Recently, the global trend toward the use of natural extracts and antioxidant agents in the cosmetic cream industry to produce whitening effects has been increasing. This has also been a persistent trend in Thailand. In this study, samples of commercial cosmetic creams on the Thai market were assessed for a functional evaluation of their antioxidant activity, tyrosinase inhibitory effects, and phenolic contents. Samples were extracted using hot water and sonication extraction method to obtain the functional cream extracts. Total phenolic contents in all samples were within the range of 0.46–47.92 mg GAE/30 g cream. Antioxidant activities of the cream extracts were within the range of 3.61–43.98 mg Trolox equivalent/30 g cream, while tyrosinase inhibition activities were within the range of 2.58–97.94% of inhibition. With regard to the relationship between the total phenolic content and the antioxidant activity of the cosmetic creams, Pearson’s correlation coefficient revealed a moderately positive relationship with an r value of 0.6108. Furthermore, the relationship between the antioxidant activity and the tyrosinase inhibitory activity of the cosmetic creams was highly positive with an r value of 0.7238. Overall, this study demonstrated that the total phenolic contents in the functional cosmetic creams could play a role in antioxidant activity and anti-tyrosinase activities. The findings indicate how the whitening and antioxidant effects of cosmetic creams could be maintained after the products have been formulated, as this concern can affect the consumer’s decision when purchasing cosmetic products. During the first decade of the 21st century, cosmetic product sales underwent fairly significant growth and represented 23% of the overall market share of consumer products. This growth was driven primarily by the Asian market . ConsequSpirulina platensis inhibited ultraviolet B (UVB) irradiation-induced intracellular-ROS in human fibroblasts [Epilobium angustifolium polyphenol extract resulted in a downregulation of the UV-induced release of MMP-1 and MMP-3, along with hyaluronidase gene expressions [Likewise, consumer demand continues to increase for the innovative uses of natural compounds to treat skin aging manifestations including wrinkles, sagging skin, skin texture changes, and hyperpigmentation ,8,9,10. roblasts . The treressions .Phenolic compounds are plant secondary metabolites that constitute one of the most common and widespread groups of substances in plants ,20,21. TCosmetic creams that are high in phenolic compounds have been used to fight against environmental free radicals that are known to lead to certain skin damaging conditions . These cGlycyrrhiza glabra, Centella asiatica, Acacia confusa, Cassia fistula, Vitis vinifera) that aim to reduce skin pigmentation [Morus alba has shown potent tyrosinase inhibition activity [Cassia fistula and Camellia sinensis extracts exhibited the anti-tyrosinase activity, antioxidant activity, and anti-aging properties, and can be use as cosmetic ingredients [Unlike Australia, there are cultural differences throughout Asian countries that dictate how the people choose to apply skin cosmetic products ,54. In centation ,56,57,58entation ,60,61,62entation ,16,63. Nentation ,57. The activity ,65. Moreredients . With reredients ,68. Vitaredients ,68,69. TIn order to trace and determine the stability of phenolic compounds and other essential ingredients  in cosmetic creams after the products have been formulated, many analytical methods, including solid-liquid extraction using ultrasound , hot watVitis vinifera, Centella asiatica, Panex ginsen, Oryza sativa, Passiflora laurifolia, Aloe barbadensis, Citrus aurantium dulcis, Lepidium sativum, Hamamelis virginiana, and Enantia chlorantha. Based on the labels of all 23 cream products, 91% of the total studied creams had indicated that they contain various natural extracts in their formulations as is shown in The presence of different ingredients in the product formulation, including plant extracts, antioxidants, and anti-tyrosinase agents were based on the cream products’ label appearing on the 23 functional cosmetic creams shown in In order to prepare the cream extract, a total of 1 g of each commercial cream sample was extracted for the phenolic content determination using hot water extraction and sonication procedure. Prior to the cream extraction experiment, we did validate our method by adding an exact amount of a standard phenolic compound   incorporx-axis) and antioxidant capacity (y-axis) as demonstrated in p = 0.0020), which indicated a moderate level of positive association between the phenolic contents in the cream extract and the antioxidant capacity. This finding confirmed that the quantity of the phenolic compounds found in the cosmetic products could be indicative of the antioxidant activity in the functional cosmetic creams.In order to determine the antioxidant capacity of the cream extract, a 0.1 mL portion of the cream extract from each of the 23 cream products was used to measure the antioxidant activity by ABTS assay. The ingredients contained in each of the 23 cream samples and their respective antioxidant activity  is shown in Glycyrrhiza glabra [Morus alba [Aloe barbadensis [Oryza sativa [Lepidium sativum [p = 0.0219) (data not shown). However, when the group of cosmetic cream samples with detectable tyrosinase inhibition activity were assessed for the relationship between antioxidant capacity and tyrosinase inhibition activity, a high positive relationship between these two factors was observed with an r value of 0.7238 (p = 0.0070). The results provide useful information with regard to the strong relationship between tyrosinase inhibitory activity and antioxidant activity. To date, no detailed reports on the tyrosinase inhibitory activity of functional cosmetic products are available.In addition to the antioxidant capacity of the cream extracts, the anti-pigmenting or whitening effects of these products could be traced by determining the inhibitory effect of tyrosinase activity. The cream extract from each of the 23 cream samples were determined for anti-tyrosinase activity using mushroom tyrosinase spectrophotometry assay. Many of the studied creams contained well-known whitening agents including kojic acid, arbutin, niacinamide, glutathione, citric acid , and soma glabra , Morus arus alba , Aloe babadensis , Oryza sa sativa , and Lep sativum . The ing sativum . It was In many Asian countries including Thailand, over 80% of the face creams on the market claim to deliver whitening properties ,6,86. InThe cosmetic industry has undertaken several measures to date to increase the stability of the active ingredients used in cosmetic products. These measures employ conjugates to change the molecular characteristics of the natural compounds, as well as to add certain synthetic antioxidants  and anti-hyperpigmentation agents, including anti-tyrosinase inhibitors (kojic acid and arbutin), and whitening synthetic compounds  ,23,68,88Vitis vinifera (sample No. 1) [Citrus species (sample No. 2 and No. 23) [Glycyrrhiza glabra (sample No. 18) [Aloe barbadensis  [Schizandra chinenisi and Scutellaria baicalensis (sample No. 20) [Morus alba (sample No. 15) [Morus nigra (sample No. 5) [Oryzasativa  [Hamamelis virginiana  [Solanum lycopersicum  [Centella asiatica  [The list of essential ingredients of all 23 functional cosmetic creams in e No. 1) , Citrus  No. 23) , Glycyrr No. 18) , Aloe ba No. 14) , and Sch No. 20) ,98. Neve No. 15) , Morus ne No. 5) , and Ory No. 19) . Interese No. 7) , Solanume No. 7) , and Cene No. 5) . The reaSargassum extracts. A positive correlation between the phenolic contents and their antioxidant activity was significantly observed [In addition to the aforementioned plant extracts, some of these products contained synthetic antioxidant compounds in their formulations. Vitamin E was commonly identified in many of these products for displaying antioxidant effects . Other pobserved .In addition to the antioxidant effects, another biological benefit of the studied creams was a declaration of a skin whitening effect. As a variety of anti-tyrosinase and anti-hyperpigmentation agents have been listed on the labels of the 23 cream samples, their mechanisms for skin whitening and anti-hyperpigmentation are diverse. Arbutin and kojic acid can directly inhibit the tyrosinase activity via the act of a competitive enzyme inhibitor ,88, whilAloe barbadensis  [Lepidium sativum (high in sample No. 12 but not detectable in sample No. 13) [Morus alba  [Oryza sativa  [According to the product marketing materials, many natural extracts and anti-tyrosinase agents have been added to the cream formulations and these were previously reported for their tyrosinase inhibition activity and showed the potent anti-tyrosinase activity in our study; these extracts were included, kojic acid (sample No. 14) , jelly f and 10) , Lepidiu No. 13) , Morus ae No. 4) , and Ory and 19) . The rea and 19) ,107,108.In this study, among the 23 cream products, it was difficult to establish the relationship between phytochemicals and the tyrosinase inhibitory activity as the r value exhibited a weak relationship. Similarly, previous study of a hundred extracts obtained from plants collected in India, Africa, and the Mediterranean area also exhibited a weak correlation between total phenolic content and anti-tyrosinase activity (r = 0.3535) . NeverthOverall, this study revealed important information regarding the total phenolic contents that could be indicative of the skin whitening and antioxidant effects of the studied products. The findings of this study could also shed light on how these products can maintain their stability by detecting the phenolic contents after a product has been formulated as well as their bioactivities. In order to gain the consumer’s trust with regard to the effectiveness of the antioxidant and tyrosinase activity of cosmetic products, further determinations on the exact amounts of the active ingredients would confirm whether those ingredients were actually included in the cream formulations as has been claimed on the products’ labels.This study would be beneficial to cosmetic manufacturing companies that are tracing the cosmetic product’s effectiveness and to ensure the stability of the phenolic compounds and the biological activities in the cosmetic products. As nowadays, many cosmetic cream brands have made claims with regard to the whitening and antioxidant effects of their products, the critical information obtained from this study would be beneficial to consumers when deciding whether to purchase a cosmetic product available in the Thai marketplace. On the other hand, this report could encourage manufacturers to improve the quality control standards of their skincare products, either before or after the product formulation process, as well as the claims they make with regard to the bioactivities described in the products’ marketing information of the given product.Mushroom tyrosinase, L-tyrosine to 3,4-dihydroxyphenaline (L-DOPA), a substrate for tyrosinase, and kojic acid (a positive control) were used for determining the anti-tyrosinase activity. The 2,2′-azino-bis (ethylbenzthiazoline-6-sulfonic acid (ABTS), a radical agent and Trolox reagent (a positive control) were used for determining the antioxidant capacity in ABTS assay. Folin and Ciocalteu′s phenol reagent and gallic acid (a standard phenolic compound) were used for determining the total phenolic contents in Folin–Ciocalteu as-say. All reagents above were purchased from Sigma-Aldrich .Cosmetic creams were purchased from supermarkets or department stores located in the northern part of Thailand, all of which claimed to provide whitening effects. This study involved 23 functional cosmetic cream samples that were manufactured in different countries including Thailand, Korea, and Japan. The selected cream samples were based on well-known brands in the Thai cosmetic market and were approved by Thai Food and Drug Administration (Thai’s FDA). All 23 cosmetic cream products had been formulated with various plant natural extracts, synthetic antioxidant agents, and whitening agents as declared on the product’s label of individual cream samples. The full detail of the ingredients on a product’s label was shown in g for 20 min. The suspension was kept and was further assessed for the determination of total phenolic contents, ABTS assay, and tyrosinase inhibitory activity.The extraction procedure of the cream samples was modified from previously described protocol . BrieflyTotal phenolic content in the cream extracts was determined by using the modified Folin–Ciocalteu assay, as has been previously described . Briefly2S2O8) . The mixture was incubated in the dark for 12–16 h until the reaction was completed. The assay was conducted on 990 μL of ABTS solution and 10 μL of each dilution of the cream extract. After 6 min, the absorbance was immediately recorded at 734 nm using a spectrophotometer and then compared to the standard curve which had been prepared with various concentrations of Trolox solution. The antioxidant capacity was shown as milligrams of Trolox equivalents per 30 g cream (mg Trolox/30 g cream).The antioxidant activity of the cream extracts was confirmed using the ABTS assay as has been previously described . ABTS rainhibition of Tyrosinase was then calculated by using the following formula:Tyrosinase inhibition assay was determined following a method previously described . BrieflyA = Slope of vehicle control (deionized water) at 490 nm.B = Slope of sample at 490 nm.p < 0.05, ** p < 0.01 and *** p < 0.001 vs. the control of each experiment.All data are presented as mean ± standard error (S.E.) values. The Pearson’s coefficient correlation test was conducted via Prism version 8.0 software, and the significance was determined at *


