and provide high stability and effective antibacterial activity during food storage , 88.Wang Y et al.  studied 4.1.1.Fruits and vegetables in the post-harvest storage and transportation process due to temperature, humidity and other external conditions susceptible to oxidation, browning, weight loss and other physiological and biochemical changes, seriously affecting the quality of fruits and vegetables and shelf life . In partTherefore, it is possible to combine active substances with nanomaterials to make nanofilms, nano coatings, nano packaging materials and other products. It provides effective help for the further preservation of fruits and vegetables. It can greatly extend the shelf life, and preservation period. Deka et al.  prepared4.1.2.In vitro lipid, digestibility tests revealed that high surfactant concentration promoted the dissolution of curcumin in the oil phase and increased the slow-release effect. This resulted in increased antioxidant activity, delayed lipid degradation and improved milk quality.Antioxidant compounds such as flavonoids are the most important plant active compounds and they have significant health-promoting effects. Direct addition of flavonoids to food, especially to foods such as beverages and dairy products, can lead to undesirable taste and color, while encapsulation with nanomaterials can reduce the loss of bioactive compounds, enhance their dispersion in aqueous solutions, and improve their oral bioavailability. Concerned scholars have added curcumin to milk to reduce the oxidative effect of lipids in milk. Hee prepared a curcumin nanoemulsion (Cur-Nes) that could be added to milk to reduce lipid oxidation, and its free radical scavenging activity did not vary significantly with water content but increased significantly with surfactant concentration . In vitrColloidal formulations containing curcumin are generally available in micelles and hydrogels, and the use of colloidal formulations containing curcumin can be equally effective in increasing its solubility, and stability. The use of colloidal formulations containing curcumin is also effective in increasing its solubility, stability, and slow-release properties, as well as its functionality and antioxidant and antimicrobial activities in food products . Esmaili4.2.Some wound dressings currently in use have interesting characteristics such as excellent porosity, good water absorption, moderate water vapor transmission, high drug loading efficiency, and good ability to provide a moist environment, but they are limited in terms of antimicrobial properties . They do5.With the improvement of people’s living standards and more and more attention to food health and safety, the demand for food is also increasing to “green” and “natural” change. On the other hand, with the abuse of chemical pesticides, pathogenic microorganisms develop resistance to drugs, endangering the environment and human health. Therefore, it has become a new direction of food safety research to find new natural antibacterial active substances with application value. This paper reviews the construction of a nano-sustained-release system for active antibacterial substances, from the selection of nanomaterials to the innovation of preparation technology. Different nano-carrier materials are selected for loading and encapsulation according to different application ways of active antibacterial substances. Food-grade antibacterial preservation packaging mainly uses green nanocarrier materials such as polysaccharides, porous starch, and protein, which can significantly improve the stability of active antibacterial substances and import safety to ensure food safety. However, fruit and vegetable pathogenic microorganisms can use inorganic and mixed nanocarrier materials. Compared with simple antibacterial substances based on the specificity and specificity of pathogenic microorganisms, there is almost no resistance to nanocarrier materials. Moreover, the nanocarrier materials of the bacteriostatic active substances can gradually destroy the bacterial membrane of bacteria and achieve an excellent bacterial inhibition effect.Although the research on using nanotechnology to deliver active antibacterial substances has been very extensive, there are still some problems in its practical application based on the instability of active antibacterial substances and the safety of nanocarrier materials. First, the current assessment methods for antibacterial preservation are limited, mainly E. coli and S. aureus, and some indicators of antioxidant tests. Less information is related to fungi, viruses, and other dangerous bacteria. Secondly, the targeted modification of active antibacterial substances based on delivery systems is still challenging to achieve scale-up production and commercial application in practice, mainly because the materials’ low loading, high cost, and potential toxicity restrict the scale-up production. At the same time, the existing preparation process and encapsulation technology methods have particular contingency and irreducibility and lack uniform quality control standards and clinical trial systems.Therefore, more research is needed to gain a deeper understanding of the interactions between these nanomaterials and active antibacterial substances and to continuously explore and optimize the preparation process of nanomaterials to accelerate the development of more economical, stable, high-utilization, slow-release nanomaterials. It is necessary to strengthen the research on the mechanism of assembly and release of bioactive substances in nanocarriers to clarify the chemical interaction between the substances and carriers. To enhance the research on the assembly and release mechanism of bioactive substances in nanocarriers, clarify the chemical interaction between the substances and the carrier, establish an ideal drug delivery method, and provide a theoretical basis for the prediction and development of the subsequent formulation of drug delivery carriers. This review will inspire researchers to develop and synthesize nano-delivery platforms and technological approaches with various properties and functions to broaden their application range in agriculture, food, and medicine.JC and MG: conceptualization and writing – original draft. JW: resources. YL and JL: methodology and formal analysis. XZ and YP: visualization. GC and XH: project administration. DX: funding acquisition. GL: writing – review and editing. All authors contributed to the article and approved the submitted version.This work was supported by National Key Research and Development Program of China (2022YFF0606800), China Agriculture Research System of MOF and MARA (CARS-23-E03), and the Risk Assessment on Vegetable Products(GJFP20210201).JL was employed by the company Internal Trade Food Science Research Institute Co., Ltd.The remaining 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.


