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Skin‐care products are designed to promote skin health and renewal and are typically used after skin cleansing. They contain a variety of active ingredients, such as aloe vera , cabbage, niacinamide, titanium dioxide, and hyaluronic acid . These products, especially those derived from plant extracts, have become increasingly popular among consumers . Plant extracts are compounds separated from various parts of plants through physical or chemical extraction methods. However, the composition and content of these extracts can vary considerably because of factors such as climate, soil composition, latitude, season, harvest time, and field management. This variability presents a challenge in standardizing the manufacturing process of skin‐care products .
|
39754370_p4
|
39754370
|
Market Trends of PEBSC Products
| 3.198389 |
biomedical
|
Other
|
[
0.9969037175178528,
0.0006071378011256456,
0.0024891654029488564
] |
[
0.08074571937322617,
0.8419356942176819,
0.07645842432975769,
0.0008601652225479484
] |
en
| 0.999998 |
Surplus agricultural production is common in Taiwan. Researchers can examine these surplus products and identify their functional ingredients that can be used for the creation of skin‐care products; this approach can increase resource use efficiency and farmer income . Using local agricultural products to create skin‐care products has several benefits, including shortened transportation distances and reduced CO 2 emissions. This approach also promotes environmental protection, local heritage, job creation, and local agricultural development . Domestic operators can also incorporate Taiwanese culture, history, and emotions as an added value to enhance Taiwan‐made skin‐care products to attract consumers . In recent years, cosmetic companies have begun to experiment with natural and environmentally friendly raw materials in response to growing public concern for environmental sustainability . With the improvement of living standards and technological advancement, products containing plant extracts have become the preferred choice for many skin‐care product consumers .
|
39754370_p5
|
39754370
|
Market Trends of PEBSC Products
| 1.758205 |
other
|
Other
|
[
0.2080593854188919,
0.0008272918057627976,
0.7911133170127869
] |
[
0.03485080227255821,
0.9622983932495117,
0.002535607200115919,
0.00031519794720225036
] |
en
| 0.999993 |
Despite the impact of the COVID‐19 pandemic, the cosmetics industry remains one of the fastest‐growing and most profitable sectors in the global economy. Although the growth rate of the global cosmetics market decreased by 8% in 2020, that of skin care and beauty products grew by 2%. As the pandemic subsides, the market is expected to rise at a compound annual growth rate of 4.6% from 2022 to 2030 . The rising awareness of health and environmental protection, coupled with the booming market for natural and organic skin‐care products, has made PEBSC products an emerging focus for consumers. Consumers believe that these products are safe, are effective, have no side effects, have high value for money, and have social significance.
|
39754370_p6
|
39754370
|
Market Trends of PEBSC Products
| 1.784973 |
biomedical
|
Other
|
[
0.5158142447471619,
0.003816433949396014,
0.48036929965019226
] |
[
0.0031207946594804525,
0.9909040331840515,
0.005675934255123138,
0.0002992005320265889
] |
en
| 0.999996 |
The success of a business often hinges on maintaining good customer relationships because acquiring new customers is often more challenging than retaining existing ones . Customer loyalty encompasses attitudinal and behavioral aspects. Attitudinal loyalty refers to a customer's psychological preferences, such as intent to repurchase, whereas behavioral loyalty refers to actual purchasing behavior, such as the number and frequency of purchases . Oliver proposed a customer loyalty model with four levels. First, customers rationally form a preference for a particular good or service (cognitive loyalty), after which they develop a preference for the product on the basis of prior purchasing experience (emotional loyalty) and develop an emotional commitment to repurchase the product (intention loyalty). Finally, they develop an intention to repurchase the product repeatedly even in the presence of conflicting incentives (action loyalty). Loyal customers are characterized by high consumption, frequent repeat purchases, low price sensitivity, willingness to recommend products, preference for the original products despite competition, and willingness to maintain a relationship with the company by purchasing other products and receiving marketing information .