Logistic regression analyses investigated whether MI was associated with specific HMDEs, risk factors , protective factors , and psychiatric symptomatology . Linear regression analyses explored how Self/Others MI, psychiatric symptomatology, and the risk/protective factors related to burnout. We found consistently high rates of MI and burnout, and that both Self and Others MI were associated with specific HMDEs, COVID-19 work impact, COVID-19 protection concern, and leadership support. Others MI was also related to prior adversity, nurse role, COVID-19 health worry, and COVID-19 diagnosis. Predictors of burnout included Self MI, depression symptoms, COVID-19 work impact, and leadership support. Hospital administrators/supervisors should recognize the importance of supporting the HCPs they supervise, particularly those at greatest risk of MI and burnout.Because healthcare providers may be experiencing moral injury (MI), we inquired about their healthcare morally distressing experiences (HMDEs), MI perpetrated by self (Self MI) or others (Others MI), and burnout during the COVID-19 pandemic. Participants were 265 healthcare providers in North Central Florida (81.9% female, M Even prior to the events of the global health emergency caused by COVID-19, workplace burnout, which is recognized in the ICD-11 as a diagnosable condition . Since tProviders have experienced increased professional demands, often with limited equipment  and miniN = 1153) found that more than 1 in 3 reported high levels of emotional exhaustion and 1 in 4 reported high levels of depersonalization . Potential participants were healthcare workers in two academic medical centers affiliated with a state university system in North Central Florida. One of the centers is a safety net hospital in a large city that receives some funding from the city to care for the indigent population, and the other center is a large tertiary care hospital in a mid-size city. During the data collection, there was a dramatic increase in rates of hospitalization at both sites, with the COVID-19 caseloads exceeding capacity in the large city.Potential participants were invited to join this longitudinal study via flyers distributed in hospitals, nursing homes, and outpatient clinics in two cities in North Central Florida. Within the two academic hospitals in the region, healthcare workers were also emailed a brochure explaining the study from the department head or administrator. Participants were eligible for the study if they worked in a healthcare setting, regardless of their type of employment. Participants that consented to participate and completed measures via REDcap were compensated in an escalating manner for number of sessions completed. The total possible compensation was USD 70 for completion of all possible assessments over a four-month period and USD 220 for completion of all possible assessments over the total eight-month period. The analyses described in this study focus on those participants who identified as HCPs. Thus, hospital workers such as patient sitters, administrative support staff, and food service workers, while eligible for participation in the larger study, were not included in these analyses. Data for each participant were collected via Redcap at four time points from October 2020 to March 2021. The analytic team was blinded to the identity of the participants.Healthcare morally distressing experiences. Participants responded to four questions created for this study that related to their perceived inability to provide optimal care in the context of the COVID-19 pandemic. Specifically, they were asked whether they were able to provide care to patients at appropriate frequency, conduct necessary assessments or procedures, refer patients to specialists, and refer patients for necessary procedures. Two other questions completed by providers doing telemedicine asked about level of comfort with telemedicine and perception of the quality of care being provided with telemedicine. For these items, the providers who disagreed  were considered to have experienced the healthcare morally distressing experiences (HMDEs).Moral injury. The Moral Injury Events Scale [strongly disagree to 5 = strongly agree) about the occurrence/anguish of moral injury perpetrated by themselves and others, and not the perception of betrayal, which was excluded to limit the load on the participants. We focused on the internally consistent total score for Self MI  and Others MI  when predicting burnout. For analyses focused on determining the factors related to moral injury we grouped the participants according to whether or not they agreed that they experienced Self and Others MI.ts Scale  assessedRisk factors. The risk factors considered included prior history of adversity and COVID-19 work factors. Prior adversity history was assessed via the Adverse and Traumatic Experiences Scale [event did not occur, 1 = occurred and no impact on my life, 2 = minimal impact on my life, 3 = some impact on my life, and 4 = big impact on my life). We focused on how impacted they were by their mental health adversity (α = 0.83) and medical health adversity .es Scale  which inα = 0.80) and COVID-19 work impact, which relates to how much COVID-19 had impacted their work life  via a 5-point Likert scale (0 = event did not occur to 4 = big impact on my life). Participants also answered two questions regarding their access to personal protective equipment and supplies via a 4-point Likert scale (0 = strongly disagree and 3 = strongly agree) which formed the internally consistent (α = 0.80) COVID-19 protection concern. Participants also indicated whether they had been diagnosed with COVID-19.Regarding the COVID-19 work factors, the participants indicated the level of their COVID-19 health worry  4-item measure answered via a 5-point Likert Scale . Leadership support was assessed via the Leadership Behavior Description Questionnaire [α = 0.75) 14-item measure that asks participants about their perception of hospital administration at making/communicating decisions and incorporating employee feedback via a 5-point Likert scale .ng Scale  which isionnaire  which isCurrent psychiatric symptomatology. Depression symptomatology was assessed via the Patient Health Questionnaire-9 (α = 0.88) [α = 0.92) that uses a clinical cutoff of 19 or above [ = 0.88)  and anxi = 0.88) . PTSD syor above .Workplace burnout. This was assessed via the Professional Fulfillment Index (PFI) a 16-item measure that we used to measure HCPs’ attitudes about their work [α = 0.92) is made up of a work exhaustion subscale (α = 0.90) that assesses sense of dread, physical/emotional exhaustion, and lack of enthusiasm, and the interpersonal disengagement subscale (α = 0.90) that assesses empathy and connection with others, particularly patients and colleagues. Each item is scored on a 5-point Likert scale . We focused on the mean scores and used recommended clinical cutoff of 1.33 to determine providers scoring above the clinical cutoff for burnout [eir work . The bur burnout .p < 0.05 as the inclusion cutoff) determined which factors differentiated between providers scoring below and above the clinical cutoff for burnout.Data were analyzed using IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp). In addition to the descriptive statistics, individual logistic regression analyses assessed whether participants reporting specific morally distressing experiences and risk/protective factors were more likely to report Self and Others MI. Additional logistic regression analyses explored the contributions of both Self and Others MI to increasing the odds of scoring above the clinical cutoff for each of psychiatric symptomatology  and burnout. Multilinear regression analyses explored the contributions of Self and Others MI total scores, psychiatric symptomatology scores, and risk and protective factors in predicting the two components of burnout, level of exhaustion and disengagement. Forward conditional logistic regression analyses  [p < 0.01) from model C and time (Model D). Model fit was determined by evaluating significant reduction in the −2 log likelihood (−2LL) coefficients as well as reductions in the Bayesian information criterion (BIC). Pseudo R2 (eta square) was calculated for within-subject and between-subject variance explained by calculating the difference between the residual variance present in the null model and the current model and then dividing by the residual variance in the null model.Multilevel modeling analyses determined whether the relationship between the independent variable of MI and the dependent variable of burnout changed over time (ctively) . MLM, whctively)  allowed M = 37.62, SD = 11.08). As reported in The participants were 265 HCPs that varied in age from 20 to 72 years of age , conduct necessary assessments/procedures (10.9%), refer patients to specialists (11.7%), and refer patients for necessary procedures/tests (13.5%).X2 = 188.10, p < 0.001 and Others MI X2 = 151.69, p < 0.001. Although not presented here, we also found that the results were similar when we focused on their responses to these components of Self and Others MI. Thus, we focused on the report of Self and Others MI and found that six providers reported experiencing only Self MI, 61 providers reported experiencing only Others MI, and 21 of reported experiencing both. Participants experiencing Self MI were more likely to have experienced Others MI, X2 = 30.86, p < 0.001.There was variability with regard to the potential risk factors, as three predictors increased the odds of experiencing Self MI and many predictors increased the odds of experiencing Others MI. Specifically, providers who were more impacted by caring for COVID-19 patients, concerned about their COVID-19 protection, and experienced less leadership support were more likely to experience Self MI. Although these predictors also increased the odds of Others MI, there were other important predictors. The odds were also increased for nurses and providers who were impacted by their prior mental and medical health adversities, had more COVID-19 health worries, and had been infected with COVID-19. Of note, level of personal resiliency and the demographic factors did not significantly impact the odds of experiencing Self or Others MI.p = 0.047 and Others OR = 2.96, 95% CI = 1.59–5.54, p < 0.001; correct classification 77.0%). However, only Self MI was associated with an increased likelihood of scoring above the clinical cut-off for anxiety , PTSD , and burnout .Many providers scored above the clinical cutoff for depression (24.1%), anxiety (24.9%), PTSD (11.7%), and burnout (44.4%). Those scoring above the clinical cutoff were more likely to have experienced MI. Logistic regression analyses with both Self and Others MI entered as predictors of likelihood of scoring above the clinical cutoff for depression, anxiety, and PTSD indicated that the experience of both Self and Others MI increased the odds of scoring above the clinical cut off for depression , depression symptoms , COVID-19 