Stroke is an acute disorder and dysfunction of the focal neurological system that has long been recognized as one of the leading causes of death and severe disability in most regions globally. This study aimed to supplement and exploit multiple comorbidities, laboratory tests and demographic factors to more accurately predict death related to stroke, and furthermore, to make inferences about the heterogeneity of treatment in stroke patients to guide better treatment planning.We extracted data from the Medical Information Mart from the Intensive Care (MIMIC)-IV database. We compared the distribution of the demographic factors between the control and death groups. Subsequently, we also developed machine learning (ML) models to predict mortality among stroke patients. Furthermore, we used meta-learner to recognize the heterogeneity effects of warfarin and human albumin. We comprehensively evaluated and interpreted these models using Shapley Additive Explanation (SHAP) analysis.We included 7,483 patients with MIMIC-IV in this study. Of these, 1,414 (18.9%) patients died during hospitalization or 30 days after discharge. We found that the distributions of age, marital status, insurance type, and BMI differed between the two groups. Our machine learning model achieved the highest level of accuracy to date in predicting mortality in stroke patients. We also observed that patients who were consistent with the model determination had significantly better survival outcomes than the inconsistent population and were better than the overall treatment group.We used several highly interpretive machine learning models to predict stroke prognosis with the highest accuracy to date and to identify heterogeneous treatment effects of warfarin and human albumin in stroke patients. Our interpretation of the model yielded a number of findings that are consistent with clinical knowledge and warrant further study and verification. Stroke is an acute disorder characterized by dysfunction of the focal neurological system, underlying cerebral vascular spontaneous hemorrhage, and inadequate blood supply . With itClinically, there are many factors that can affect the prognosis of stroke, which in general can be mainly divided into basic information for patients, complications, subtypes of stroke, and the treatments –9. Many Several previous studies used machine learning to solve problems related to stroke and other diseases. Cheon et al. used a fully connected neural network (FCNN) to identify factors affecting stroke mortality and had an AUC of 0.8. However, their principal component analysis (PCA) was not clinically interpretable . Heo et Given the particular complexity and variety of contributing factors to stroke outcomes, which are difficult to predict globally using traditional research methods, such study limitations reduced predictive accuracy and limited to a comprehensive consideration of multiple factors. The aim of our study is to supplement and exploit multiple comorbidities, laboratory tests and demographic factors to more accurately predict death related to stroke, and furthermore, to make inferences about the heterogeneity of treatment in stroke patients to guide better treatment planning.We conducted a retrospective study of the risk factors for death in stroke patients and trained several machine learning (ML) models to predict their mortality during hospitalization and within 30 days after discharge. Patients with stroke were enrolled from the Medical Information Mart from Intensive Care (MIMIC)-IV version 2.0 , based oPatients diagnosed with stroke were included according to the ICD-10. We extracted a total of 8,276 patients with stroke, excluding 36 patients admitted to the hospital many times and 757 patients whose records did not contain adequate and relevant information within one month from the outcome (more than 30%). Finally, we extracted and sorted all the information of the remaining 7,483 patients, and a flowchart of patient selection and data collection is shown in The dependent variable was the mortality rate of stroke patients. Participants who died during hospitalization and within 30 days after discharge were considered deaths. The independent variables reflecting sociodemographic status included age, gender, marital status, race, insurance type, height, weight, and body weight index (BMI). Medical variables included the course of the disease, laboratory tests, and complications. Drug-related information included the usage of warfarin and human albumin, which was the most frequently used medicine for stroke patients in this database. We also included the detailed subtypes of stroke and whether the stroke was recurrent as independent variables. We excluded complications without a clear diagnosis to make our study reproducible and explainable. We obtained 145 variables for the ML model.We used six ML algorithms, which were Neural Oblivious Decision Ensemble (NODE) ; CatBoosvia backpropagation. The final prediction of NODE was obtained by averaging the outputs of all ODTs from all layers. We used Quasi-Hyperbolic Adam as an optimization strategy, which was recommended in the original paper  model specialized for tabular data, uses oblivious decision trees (ODTs)  as weakeal paper . An FCNNAll patients were randomly allocated to a testing set of 25% samples unseen in the model development and used to evaluate the final model performance. A training set of 75% of the samples was used for building the model. During the training period, we used 3-folds-cross-validation to tune the model hyperparameters; for each time, the model trained on two-thirds of the training set and validated on the remaining one-third of the training set. For DL models, the loss of each step was recorded. The training was terminated automatically if it did not decrease in 1,000 iterations. For GBDTs, we used a random search algorithm to obtain the best models. A flowchart of the model development is shown in We further estimated the therapeutic effects of human albumin and warfarin in individual patients using Meta-learner . It was ITE was defined as the outcome estimation of a patient receiving human albumin or warfarin minus the outcome estimation for the same patient not receiving human albumin