|
39754370_p7
|
39754370
|
Consumer Loyalty and Perceived Value
| 1.036154 |
other
|
Other
|
[
0.0012985715875402093,
0.0004697141994256526,
0.9982317090034485
] |
[
0.008637632243335247,
0.9883154630661011,
0.0019629616290330887,
0.0010838932357728481
] |
en
| 0.999998 |
Perceived value is a customer's overall assessment of the utility of a product or service; this assessment is based on their perception of the benefits that they receive and the costs that they incur . Perceived value has three characteristics: (1) it is diverse, encompassing various perceived benefits and costs; (2) it is subjective, with different customers having varied perceptions of the same product; and (3) it is competitive, with companies that deliver superior value gain achieving sustainable competitive advantages . Sheth, Newman, and Gross proposed consumption value theory with five categories of perceived value: functional, social, emotional, epistemic, and conditional value. Functional value refers to the quantifiable or unquantifiable price, function, use, and quality of the product or service itself; social value refers to connections with other social groups (obtaining group recognition, complying with social norms, gaining a sense of belonging, and demonstrating internal image or display of status); emotional value refers to consumers' emotional reactions to products or services; epistemic value refers to the novelty of a product or service that can arouse customers' curiosity and desire for knowledge; and conditional value refers to the higher functional or social value that consumers can temporarily obtain from a product in specific situations . Sweeney and Soutar suggested that these value dimensions are not independent, and the relative importance of each value might differ between products or services. Studies on skin‐care products have consistently measured perceived value using these dimensions (e.g., ).
|
39754370_p8
|
39754370
|
Consumer Loyalty and Perceived Value
| 1.865544 |
other
|
Other
|
[
0.012722906656563282,
0.0004522653471212834,
0.9868248105049133
] |
[
0.26798367500305176,
0.5720623135566711,
0.15792082250118256,
0.0020331428386271
] |
en
| 0.999997 |
Perceived value is a key determinant of customer loyalty. A higher perceived value leads to a stronger purchase intention and more robust customer loyalty . Perceived value can influence customer loyalty in various ways. For instance, Ghazali et al. found that higher perceived health, safety, hedonic value, and social value increased repurchase intention for organic cosmetics, Song, Guo, and Zhang found that social value, price, and brand value positively affect customer loyalty to environmentally friendly cosmetics. Choi and Lee indicated that the factors determining willingness to repurchase environmentally friendly cosmetics are often related to identity, acceptance, and pride, which are aspects of social value. Therefore, the following hypothesis is proposed with regard to Taiwan‐made, PEBSC products: Perceived value positively affects customer loyalty .
|
39754370_p9
|
39754370
|
Consumer Loyalty and Perceived Value
| 0.995459 |
other
|
Other
|
[
0.0037533503491431475,
0.0002759501803666353,
0.9959706664085388
] |
[
0.2235357165336609,
0.7688987255096436,
0.005769952666014433,
0.0017956327646970749
] |
en
| 0.999997 |
Prior experience refers to customer reactions and feedback after exposure to an environment, a product, or a service; experiences include consumer cognition, preferences, emotions, beliefs, physiological and psychological reactions, and sources of achievement . Prior experience encompasses personal experiences, lifestyle, and interactions with the product . Taiwan's dynamic climate can significantly affect consumer experiences and perceived benefits of using skin‐care products, which is reflected in consumer behavior. For example, in Taiwan's summer, sun exposure may cause solar dermatitis, solar keratosis, cell damage, and accelerated skin aging. Varying weather and high‐temperature differences between day and night might induce urticaria, and extreme weather events may double the chance of bacterial skin infection. Summer humidity and heat can cause sweat rash, impetigo, and fungal infection and exacerbate contact dermatitis. The dry, cold winter can cause dry skin . People who regularly engage in outdoor activities prioritize skin‐care products that offer ultraviolet protection.