work impact , and leadership support , and correctly classified 75.3% of providers above and below the clinical cutoff for burnout. The odds ratios above suggest that Self MI was the variable associated with the greatest likelihood of experiencing burnout.Forward conditional logistic regression analyses predicting burnout indicated the significant model, X2(2) = 8.64, p < 0.05. It shows that on average there is a small but significant increase in burnout over time b = 0.42, p < 0.05, d = 0.39. Model C was also an improvement in fit from Model B, X2(8) = 96.59, p < 0.001. It indicates that (1) providers who averaged more Others MI b = 0.97, p < 0.001, d = 0.54, and Self MI b = 0.52, p < 0.001, d = 0.43, experienced higher burnout; (2) providers who had higher Self MI at any given time point also had higher burnout at that time point b = 0.21, p < 0.05, d = 0.48; and (3) Others MI did not matter from month to month in relation to burnout. Lastly, Model D was not an improvement in fit from Model C, X2(3) = 0.13, p = 0.99, indicates that the addition of time interaction did not explain any additional variance and Model C should be retained as the best fitting model.This study focused on the experience of morally distressing events and the factors that relate to Self and Others MI in healthcare providers and in determining how Self and Others MI impact professional burnout (including exhaustion and disengagement) during the height of the COVID-19 pandemic. Given the concern about the increased risk of burnout and other negative consequences for HCPs, working in the healthcare field, it was important to investigate potential risk factors, especially those that can be mitigated with the aim of reducing burnout. We also hoped that the protective factors of personal resilience and leadership support would positively impact levels of MI and burnout.As hypothesized, we found that over the first four months of this study, which was conducted at the height of the COVID-19 pandemic, HCPs reported very high rates of burnout (44%), with burnout rates increasing over time. At baseline, HCPs (33.2%) reported high levels of MI, both directly experienced (Self) and observed (Others).To our knowledge, this study is the first to examine the relationship between Self and Others MI among HCPs, which we found to be correlated but best viewed as separate constructs. Although we do not know why the majority of reported MI was Others MI rather than Self MI, we note that many of the providers who endorsed Self MI also endorsed Others MI. Based on this observation, we hypothesize that perhaps the majority of providers who believed they violated their own morals also believed that this was true of others. It may be easier for the HCPs to acknowledge Self MI if they believe others are also having such experiences. Alternatively, it may be that at least some of the HCPs who reported experiencing Self MI and Other MI were blaming themselves in a belief that they did not do enough to intervene when observing others do what they viewed as morally wrong.The concerning rate of MI may relate to the high rates of morally distressing experiences related to patient care . In addition, both Self and Others MI were associated with specific HMDEs, COVID-19 work impact, COVID-19 protection concern, and leadership support. Others MI was also related to adversity history, COVID-19 health worry, prior COVID-19 diagnosis, and nurse role. The latter finding may be because nurses are spending more time with the patients and feeling less control or authority over their care. Although these associations were found, it is likely that MI may be more related to the actual events that occurred and other factors not investigated in this study, such as levels of stress or prior training.As hypothesized and similar to previous findings , we founOur findings suggest that firsthand involvement in moral violations  may be more impactful on psychological wellbeing than secondhand observation of moral violations . We found that it was Self MI (and not Others MI) that was strongly associated with burnout, and that additional factors, particularly leadership support, presence of depression, and COVID-related factors, were also important in predicting burnout. Together, these predictors correctly classified 70.7% of HCPs as scoring above or below the clinical cutoff for burnout, suggesting that they have substantial clinical relevance. These factors should be further addressed, both with additional research and with interventions to ameliorate their impact. Contrary to prior research , we alsoThe finding that Self MI was the variable associated with the greatest likelihood of having burnout is unique but not surprising, given that research with Chinese HCPs  that MI Self MI and perceived leadership support were significant predictors of both exhaustion and disengagement. While exhaustion was also impacted by their COVID-19 health worry and depression symptoms, disengagement was also influenced by how impacted they were by COVID-19 at work. This finding is particularly concerning because disengaged employees are more likely to withdraw, have lower job performance, and leave their jobs . Thus, iFinally, to our knowledge, the finding that perceived support by hospital or system leadership was inversely associated with burnout among HCPs is unique and consistent with the finding that nurse leaders can influence levels of engagement and improve patient outcomes . Our finAlthough the current study has many strengths, including its longitudinal design and focus on HCPs in the southeastern US, it also has some limitations. For example, the location limits the generalizability of the findings to other regions in the country that may have been impacted by the COVID-19 pandemic differently. Although the total sample was reasonably large, as is the case for many longitudinal studies, we saw a drop in the participation over time. This attrition may have had an impact on our longitudinal findings, as power dropped over time. It also negatively affected the collection of prior adversity information, as some of this data were collected at time 2 to minimize the burden at time 1.Additionally, there is a possibility the HCPs experienced morally distressing experiences not included in the current study, such as shortages of ICU beds, triaging of patients to other facilities, and withholding care due to lack of resources. They may also have experienced distress due to lack of resources, watching patients suffer, or feeling as if they or their team were incompetent ,22. FutuAnother limitation is the exclusion of the betrayal questions from the MI scale to limit the load on the participants. In retrospect, this data may have contributed to our understanding of leadership support. It is likely that less leadership support would have related to greater betrayal.The level of COVID-19 and the stress on the healthcare system in the areas investigated in this study were lower at that time than major hotspot areas of the pandemic. Despite this, we found high rates of both MI and burnout among HCPs at all four time points, and that MI was associated not only with high rates of burnout but also with clinically significant levels of psychiatric symptomatology and COVID-19 factors. We also found that HCPs who were more worried about getting COVID-19 and more negatively impacted at work by COVID-19 were particularly vulnerable and at greater risk of burnout. Our findings suggest the need to provide HCPs with stronger leadership support, particularly in the context of crisis situations such as the COVID-19 pandemic.


Strong relationships existed between both colorimetric (hue°) and anthocyanin analysis to panelist-based scores . The initial crispness was similar for movable, standard, diffuse, and block coverings at 5.3 on average, which was higher than the open field at 4 (p < 0.01). The open field lettuce grew under cooler soil temperatures, which may have slowed down maturation and resulted in softer tissue. Based on this study, HT growers can implement specific coverings to cater to markets that value visual quality.Leafy green production in high tunnels (HTs) results in increased yields, improved visual quality, and extended production with polyethylene (poly) film and/or shade cloth coverings. However, altering visible and ultra-violet light with HT coverings may reduce phytochemicals, thus influencing plant pigmentation and taste. The objective of this study was to examine various HT coverings on the sensory perceptions, soil temperature, color, and anthocyanin accumulation of red leaf lettuce. The coverings included standard poly, standard poly with removal two weeks prior to harvest (movable), diffuse poly, clear poly, UV-A/B blocking poly (block), standard poly with 55% shade cloth, and the open field. A highly trained descriptive panel evaluated the samples using a scale from 0 (none) to 15 (extremely high) and determined a list of 20 sensory attributes. The color intensity attribute had the most differentiation between coverings, and the open field was higher  than the others at 7.5 ( Fruit and vegetable consumption may lead to the reduction of certain diseases, due to their antioxidant properties ,2. The pLettuce, especially red leaf lettuce, is a good source of phenolic acids and flavonoids, including quercetin glucosides, anthocyanin conjugates, and caffeic acid derivatives ,13,14,15With the recent growth in local food production, there has been an expansion of high tunnel (HT) systems . HTs areLooking specifically at natural light sources, UV light obtained from solar radiation is a large factor affecting certain phenolic compound accumulation and subsequent plant pigmentation and appearance ,29,30,31There have been a few studies that report the effects of HT vegetable production on sensory quality ,33,34. RThis study examines the individual sensory attributes of the red lettuce grown under different HT coverings and compares them to soil temperature, leaf color, and anthocyanin concentration. By identifying and evaluating these lettuce attributes, we can inform growers on the ways in which light quality under HTs affects lettuce quality. This study is a portion of a larger study that researched the effect of HT coverings on microclimate, productivity, phytochemical accumulation, and now- sensory attributes. The first objective of this study was to develop sensory profiles by a highly trained descriptive panel to describe color, flavor, texture, and mouthfeel characteristics of red leaf lettuce to determine if any differences exist when grown under different HTs coverings. The second objective was to quantify the effects of the coverings on microclimate (soil temperature), leaf color, and anthocyanin concentration, and test relationships to the perceived panelist score of color intensity.Trials were conducted at the Kansas State University Olathe Horticulture Center, located in Olathe, Kansas. The trial was conducted in four “caterpillar” HTs that were 39.6 m long × 3.7 m wide × 2.1 m high. The construction of a homemade HT allowed for customization to suit the needs of the experiment regarding plot size and tunnel length. The overall design of the caterpillar tunnel is long and narrow with low ceilings, which provides an ideal structure for an experiment that specifically examines the impact of solar light. Each replication (high tunnel) had a total of six consecutive covering plots (6.1 m long) that spanned the width of the tunnel (3.7 m wide) and were joined at the long end by hip boards. An additional 2.1 m buffer area was included at the ends of each tunnel as well as 1.5 m at either end of each plot to minimize interplot interference. Data were collected from the middle 3.1 m of each plot. The lettuce trials utilized a split-plot randomized complete block design (RCBD), blocked by HT. Two beds ran lengthwise in each HT (39.6 m long × 0.61 m wide), and the lettuce varieties, ‘New Red Fire’ and ‘Two Star’ , alternated between the north and south bed at every other tunnel . For the purpose of this study, only the red variety, ‘New Red Fire’, will be discussed. Lettuce was seeded 7 September 2017, into 72-cell propagation trays (4 cm diameter)  with potting mix and transplanted four weeks later (6 October 2017). Common cultural methods for the region were practiced during production . LettuceEach tunnel, or rep, included six individual plots that were randomly assigned to the six