or warfarin. We then divided patients into consistent (Consis.) and inconsistent (In-consis.) groups in the testing set based on the actual treatment they received and the ITE values. This process was illustrated in t-test and Mann–Whitney U-test, as appropriate. The chi-square test and Fisher's exact test were used to compare categorical variables, as appropriate.PostgreSQL was used to extract and store the data from MIMIC-IV. All statistical analyses were performed using R, continuous variables were reported as the median and interquartile range (IQR), and categorical variables were presented as numbers and percentages (%). To compare continuous variables between the two groups, we used the Welch A total of 7,483 participants were included in this study, with 6,069 and 1,414 participants in the control and death groups, respectively. The median age was 69.0 years (59.0–79.0 years), and 50.3% of the patients were male. The total mortality rate was 18.9% (95% CI 18.0–19.8%).p < 0.001). Most of the participants in the control group were married , whose proportion was higher than that of the death group . The proportion of single and divorced showed the same traction. However, the proportion of widowed individuals showed an opposite trend. The proportion of widowed individuals was 20.9% (95% CI 18.8–23.1%) in the death group and 14.5% (95% CI 13.6–15.4%) in the control group. The body mass index (BMI) of the death group was lower than that of the control group . No statistically significant differences were found in sex or race.A comparison of demographic status is shown in We calculated accuracy (ACC.), the area under the receiver operating characteristic curve (AUC), which is the ability to weigh true positives and false positives, precision score (Prec.), and F-measure (F1), which is a comprehensive indicator reflecting the true positive rate and sensitivity rate. The validation AUC curve during the training period is shown in We presented the fatality rates (FR) of the treatment group, control group, Consis. group and In-consis. group of warfarin and human albumin in In the testing set , 1,706 (91.2%) patients have been taken warfarin while the treatment was deemed appropriate for 987 (57.3% of treated with warfarin) patients, and 96 (58.2% of non-treated with warfarin) patients were considered should be on warfarin. 294 (15.7%) patients were in human albumin treatment group; 821  patients were considered by the model that should be treated.p < 0.0001; in human albumin, 13.3% vs. 22.4%, p < 0.0001). Significant differences remained after correction for confounders . The odds ratio (OR), AIPW adjusted OR (adj-OR), CDE, and NDE of Consis. remained significant and lower than treatment, except for CDE of human albumin ; human albumin: −0.06). The adj-OR of Consis. in warfarin was 0.54 (0.47–0.62) and that of human albumin was 0.66 (0.57–0.76), indicating a strong protective factor. The CDE and NDE also showed that Consis. had a direct effect on outcome (unaffected by treatment ratio and other confounders).We observed a lower fatality rate (FR) in the Consis. than in the In-consis.  analysis to reveal the distribution of the effect of each input acting on CatBoost. 2), the higher the SHAP value, which means that the patient is more likely to die. The protective factors were red blood cell count (RBC), followed by weight, course of disease, and blood bicarbonate (HCO3−). The most important risk factor was other disorders of the nervous system (ODNS), followed by white blood cell count (WBC), age, glucose (GLC), and malignant neoplasms of ill-defined, secondary and unspecified sites (MNISUS). We also presented the SHAP plot of Meta-learner of warfarin , however, this association may depend on age . Previous studies have suggested that FCNN or Deep Neural Network (DNN) is the best model for predicting post-stroke mortality and outperforms other traditional ML models . HoweverWe further used meta-learner to identify heterogeneous treatment effects in the stroke population. We observed that 55.6% of the warfarin current use (or not use) and 52.1% of the status quo human albumin treatment (or control) in the testing set were considered inappropriate by model. Even after controlling for treatment factors, demographic factors and subtypes, survival outcomes were still significantly better in those who were consistent with the model judgments than in those who were inconsistent. Extrapolation of treatment effects for the population level does not necessarily hold in individual patients  and treaML is a good predictive tool and usually has high accuracy. However, it has always been regarded as a “black box,” indicating poor interpretability. In our study, we conducted SHAP analysis to interpret one of our best models and obtain several risk and protective factors to help better understand the role of various factors in post-stroke mortality. Most of the results were consistent with clinical knowledge –49. In aIn summary, we used several highly interpretive machine learning models to predict stroke prognosis with the highest accuracy to date and to identify heterogeneous treatment effects of warfarin and human albumin in stroke patients. Our interpretation of the model yielded a number of findings that are consistent with clinical knowledge and warrant further study and verification.Our study has some limitations. The data we used included only inpatients from one hospital. These inpatients are already affected by stroke and usually have more serious conditions than the average population of stroke patients , 51. ThiThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were approved by the Massachusetts Institute of Technology  and Beth Israel Deaconess Medical Center . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.EZ: experimental design, data analysis, model development, and manuscript writing. ZC: data acquisition, data analysis, and manuscript writing. PA: experimental design, data analysis, and manuscript writing. JW: experimental design and manuscript writing. MZ and ZX: data analysis and model development. JL: data analysis and manuscript revise. ZA: experimental design and manuscript revise. All authors contributed to the article and approved the submitted version.