coverings. An open field (open) bed was added adjacent to the HTs, but the replicates were not randomized and used for comparison purposes. The six HT coverings included commercially available greenhouse and HT poly films as well as shade cloth. The standard poly (standard) was rated for 92% PAR transmission and blocked <350 nm [single-layer 6-mil ]. Standard poly + removal (movable) allowed for plant establishment in a semi-protected environment before full solar exposure 2 weeks prior to harvest. The movable covering simulated the potential use of a movable tunnel . DiffuseOnce the lettuce was mature within the HTs, plants were harvested the morning of 7 November from each plot, using a lettuce knife  at the soil level to remove the full plant along with any outer whirl leaves, minus the root system.For the descriptive study, two lettuce plants were chosen at random from each covering plot, within the four replications, bagged, and boxed in coolers of ice for transport to the testing facilities in Manhattan, KS for sensory evaluation in an air-conditioned vehicle. This study used the methods described in the manuscript, “Lexicon to Describe Flavor of Fresh Leafy Vegetables” . The stuFor both instrumental (colorimetric) measurements and spectrophotometric (anthocyanin) analysis, six plants were chosen randomly from each covering plot, within the four replications, placed in plastic bags, and transported in an air-conditioned vehicle to the postharvest physiology lab at KSU-Olathe. Analysis occurred on the day of harvest and after 5 days of storage in optimum conditions of 1.5 °C and 90% RH in environmental chambers . These time points were chosen to account for any changes that would occur during the time required for the descriptive lexicon development and evaluation stages.n = 5) composed of four females and one male between 58 and 77 years of age from the Center for Sensory Analysis and Consumer Behavior at Kansas State University  evaluated the samples. These panelists completed at least 120 h of training and had a minimum of 2000 h of sensory testing experience. More specifically, panelists had previous experience in the evaluation of vegetables and other vegetable products [A highly trained descriptive panel . For preparation, each lettuce sample was rinsed with deionized water and dried using a salad spinner. Random, similar leaves with no evidence of deterioration were chosen for evaluation . Each replicate for each lettuce covering was served in sample sizes of four to six leaves, and three replications were utilized in total. The leaves were served on 4-inch foam plates with random 3-digit codes to reduce bias. If needed, leaves were cut to fit onto the plates. Each panelist received one random leaf. To test the lettuce, panelists were instructed to fold the leaf in half through the middle and take one bite from the middle of the fold. The panel room had neutral colors, was well lit, ventilated, temperature-controlled, and it was compliant with ASTM standards .Various aspects of the microclimate  were observed in the trials, and details are reported in Gude . HT soilThe color was measured on each of the four replicates of each of the covering treatments, comprised of three lettuce heads, using an A5 Chroma-Meter . Two measurements were taken on the left and right sides of the midrib on an undamaged outermost leaf, 1 to 3 cm from the tip. Color results were expressed by the chromatic coordinates CIE L*, a*, b*, hue, and Chroma . Followiv/v) , vortexed (20 s), sonicated (5 min) , and centrifuged  . The supernatant was transferred into a test tube, and the extraction was repeated. Both supernatants were combined and evaporated to dryness under nitrogen flow (2–6 ppm) and recovered with 4 mL of 30 mM ammonium acetate  in de-ionized (D.I.) water with 5 pH adjusted with formic acid  and filtered through a 25 mm 0.22 μm filter  into several 1.5 mL Eppendorf tubes for reserve and the sample extract was stored in darkness at −70 °C until analysis.To extract and measure anthocyanin, each of the four replicates of the covering treatments was comprised of three full lettuce heads and was extracted and analyzed in a darkened room with a red safety light to avoid photo-oxidation, following a previous procedure . LyophilPrior to analysis, a portion of each extracted sample was thawed, vortexed and 150 µL sample extract was pipetted in triplicate on 96-well microplates. Absorbance in the microplate reader with the spectrophotometer  was measured at 530 nm to correspond with anthocyanin pigments in red lettuce . FinallyAnalysis of variance (ANOVA) and Fisher’s LSD (Least Significant Difference) were conducted on the dataset to determine significant differences between coverings. The fixed effects of the 3-way ANOVA model were covering, panelist, and replication. Multivariate analysis was also done in the form of a principal component analysis (PCA) and cluster analysis using the Ward method to assess distances and to further compare relationships between covering groups. The analysis was performed using XLSTAT 2018.5.52459 .The soil temperature, lettuce color, and anthocyanin response parameters were analyzed under the linear mixed model. Fixed effects of the model were covering and analysis day (lettuce color and anthocyanin). The random effect of the model is HT. Pairwise comparisons between coverings were performed based on the 2-sided test for non-zero difference in means. The adjustment for multiplicity was carried out using Tukey’s method at the 0.05 significance level. When there was no statistical difference between the sampling days, as in the case of the lettuce color, and anthocyanin concentration, the values were combined between analysis days. The analysis was performed using JMP Software .A lexicon of 20 attributes  was devep < 0.0001; Color intensity was the attribute that had the most differentiation between samples grown under different coverings as compared to the other attributes . It has been reported that immature lettuce leaves have softer tissue [n = 24) to better focus on the effect of covering on temperature.The texture characteristic of initial crispness scored similarly between movable, standard, block, and diffuse coverings and greater than the open field . The flavor attributes of woody and musty/earthy scored low for all coverings. However, the woody attribute was high for the diffuse covering in comparison to open, clear, and movable coverings. Other terminologies, such as sweet-overall, sour, bitter, salty, and umami, were used to describe the taste. All lettuce samples scored very low for all of these attributes, except for the “bitter” category, where it scored moderately. However, no significant differences were noted between coverings, except for overall sweetness. Diffuse scored significantly higher than standard, and shade coverings and open field.Regarding flavor, the “green” flavors in this study included green-overall, green-peapod, green-grassy/leafy, and green-viney. Of the green flavors listed, the mean intensity scores of each covering were low to moderate and not significant . In addiFor the mouthfeel characteristic, water-like, the standard covering scored statistically higher than all other coverings . For toop < 0.0001), initial crispness (p < 0.001), and water-like attributes .Furthermore, lower environmental temperatures have been shown to increase plant pigmentation while slowing down plant maturation ,29,33. I2 = 0.847; 2 = 0.640; 2 = 0.507; Increases in color intensity scores from the panelists were strongly associated with decreases in hue angle . There was little difference in the flavor attributes between lettuce coverings. These results indicate that the spectral quality of UV and visible radiation alters perceived texture, mouthfeel, and visual parameters. Since these parameters are known to play an important role in the commercial value of red leaf lettuce, covering materials may be of considerable importance from a color intensity standpoint.


Proteus spp., Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli. The usage of prophylactic antibiotics for surgical procedures was high and varied between hospitals. Hospital B had significantly lower concordance to antibiotic therapeutic guidelines, resulting to a higher infection rate, compared with hospital A. ASHP adherence components were then further investigated, after which antibiotic dosing interval and injection time was found to be a significant predictor for positive bacterial growth based on logit–logistic regression. Further interventions and strategies to implement antibiotic stewardship is needed to improve antibiotic prescriptions and their use.Clean surgery without contamination does not require prophylactic antibiotics, but there are high-risk surgical procedures that may cause infection and/or involve vital organs such as the heart, brain, and lungs, and these indeed require the use of antibiotics. This study aimed to determine the quantity of antibiotic use based on the defined daily dose (DDD) per 100 bed days and the quality of antibiotic use based on the percentage of concordance with The American Society of Health-System Pharmacists (ASHP) therapeutic guidelines . This includes the profiles of surgical site infection (SSI) in surgical patients from January through June 2019. The study subjects were 487 surgical patients from two hospitals who met the inclusion criteria. There were 322 patients out of 487 patients who had a clean surgical procedure. Ceftriaxone (J01DD04) was the most used antibiotic, with a total DDD/100 bed days value in hospitals A and B, respectively: pre-surgery: 14.71, 77.65, during surgery: 22.57, 87.31, and postsurgery: 38.34, 93.65. In addition, 35% of antibiotics were given more than 120 min before incision. The lowest concordance to ASHP therapeutic guideline in hospital A (17.6%) and B (1.9%) was antibiotic selection. Two patients experienced SSI with bacterial growths of  Antimicrobial resistance threatens global health; antibiotic use in surgical specialties is an infection control indicator and may reflect the incidence of surgical site infection. In most developing countries, particularly Indonesia, antibiotics are given before the incision but also during the time from admission to discharge from the hospital which may result in higher chances of antimicrobial resistance. A new strategy is therefore needed to overcome this problem.Surgery is a medical procedure in the form of an incision made by a surgeon with the aim of preventing or treating an illness. In general, all surgical procedures can pose a risk of infection. Thus, antibiotic prophylaxis is needed to prevent postoperative infection. However, not all types of surgery require antibiotic prophylaxis. Clean surgery without contamination does not require prophylactic antibiotics unless there are high-risk procedures that may cause infection and/or involve vital organs such as the heart, brain, and lungs. Prophylactic antibiotics are generally recommended in some clean and all contaminated operations . In geneThe mismatch of antibiotic use with therapeutic guidelines is reported to be high in surgical ward , ICU 3,,3,4, andPrescribing antibiotics preoperatively can reduce the occurrence of wound infection. Whereas not following the guidelines, for example, by using different spectrum antibiotics or different tissue antibiotic concentrations at the start and during surgery, can reduce antibiotics’ effectiveness. Moreover, antibiotic selection pressure leads to antibiotic resistance. The incidence of SSI is significantly higher when prophylactic antibiotics are given postsurgery than when given presurgery with an odds ratio (OR) of 1.89 (95% CI 1.05–3.4). Prophylactic antibiotics more than 120 min preincision showed a higher prevalence of SSI than those within 120 min ) ,8. The uWorld Health Organization 2019) states that implementing antimicrobial stewardship by evaluating the use of antibiotics can optimize the use of antibiotics, encourage behavior change in prescribing antibiotics, improve quality of care and patient outcomes, save unnecessary health care costs, and reduce the emergence, selection, and further spread of antimicrobial resistance (AMR)  states t,12,13,14A total of 487 patients in both hospitals met the inclusion and exclusion criteria. Pre-, During, and Postsurgeries = 66.124, p < 0.001).Based on the recapitulation of antibiotic prophylaxis (DDD/100 bed-days) in hospitals A and B, respectively, between January and June 2019, the antibiotic use prophylaxis presurgery was 44.26 and 133.58; during surgery was 33.32 and 132.4; postsurgery was 66.65 and 148.68. Ceftriaxone had the highest DDD/100 patient days in the pre-, during, and postsurgery, with sequences of 14.71 and 77.65, 22.57 and 87.31, 38.34, and 93.65 . Overall2 = 283.62; p < 0.001) and dosing interval  = 4.165; p < 0.041) were significant predictors for infection cases in hospital B.Other than the route of administration, compatibility with ASHP guidelines was less than 50%. Order from highest to lowest conformity, the concordance to the ASHP guidelines was route of administration, injection given time, dosage, dosing interval, and selection . In geneProteus spp. and S. aureus, while the second patient had E. coli and S. epidermidis. Profiles of the types of bacteria that cause SSI are shown in Surgical site infection occurs related to surgical incision procedures within 90 days of follow-up. Only two patients experienced SSI in this study. Both patients experiencing postoperative SSI were identified after undergoing a third review in the first patient, and after the first review in the second patient. The results of the first patient’s pus culture showed the presence of Escherichia coli bacteria are still sensitive to several types of antibiotics, such as cefoxitin, chloramphenicol, fosfomycin, oxacillin, tetracycline, and vancomycin. Bacteria Proteus spp. were sensitive to antibiotics such as amoxicillin, amoxicillin–clavulanate, ampicillin, ciprofloxacin, cotrimoxazole, fosfomycin, norfloxacin, ofloxacin. Proteus spp. and had intermediate sensitivity to cefoxitin and chloramphenicol. Staphylococcus aureus bacteria were sensitive to chloramphenicol, oxacillin, and vancomycin and had intermediate sensitivity to amoxicillin, amoxicillin–clavulanate, and cefoxitin.The results of antibiotic sensitivity tests showed that The assessment of the quantity of antibiotic use was conducted by calculating DDD/100 bed-days based on the classification  that has been approved worldwide by the World Health Organization (WHO). DDD is defined as the use of antibiotics based on the average daily dose given to 70 kgs adult patients according to main therapeutic indications. However, DDD cannot provide information pertaining to the suitability of the actual daily dose prescription. DDD calculation is influenced by the amount of antibiotic use (grams) and the total length of stay (bed-days). The higher percentage of antibiotics use leads to the greater the DDD value .The calculation of DDD/100 bed-days between January and June 2019 was divided into pre-, during, and postsurgeries. Overall, the average of prophylactic antibiotic use in pre, during, and postsurgeries in hospital B was higher than in hospital A. Ceftriaxone is the most widely used antibiotic including surgery. Tolbert’s 2019 evaluative study on the use of ceftriaxone in tertiary hospitals in Tanzania showed 322 (51.1%) of 630 research samples used ceftriaxone antibiotics. A total of 44 samples (40.7%) received ceftriaxone for surgical prophylaxis purposes that were divided into 32 (72.7%) samples receiving antibiotics before surgery, 3 samples (6.8%) samples receiving ceftriaxone antibiotics during surgery, and 9 samples (20.5%) receiving antibiotics after surgery . Anotherp = 0.047). In clean-contaminated operations, the incidence of SSI in ceftriaxone was 4.6% and comparator 6.4%  [Prophylactic antibiotics can significantly reduce the risk of postoperative infections. A meta-analysis of 40 studies testing the effectiveness of ceftriaxone compared with the comparators as the surgical prophylaxis  showed that in clean operations, the incidence of SSI in ceftriaxone was 5.14%, and comparator 6.2%  .The average value of DDD/100 prophylactic antibiotic bed-days in this study is higher than other studies in one hospital in Indonesia but is still lower than that in the study of the use of prophylactic antibiotics in one hospital in Turkey. The ceftriaxone antibiotics dosage used in hospital B was 87 DDD/100 bed-days, which means there were 87 out of 100 patients who received ceftriaxone 1 DDD antibiotics per day. A primary study of surgical patients in the hospitals in Surabaya assessed the total use of ceftriaxone prophylactic antibiotics using the DDD/100 bed-days unit, and the total use of these antibiotics was 30–54 DDD/100 bed-days ,20. ThesAccording to Permenkes RI RI No. 2406/MENKES/PER/XII/2011 on General Guidelines for the Use of Antibiotics in 2011, the basis for selecting antibiotics should be drawn from the patterns of bacterial sensitivity to antibiotics, the clinical condition of patients, the selection priorities of first-line antibiotics or antibiotics with a narrow spectrum, cost, and adjusted according to the hospital diagnosis and therapy (PDT) Guidelines [Based on ASHP therapeutic guidelines, to ensure adequate plasma and tissue concentration during surgery, it is recommended that the drug to be given intravenously within one hour of an incision. In this study, more than 95% of patients received prophylactic antibiotics intravenously, but only around 50% in concordance with the preoperative dosage timing recommendation.Some antibiotics, such as vancomycin and fluoroquinolones, must be given 120 min before surgery due to the influence of the half-life and protein binding of each antibiotic ,23. Allep = 0.012). In addition, antibiotic resistance was observed in most types of bacteria in the surgical ward. One of these bacteria, Escherichia coli, was resistant to the antibiotics such as ceftriaxone, chloramphenicol, ciprofloxacin, and gentamicin [The incidence of SSI in surgery patients in hospital B from January through June 2019 was 2 out of 323 patients (0.62%). The SSI patients in this study both had ceftriaxone at intervals and doses of 2 × 1 g. The administration time was more than 2 h preincision. Mismatched timing of prophylactic antibiotics can cause SSI and the growth of resistant bacteria. Research conducted by Billoro in 2019 to evaluate the use of prophylactic antibiotics in 255 surgical patients in southern Ethiopia, using a prospective cohort study, showed that administration of surgical prophylactic antibiotics earlier than 1 h before the incision was associated with 20% of SSI cases, whereas administration within 1 h had a lower incidence, at 11.4%  [p = 0.012) [p = 0.002)). Our SSI patients were known to have a record of concomitant diabetes mellitus with preoperative blood sugar levels of 149 mg/dL and 138 mg/dL. Patients with blood sugar level that exceeded 100 mg/dL preincision had shown a 1.7 times greater risk of SSI [Extended preoperative waiting times for hospitalized patients increased the risks of SSI. Preoperative waiting time >7 days could increase the risk of SSI 2.48 times greater than preoperative waiting time <7 days (ARR = 2.48 (95% CI 1.28–4.79); = 0.007) . Both ou= 0.012) . Gachaba= 0.012)  found thk of SSI .The strength of this study is its large number of patients (n > 400) and follow-up. The reported cases of surgical site infection were not when the patient was in the hospital (inpatient) but during 30–60 days after the day of surgery when they returned to the outpatient clinic. The limitation of this study is that severe cases in ICU and those who died were not accounted for, and there were laboratory limitations, and therefore, the bacteria that cause SSI were not identified.A retrospective observational study in both hospitals was conducted by observing patients who underwent surgical procedures during hospitalization at a private hospital in Surabaya  and West Nusa Tenggara  in the period January–June 2019. Hospital A is a private hospital with 235 beds, whereas hospital B is a government hospital with 411 beds. Both hospitals are referral hospitals. Surgical procedures classifications were (1) clean surgery—surgery performed on an area without preoperative infection and without opening the tract , planned surgery, or primary skin closure with or without the use of closed drains, (2) clean-contaminated operations—operations performed on the ducts  or operations without significant contamination, and (3) contaminated surgery—surgery that opened the digestive tract, bile duct, urinary tract, airway to the oropharynx, or reproductive tract except for ovaries with gross spillage .Inclusion criteria included patients aged >18 years old who received prophylactic antibiotics, underwent surgery, and hospitalization in the surgical ward, including surgical wound control within <90 days postoperatively. The exclusion patient criteria were patients in the intensive care unit (ICU), patients who had an infection before surgery, those discharged “against medical advice” (AMA), and those who died.Slovin’s formula was used to calculate the appropriate sample size (n) from a population using the known population size (N) and the acceptable error value (e). In this study, simple random sampling was used from the population of admitted patients in the study period; N = 267 participants, e = 0.05; therefore, n = 160 participants hospital A; N = 1597 participants, e = 0.05; therefore, n = 320 participants hospital B.Slovin calculations used Equation (1) as follows:Antibiotic usage data were obtained from patient medical records and antibiotic use records compiled by pharmaceutical software, which stores all patient data. Data were collected from inpatient medical records, including diagnosis, surgery, length of hospitalization, drug name, dose, and the number of antibiotics received. The dataset was anonymized prior to analysis.In Indonesia, antibiotics can be prescribed to the patient at admission, during patient care, until the patient’s discharge, and usually two weeks after discharge (next outpatient consultation). In this study, antibiotic use classifications were pre-, during, and postsurgery. Presurgery represents antibiotics given before the day of surgery; antibiotics during surgery are given on the day of surgery (120 min preincision to <24 h after surgery), and antibiotics postsurgery are given >24 h after surgery.The obtained data were evaluated for antibiotic uses quantitatively and qualitatively. The quantitative evaluation used DDD per 100 bed-days, while the qualitative analysis was the percentage of antibiotic concordance to the American Society of Health-System Pharmacists (ASHP) Therapy Guidelines in (1) route of administration, (2) time, (3) type, (4) dosage, and (5) duration.Data on bacterial culture test results were obtained from clinical pathology laboratories, and prevention and control committees of infection to follow up regarding the bacteria that cause SSI in postsurgical patients. Patients with SSI were observed in the time they were in the hospital, and when they went to the doctor for review, until the patient was declared cured.All patient data were anonymized prior to analysis. Data analysis was performed descriptively in the form of an analysis of the quantity of prophylactic antibiotic use with the DDD/100 bed-days, which was calculated using the following formula:The percentage of compliance with guidelines of antibiotic use with the ASHP therapeutic guidelines was analyzed using the 2014 SIGN criteria as a quality analysis, including the sensitivity profile of the bacteria causing SSI.A generalized ANOVA model was also carried out on the aggregated DDD dataset to identify the overall difference between the two hospitals in this study. Z-test, in conjunction with Monte Carlo simulation, was also used to investigate which hospital was most adhering to ASHP guidelines. In addition, logit–logistic regression was utilized in this study to further investigate which ASHP adherence components that would be the significant predictor for reported infection cases. Participants’ demographics , comorbidities, and antibiotic usage were included as covariates in the model.The usage of prophylactic antibiotics for surgical procedures was high and varied between hospitals. The low concordance to antibiotic therapeutic guidelines suggested injudicious antibiotic use. Further surveillance is needed to identify the incidence of antibiotic-resistant bacteria in the future. It is highly recommended that surgeons abide by guideline recommendations, using only a single antibiotic dose for clean surgery. Further intervention and strategies in implementing antibiotic stewardship are needed to improve antibiotic prescribing and its use.


Cardiospermum halicacabum L.  obtained from flower, leaf and vine was loaded into modified phospholipid vesicles aiming at obtaining sprayable, biocompatible and effective nasal spray formulations for the treatment of nasopharyngeal diseases. Penetration enhancer-containing vesicles (PEVs) and hyalurosomes were formulated, and stabilized by adding a commercial gelatin from fish (20 mg/mL) or chondroitin sulfate from catshark cartilages . Cryo-TEM images confirmed the formation of spherical vesicles, while photon correlation spectroscopy analysis disclosed the formation of small and negatively-charged vesicles. PEVs were the smaller vesicles (~100 nm) along with gelatin-hyalurosomes (~120 nm), while chondroitin-PEVs and chondroitin-hyalurosomes were larger (~160 nm). Dispersions prepared with chondroitin sulfate were more homogeneous, as the polydispersity index was ~0.15. The in vitro analysis of the droplet size distribution, average velocity module and spray cone angle suggested a good spray-ability and deposition of formulations in the nasal cavity, as the mean diameter of the droplets was in the range recommended by the Food and Drug Administration for nasal targets. The spray plume analysis confirmed the ability of PEVs, gelatin-PEVs, hyalurosomes and gelatin-hyalurosomes to be atomized in fine droplets homogenously distributed in a full cone plume, with an angle ranging from 25 to 30°. Moreover, vesicles were highly biocompatible and capable of protecting the epithelial cells against oxidative damage, thus preventing the inflammatory state.The extract of  Cardiospermum halicacabum L.  belongs to the Sapindaceae family, which includes about 1200 species commonly found in India, South America and Africa. The beneficial properties of C. halicacabum have been known for centuries as a natural cortisone for the treatment of rheumatism, as well as a remedy for digestive and respiratory disorders, joint and back pain and muscle sprains, and also as a product capable of contrasting the poisoning effect of snake bites [C. halicacabum is still used in traditional eastern medicine as an anti-inflammatory remedy against rhinopharyngitis, but the effect has never been evaluated in scientific studies. The main bioactives contained in the plant are flavonoids, triterpenoids, glycosides, fatty acids and volatile esters [C. halicacabum counteracts free radicals, due to its content of powerful antioxidants including flavonoids, saponins, tannins, and glycosides [ke bites ,7,8,9,10e esters . They sye esters . Moreoveycosides ,14.Considering the promising anti-inflammatory and antioxidant power of this plant, its formulation in a nasal spray should represent an optimal alternative to effectively reach the nasal cavity for the treatment of nasal congestion and rhinitis, especially if associated with a suitable nasal preparation with a moisturizing effect, capable of counteracting the dryness and crusting usually associated with these disorders . PhosphoC. halicacabum with the phospholipid vesicles in a nasal spray represents a promising strategy for the local treatment of nasal congestion and rhinitis [C. halicacabum extract was not previous loaded in phospholipid vesicles and the positive effects provided by this association has not explored previously, along with their suitability as nasal spray. Indeed, to provide a local effect, nasal sprays must have specific features, such as adequate spray plume and droplet size distribution, which depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied [Scyliorhinus canicula, such as antithrombotic [The combination of the extract of rhinitis ,22,23,24 applied . These p applied ,25,26. P applied ,28. Chon applied ,30,31. Rrombotic , anticoaC. halicacabum was loaded in penetration enhancer-containing vesicles (PEVs) and hyalurosomes, which were further modified by adding a commercial gelatin from cold-water fish or a biopolymer chondroitin sulfate, extracted from catshark cartilages of Scyliorhinus canicular [Considering the lack of knowledge in the present study, the glycolic extract of anicular ,33,34,35C. halicacabum was kindly supplied by Sakura srl . Sodium hyaluronate with low molecular weight (200–400 kDa) and a polydispersity of 1.4 Mw/Mn was purchased from DSM Nutritional Products AG Branch Pentapharm . PEG400 was purchased from Galeno S.r.l. . Chondroitin sulfate was extracted from catshark cartilages (Scyliorhinus canicula) and kindly supplied by REVAL Institute  [Lipoid S75  was purchased from Lipoid GmbH . The 2:1 glycolic extract from flower, leaf and vine of , Spain) ,28,29. TC. halicacabum extract was hydrated with 1 mL of a mixture of distilled water (900 µL/mL) and PEG400 (100 µL/mL) to obtain PEVs, or with 1 mL of dispersion of sodium hyaluronate (0.1%) in water (900 µL/mL) and PEG400 (100 µL/mL) to obtain hyalurosomes. In addition, PEVs and hyalurosomes were modified by adding gelatin  or chondroitin sulfate .For vesicle preparation, 90 mg of S75 and 3 mg of C. halicacabum extract were prepared as well and used as controls. Vesicles were stored at 4 °C.The dispersions were sonicated  by using a Soniprep 150 sonicator  to obtain a homogeneous dispersion with small vesicles. Empty vesicles without The morphology of the vesicles has been evaluated by cryogenic transmission electron microscopy (cryo-TEM), by using a TECNAI G2 20 TWIN (FEI) microscope , operating at an accelerating voltage of 200 KeV in a bright-field image mode and low-dose image mode. We applied 3 μL of sample dispersion to a glow-discharged 300 mesh Quantifoil TEM grid, which underwent plunge freezing into liquid ethane on a FEI Vitrobot Mark IV . The frozen grid was then transferred to a 626 DH Single Tilt Cryo-Holder , maintained below −170 °C, and then transferred to TEM at the same temperature.The average diameter, polydispersity index and zeta potential of each sample were determined by means of light scattering technique by using a Zetasizer Ultra . These parameters were also measured over a storage period of 7 months at 4 °C, to evaluate the long-term stability of vesicles.® membranes, 12–14 kD, 3 nm pore size; Spectrum Laboratories Inc., Rancho Dominguez, CA, USA) against water (2:1) at room temperature for 2 h and refreshing the water after 1 h. The antioxidant activity (AA) of the extract-loaded vesicles was measured by means of a 2-diphenyl-1-picrylhydrazyl (DPPH) colorimetric test, before and after the dialysis process. Twenty microlitres of each formulation was dissolved in 1980 µL of DPPH methanolic solution previously prepared (1:50). The methanolic solution of DPPH at the same dilution was used as a control (100% absorbance). Samples were incubated for 30 min in the dark at room temperature. Subsequently, the absorbance of each solution was measured at λ = 517 nm with a UV spectrophotometer . All the experiments were performed in triplicate. The antioxidant activity was calculated according to the following Formula (1) [Each sample (2 mL) was purified from the non-incorporated extract by dialysis (Spectra/Pormula (1) :(1)AA(%)The entrapment efficiency (EE) of the vesicles was expressed as the percentage of the antioxidant activity before and after dialysis.The velocity and angle of droplets generated by the nasal devices integrated with data provided by the measurement of droplet size distributions are essential parameters to evaluate the suitability of nasal spray formulations to evaluate their effective deposition in the nasal cavity and their correct administration to patients ,38.® . For in vitro tests, the Food and Drug Administration (FDA) recommends determining the droplet size distribution at two distances comprised between 2 and 7 cm from the nozzle tip, with a difference of 3 cm apart [The size of the particles generated by spraying the formulations was measured by means of laser diffraction technique by using a Malvern Sprayteccm apart ,40,41. Tcm apart .Measurements were performed in triplicate at 25 °C, at 4 cm and 7 cm of distance and rotating the pump device 45° in relation to the laser beam. Data were reported as the D10, D50, and D90 volume diameter percentiles, expressed as 10%, 50% and 90% of the cumulative volume undersize. To characterize the width of droplet size distribution, the Span number was also reported as (D90−D10)/D50) as previously .The distribution of sprayed droplets and their average velocity were measured by laser plane visualization and particle image velocimetry. This technique allows the capture of two components of the velocity with high spatial resolution in a whole slice of the flow . To visuThe mean velocity field of the spray droplets was obtained from 100 instantaneous measurements  that havTo eliminate the influence of the operator in the generation of the spray, a pneumatic actuator to drive the manual atomizer was assembled. The duration of the liquid exiting from the nozzle  varies depending on the pressure supplied to the pneumatic device. This pressure has been adjusted to obtain a reasonable actuation, with a pulse duration of 150 m, as measured from the images.The spray speed and angle measurements were taken 83 m after the start of the atomization; that is, about 8 m after the mid-pulse. Finally, the commercial atomizers used were manufactured with plastic injection molding, so certain variability in the atomization of each device could be expected. To evaluate the device variability, the actuation of 3 atomizers with distilled water was measured as previously reported .2 flasks, incubated with 100% humidity and 5% CO2 at 37 °C. They were cultured with phenol red-free Dulbecco’s modified Eagle medium (DMEM) with high glucose, supplemented with 10% fetal bovine serum (FBS) and penicillin and streptomycin. The cells were seeded into 96-well plates at a density of 7.5 × 103 cells/well, and after 24 h of incubation, they were treated for 48 h with the extract in dispersion (water and PEG400) or loaded in vesicles. All the dispersions were properly diluted with the cell medium to reach the desired concentrations . The possible toxic effects of the formulations towards HaCaT cells has been assessed by measuring the viability by means of the MTT -2,5-diphenyltetrazolium bromide) colorimetric test. After 48 h, the medium was removed and MTT (100 µL) was added to each well and incubated at 37 °C for 2/3 h. The formazan crystals formed in viable cells were dissolved in DMSO, and the absorbance was measured at 570 nm with a microplate reader . All the experiments were repeated at least three times and each time in triplicate. The results are expressed as the percentage of live cells compared to untreated cells (100% viability).Human immortalized keratinocytes (HaCaT), used as model cells, were grown as monolayers in 75 cm4 cells/well) were seeded in 96-well plates with 250 μL of culture medium and incubated at 37 °C for 24 h, then stressed for 4 h with hydrogen peroxide  and simultaneously exposed to the extract in dispersion or incorporated into the vesicles . Unstressed cells were used as the positive control (100% viability) and hydrogen peroxide-stressed cells, treated with extract-free medium, were used as the negative control. After 4 h of incubation, the medium was removed and the viability of the cells was determined with the MTT colorimetric test, adding 100 μL of reagent in each well. After 2/3 h, the formed formazan crystals were solubilized by adding dimethyl sulfoxide, and their concentration was measured spectrophotometrically at 570 nm as above , and the Tukey’s test and Student’s t-test were performed to substantiate differences between groups using XL Statistics for Windows (XLSTAT BASIC+). The minimum level of significance chosen was C. halicacabum extract-loaded vesicles were evaluated by means of cryo-TEM observation. All tested vesicles were mostly small and unilamellar, but some larger vesicles were present as well . On the contrary, the loading of the extract produced an increase of mean diameter of chondroitin-PEVs and chondroitin-hyalurosomes (p < 0.05 versus the mean diameter of corresponding empty vesicles) and a reduction of size of the other formulations. The photon correlation spectroscopy only estimates the average size of vesicles by a cumulative intensity-based value, which is weighed according to the scattering intensity of the volume of different particle fractions. In this case, the fraction volume of few larger vesicles present in the dispersions was not clearly represented in the cumulative analysis, causing a small discordance with cryo-TEM images. In addition, the mean diameter of vesicles and its standard deviation were calculated as an average of at least six analyses, which were very repeatable as the standard deviation was very low.The mean diameter, polydispersity index, zeta potential and entrapment efficiency of the obtained vesicles were measured . Empty vp < 0.05 versus the mean diameter of PEVs), less polydispersed (polydispersity index 0.3), and negatively charged (~−45 mV) like PEVs . The addition of gelatin did not modify the mean diameter and polydispersity index of both PEVs and hyalurosomes, but markedly affected the zeta potential, which became less negative  due to the positive charge of gelatin on the vesicle surface.Extract-loaded PEVs were slightly polydispersed (polydispersity index 0.4) and negatively charged (~48 mV). Hyalurosomes were smaller, ~65 nm (p < 0.05 versus the mean diameter of PEVs) and chondroitin-hyalurosomes , which were the largest vesicles. On the contrary, chondroitin sulfate allowed the formation of more homogeneous dispersions, as the polydispersity index of chondroitin-PEVs was ~0.1, and that of chondroitin-hyalurosomes ~0.2. Chondroitin did not affect the zeta potential, which might be related to a strong interaction and intercalation of chondroitin within the bilayer, leading to an enlargement of the vesicle diameter.The behavior of chondroitin sulfate was different. Its addition led to an increase of the mean diameter of extract-loaded chondroitin-PEVs .The entrapment efficiency of the extract in PEVs was very high (~99%) and the addition of the polymers led to a decrease of this parameter ~75%, . On the p < 0.05) after three months of storage, and became undeterminable already at the fourth month due to the phase separation and formation of a precipitate of both aggregated vesicles and free extract. The addition of the polymers further reduced the stability of PEVs as the size of gelatin-PEVs and chondroitin-PEVs reached ~950 nm after only one month of storage. After that, it was impossible to measure the size and zeta potential due to the formation of a precipitate mainly composed of aggregated vesicles. Hyalurosomes doubled their diameter after one month of storage , and after three months the mean diameter was undetectable due to the formation of large aggregates. The addition of gelatin or chondroitin sulfate to hyalurosomes led to an improvement of the stability of vesicles in dispersion. Indeed, the mean diameter of chondroitin-hyalurosomes increased up to ~260 nm, that of gelatin-hyalurosomes reached ~141 nm after one month of storage, and both remained constant for the following six months. This could indicate that the combination of sodium hyaluronate with fish gelatin or chondroitin sulfate promoted the stability of vesicles in dispersion and facilitated the loading of C. halicacabum extract. The zeta potential followed the same trend, remaining coherent and strongly negative during the entire period of the stability check  and the European Medicines Agency (EMA) request droplet sizes of greater than 10 µm, to avoid the possibility to being inhaled and reaching the lungs . It is wC. halicacabum extract loaded in vesicles , and containing a small number of particles >200 µm (D90).Hyalurosome and gelatin-hyalurosome dispersions generated a full cone plume. Gelatin-hyalurosomes atomization was poorer, and in some cases, a liquid column was generated . The loading of the extract in vesicles differently affected the cell viability as a function of the used carriers and the dilution tested. More specifically, when PEVs were used at the lower concentrations (0.03 and 0.3 µg /mL), the viability was ~115% (p > 0.05 versus the viability of cells treated with the dispersion), as found using the extract dispersion. At the highest concentration (3 µg /mL), the cell viability strongly decreased , denoting a low toxicity at this concentration. Using hyalurosomes and gelatin-hyalurosomes, the cell viability was ~80% (p < 0.05 versus the viability found using the dispersion), irrespective of the used concentrations. Using gelatin-PEVs and chondroitin-PEVs, the cell viability was ~112% (p > 0.05 versus the viability of cells treated with the dispersion or the PEVs at lower concentrations), irrespective of the carrier and concentration used. The addition of chondroitin sulfate in hyalurosomes seems to stimulate cell proliferation, as the viability approached ~150%  when the lower concentrations (0.03 and 0.3 µg/mL) were used. The cell proliferation can be related to the dual effect of sodium hyaluronate and chondroitin, associated with the extract, which can favor the proliferation of keratinocytes, thus suggesting a positive contribution of this formulation in accelerating epithelial regeneration processes [p < 0.05).Considering the promising technological properties of the obtained vesicle dispersions, the in vitro biocompatibility and antioxidant activity against keratinocytes were evaluated as well, and compared with that of the extract in dispersion ,12,48,49p < 0.01 versus the viability of untreated cells), except when chondroitin-hyalurosomes were used, as these formulations only partially protected the cells, allowing a cell viability of ~85% .The protective effect of extract-loaded vesicles (0.3 and 3 µg/mL) against oxidative stress damage was evaluated using keratinocytes . The expC. halicacabum extract was loaded into phospholipid vesicles specifically tailored for nasal delivery. C. halicacabum extract was selected based on its rich phytocomplex, which contains apigenin, apigenin-7-O-glucuronide, chrysoeriol-7-O-glucuronide, luteolin, luteolin-7-O-glucuronide, saponin, quebrachitol, proanthocyanin, beta-sitosterol and stigmasterol, and its beneficial properties, well known for centuries [C. halicacabum, which has anti-inflammatory and antioxidant activities, is expected to provide a synergic effect [C. halicacabum and 92 mg/mL of a commercial mixture of soy phosphatidylcholine (Lipoid S75). The former were hydrated with a mixture of water and PEG400 to prepare PEVs, and with a dispersion of sodium hyaluronate in water and PEG400 to obtain hyalurosomes. PEVs and hyalurosomes were further modified using a commercial cold-water fish gelatin or chondroitin sulfate extracted from catshark cartilages (Scyliorhinus canicula) to stabilize the vesicles. Gelatin is widely used in cosmetic, biomedical and pharmaceutical applications [Aiming at developing an effective nasal spray based on natural components and capable of reaching the anterior part of nasal mucosa to attenuate nasopharyngeal congestion and rhinitis, enturies ,2,51. Itenturies ,17. Defic effect . To loadications . Chondroications .3+ groups [The obtained vesicles were small sized and negatively charged; the addition of gelatin markedly affected the zeta potential, which became less negative due to the positive charge of gelatin, which is a polyampholyte molecule  with cationic and anionic nature as a function of pH and temperature, that may modify its behavior in solution ,54,55. F+ groups . In the The addition of chondroitin sulfate mostly affected the mean diameter, forming larger vesicles while the zeta potential remained strongly negative due to its carboxyl groups and sulfo groups, which are probably mainly located on the vesicle surface . The preConsidering the small size of the obtained formulations, which are suitable for skin and mucosal delivery, their spray-ability into the nasal cavity was firstly evaluated in vitro by measuring the droplet size distribution, spray angle and droplet velocity ,57. IndeThe spray plume analysis confirmed the ability of PEVs, gelatin-PEVs, hyalurosomes and gelatin-hyalurosomes to be atomized in fine droplets homogenously distributed in a full cone plume, with an angle ranging from 25 to 30°. Generally, significant changes in the area of deposition have also been reported as a function of plume angle . As the Thus, overall results on sprayed plume underlined that PEVs, hyalurosomes and gelatin-hyalurosomes have the most suitable characteristics for nasal local delivery thanks to their ability to form a full cone of homogeneous droplets having a size of always <196 µm, a cone angle ~27° and high-speed ~14 m/s. The formed droplets can be well deposited in the nasal cavity, which serves as a target site for the treatment of local diseases such as nasal allergic conditions and nasal congestions .C. halicacabum extract in dispersion or loaded in vesicles confirmed that all PEVs and chondroitin-hyalurosomes, along with the extract in dispersion, at lower concentrations (0.03 and 0.3 µg /mL), were not toxic and favored cell proliferation, as the viability of epithelial cells after 48 h of incubation was ≥100%. Differently, using hyalurosomes and gelatin-hyalurosomes the cell viability was ~80%, indicating a weak toxicity of these formulations as previously observed using phospholipid vesicles [Cardiospermum halicacabum extract and phospholipid vesicles were previously demonstrated, to perform a preliminary biological evaluation of formulations, their ability to protect the tissues from the oxidative damages was also evaluated. Indeed, oxidative stress can activate a variety of transcription factors, which lead to the differential expression of some genes involved in inflammatory pathways. The inflammation triggered by oxidative stress is the cause of many chronic diseases [In this study, the analysis of technological properties of vesicle dispersions has been associated to the evaluation of their biological efficacy. The biocompatibility of vesicles . Considediseases . All thediseases . Their ediseases ,70. The C. halicacabum extract-loaded vesicles indicated that the prepared formulations, especially PEVs, hyalurosomes and gelatin-hyalurosomes, are suitable to be atomized and deposited in the anterior nasal cavity, where they can exert local activity against congestion and rhinitis. In addition, they are able to protect the epithelial cells from oxidative stress, avoiding local tissue damages. Gelatin-hyalurosomes showed long-term stability with storage and seemed to be the most promising formulation for nasal delivery, thus encouraging their possible application for the treatment of nasopharyngeal congestion and rhinitis associated with oxidative stress. Alternatively, the other formulations, like PEVs and hyalurosomes, which could not keep their physicochemical properties during storage, could be further stabilized by using other additives.The evaluation of physicochemical, technological and biological properties of


Clinicians should pay more attention to the cognitive function of patients with heart disease, especially those with heart failure. In addition, further research elucidating the associated mechanisms would help discover new therapeutic targets to intervene in the process of cognitive dysfunction after heart disease. This review discusses cognitive dysfunction in relation to heart disease and its potential mechanisms.The functions of the brain and heart, which are the two main supporting organs of human life, are closely linked. Numerous studies have expounded the mechanisms of the brain-heart axis and its related clinical applications. However, the effect of heart disease on brain function, defined as the heart-brain axis, is less studied even though cognitive dysfunction after heart disease is one of its most frequently reported manifestations. Hypoperfusion caused by heart failure appears to be an important risk factor for cognitive decline. Blood perfusion, the immune response, and oxidative stress are the possible main mechanisms of cognitive dysfunction, indicating that the blood-brain barrier, glial cells, and amyloid- The structure and the function of the heart and brain have been studied for several decades due to their important roles in life. With further understanding of the independent mechanisms of the two organs, scientists began to seek a connection between the heart and the brain, which was announced by Barrow in the middle of the 19th century . In the United States alone, approximately 300,000 people undergo CABG each year . In geneThe most obvious clinical manifestation of Alzheimer's disease (AD), a severe degenerative disease of the nervous system, is impaired cognitive function , 28. ComMany research groups have explored the potential mechanisms of cognitive impairment based on the important functions of the heart and brain and their interconnectivity. Among them, blood perfusion and inflammation are the two main mechanisms that have been explored .The brain is a highly energy-consuming organ, accounting for approximately 20% and 25% of the body's oxygen and glucose, respectively . Its funHypoperfusion due to low cardiac output is a key factor in cardiovascular disease, which accelerates changes in the brain structure , 38. In Vascular damage in the brain itself, such as small vessel disease, may also increase the vulnerability of the brain to changes in perfusion pressure . In contIncreasing evidence supports the role of blood perfusion in the pathogenesis of AD , 28. EarIn the case of cerebral hypoperfusion, the metabolic activity of the whole brain is significantly reduced . SpecifiExcept for heart diseases, such as myocarditis and myocardial infarction (MI) that directly lead to inflammation, hypoperfusion can cause inflammation of brain tissues in diseases with decreased cardiac function, such as HF . In respAerobic exercise has demonstrated amelioratory effects on the blood supply to the brain. On the basis of the mechanism discussed above, aerobic exercise is beneficial for cardiac disease patients with cognitive impairment. Regular aerobic physical activity can increase the blood flow in the prefrontal cortex, promote the formation of blood vessels in the frontal cortex, and increase the concentration of the vascular endothelial growth factor . Moreoveα, and interleukin- (IL-) 6, was significantly upregulated in the cortex and hippocampus in a mouse model of HF [α, IL-1, IL-6, IL-8, and monocyte chemoattractant protein- (MCP-) 1, mainly derived from neutrophils, monocytes, and macrophages [The inflammatory response and oxidative stress are usually interdependent and may be potentially associated with brain dysfunction after heart disease , 62. Stuel of HF . As for rophages . These pα, which is considered the main regulator of the brain's proinflammatory response, can cause cell damage and death by increasing neurotoxicity via neuronal glutamate [α pathway is involved in the destruction of tight junctions soon after chronic cerebral hypoperfusion [β in the central nervous system, which is an important regulator of the inflammatory cascade [α and IL-1β in the ischemic brain can reportedly induce the production of IL-6, and increased IL-6 levels in the serum and cerebrospinal fluid are related to cognitive impairment [β and TNF-α can upregulate the expression and function of CD73, which plays a protective role in the occurrence of white matter lesions induced by cerebral hypoperfusion and cognitive impairment by regulating the activation of glial cells and expression of proinflammatory cytokines [β, IL-6, and TNF-α. Therefore, CD73 plays a key role in the counter-regulatory feedback mechanism, helping to relieve inflammation [TNF-lutamate , 68. Recerfusion . Insuffi cascade . TNF-α apairment . Furtherytokines . Specifiammation .β (Aβ) and causing damage to the cognitive function of the brain [The inflammatory response and oxidative stress mainly cause cognitive dysfunction through damage to the self-repair mechanism, destruction of the blood-brain barrier (BBB), and activation of glial cells , 73, 74.he brain –77.In view of the importance of the inflammatory response and oxidative stress, anti-inflammatory or antioxidant therapies have become an innovative clinical approach . NaturalThe inflammatory response and oxidative stress are believed to play important roles in neurovascular dysfunction. Oxidative stress can cause endothelial dysfunction, BBB disruption, and cytokine production . In turnApolipoprotein E (ApoE) subsequently affects neurovascular units through pericytes, causing changes in microvascular flow and triggering neurodegenerative changes . CerebraOverall, the inflammatory response and hypoperfusion can damage the brain repair mechanism, which in turn promote the occurrence of small vessel diseases.κB-matrix-metalloproteinase-9 [α pathway. Animal experiments have demonstrated that the use of compound K811, a specific ASK1 inhibitor, can prevent cognitive impairment in a mouse model of hypoperfusion [Abnormal function of the BBB, including activated endothelial cells, destroyed pericytes, and abnormal endothelial-endothelial and endothelial-pericyte connections, occupies an important position in the pathogenesis of cognitive dysfunction after heart disease . Inflammeinase-9 , 74. Cereinase-9 . Thus, derfusion . ASK1 maDamage to the BBB increases its permeability, causing leakage of plasma components and exchange of substances . After tGenerally, destruction of the BBB by ROS and inflammation after heart disease will lead to further aggravation of inflammation and promote contact of neurotoxic proteins with neurons. The relationship between BBB destruction and immune cell activation is described later.11C-methionine uptake can help reflect inflammation in the brain [After inflammation occurs, astrocytes are activated slightly earlier than microglia . The acthe brain . Neutrophe brain . In addihe brain .α) and obvious tissue damage were significantly detected in the white matter of a mouse model of chronic cerebral hypoperfusion with BCAS [The increased permeability of the BBB also enhances the adhesion and migration of monocytes from the periphery to the central nervous system, and then differentiation into microglia to promote neuroinflammation . As the ith BCAS . Proinflith BCAS . This reith BCAS .To study the mechanism of inflammation in depth, Miyanohara et al. confirmed that transient receptor potential melastatin 2 (TRPM2), a Ca2+ permeable channel, participated in cognitive impairment related to chronic cerebral hypoperfusion by enhancing the production of cytokines, leading to subsequent white matter damage , 107. Spα and IL-1β [Apart from TRPM2, IL1R, CX3CRI, leptin, and tamoxifen may also be involved in regulation of the inflammatory response. Zhou et al. reported that the loss of IL1R expression improved white matter damage and promoted the migration of oligodendrocyte precursor cells from the subventricular zone . Furthernd IL-1β .In short, inflammation and destruction of BBB permeability after heart disease promote the activation of glial cells, leading to neuroinflammation, which is considered an important factor in the progression of AD.β deposition in the hippocampus, endothelium, and neocerebral cortex, which led to neuronal death [Although HF and cognitive dysfunction in patients with AD have long been considered independent factors, an increasing number of studies have confirmed that they may be related, with similarities such as common risk factors and similar epidemiological stratification . Moreoveal death .β is removed from the brain through the BBB, the interstitial bulk flow clearance (glymphatic) system, or meningeal lymphatic vessels [β accumulates in the perivascular space [β deposition, new evidence suggests that immune mediators also contribute to disease progression, especially in microglia [β clearance in the brain [β plaque, accompanied by impaired function [β is further reduced, providing an ideal environment for accumulation, aggregation, and further formation of plaques. In addition, active astrocytes also express high levels of amyloid precursor protein [Under normal circumstances, A vessels , 118. Unar space . In the icroglia . Such sche brain . Chronicfunction . Thus, t protein . Therefo protein .β, in turn, caused oxidative imbalance through Aβ accumulation in the mitochondria, which aggravated mitochondrial dysfunction, ROS production, and overall oxidative imbalance [β accumulation in the brain also reportedly has a profound effect on blood vessels, thereby promoting neurodegenerative processes [Studies with mouse models of AD and AD patients reported that Ambalance , 124. Throcesses .β lead to the accumulation of Aβ, eventually causing cognitive impairment. Interestingly, HF with preserved ejection fraction can promote cognitive dysfunction in AD and vice versa [In summary, under the condition of chronic hypoperfusion, damage to the drainage system and decreased ability of glial cells to clear Ace versa . Overallce versa . In viewβ metabolism [Cognitive dysfunction occurs in a large number of patients with heart disease, causing a great burden to families and the healthcare system. However, systematic research still needs to be conducted. Recently, increasing evidence has shown that extracellular vesicles are involved in molecular transport within and between organs, including interactions between the heart and brain . In the tabolism , 128. Attabolism . Furthertabolism .β degradation in the central nervous system, thereby increasing the risk of AD [β1-42 into Aβ1-40. ACEIs block this process and increase the deposition of Aβ1-42 in the brain [In addition to probing the mechanisms of cognitive dysfunction after heart disease, the clinical application of these mechanisms is also an important point for scientists and doctors. The impact on cognitive function of drugs used to treat heart disease needs to be carefully evaluated, especially new therapies such as sacubitril/valsartan. Theoretically, neprilysin inhibition reduces Ask of AD . ACEI drhe brain . However