|
39754370_p10
|
39754370
|
Prior Experience, Perceived Value, and Customer Loyalty
| 2.46209 |
biomedical
|
Other
|
[
0.6120652556419373,
0.0014681217726320028,
0.3864666223526001
] |
[
0.04916227236390114,
0.9470320343971252,
0.00349572766572237,
0.00031001472962088883
] |
en
| 0.999997 |
The consumption experience is a crucial factor in evaluations of perceived value . As the quality of experience increases, so does the customer's perceived value. Customers whose expectations are met by consumption tend to have a positive feeling toward the relevant product, have a strong emotional connection with the product, have a high evaluation of the product, and continue using the product . Prior experiences can influence customer impressions of products and services, further solidifying their loyalty . Several studies have indicated that perceived value can act as a mediating variable between consumption experience and purchase intention . Therefore, the following research hypotheses are proposed: Prior experiences positively affect perceived value . Prior experiences positively affect customer loyalty . Perceived value enhances the effect of prior experience on customer loyalty .
|
39754370_p11
|
39754370
|
Prior Experience, Perceived Value, and Customer Loyalty
| 1.003319 |
other
|
Other
|
[
0.0024793280754238367,
0.00032039391226135194,
0.9972002506256104
] |
[
0.11357040703296661,
0.8820396661758423,
0.0026966005098074675,
0.0016934140585362911
] |
en
| 0.999996 |
Social judgment theory is based on self‐persuasion and posits that people perceive and evaluate new information on the basis of their existing attitudes. This theory led to the development of involvement theory . Involvement refers to an individual's interest in and concern for a specific thing or the psychological state triggered by specific stimuli and situations. It represents an individual's perception regarding the relevance of something, which depends on their needs, interests, and values . Consumers with high involvement resist accepting opinions that contradict their original ideas . Initially used in media research, involvement theory is now widely applied in marketing . Consumers with high involvement actively and extensively collect information, whereas those with low involvement are passive, expose themselves to limited information, and perform decision‐making with the simple stages of awareness, trial, and adoption .
|
39754370_p12
|
39754370
|
Involvement, Perceived Value, and Customer Loyalty
| 1.441392 |
other
|
Other
|
[
0.005455438978970051,
0.0006802576244808733,
0.9938642978668213
] |
[
0.004588814917951822,
0.9831410646438599,
0.011383038945496082,
0.0008870362653397024
] |
en
| 0.999997 |
Previously, scholars categorized involvement as enduring, situational, and response involvement . Enduring involvement is an individual's ongoing concern for things according to their needs, interests, and values, and such involvement is unaffected by external changes. Situational involvement is a temporary state triggered by a specific situation, which reverts to the original state once a goal is achieved or the situation changes. Response involvement refers to the behavioral and cognitive outcomes resulting from the combination of situational and enduring involvement . Involvement was later reclassified into product, message, and situation involvement . Product involvement is similar to enduring involvement but is more closely tied to consumer products. Message involvement relates to an individual's concern for product information or their psychological state when they are exposed to this information. Situational involvement refers to personal cognition and the attention that an individual pays to consumption behavior in a purchasing situation . The present study adopted the later classification because of its clear distinction between concepts and its consideration of message impact.
|
39754370_p13
|
39754370
|
Involvement, Perceived Value, and Customer Loyalty
| 2.197308 |
other
|
Study
|
[
0.028609294444322586,
0.00038427746039815247,
0.971006453037262
] |
[
0.8873524069786072,
0.09254715591669083,
0.019140325486660004,
0.0009600739576853812
] |
en
| 0.999997 |
Studies have indicated that product involvement significantly influences perceived value and customer loyalty. Consumers' perceived value varies depending on their level of product involvement, which also enhances customer loyalty . When consumers with high product involvement are satisfied, they exhibit high customer loyalty, which indicates that perceived value mediates the relationship between product involvement and customer loyalty. Similarly, message involvement positively affects perceived value and customer loyalty; if the message content is engaging, it can stimulate consumer recall, understanding, be more persuasive, reduce perceived sacrifice, and improve perceived value . Situational involvement also affects perceived value and customer loyalty, particularly when time is limited and perceived risk is reduced . Customers with firm loyalty insist on purchasing a specific brand even if they urgently need the relevant product or the store is out of stock. Wu, Liang, and Ip claimed that situational involvement affects purchasing decisions to a greater extent than product or message involvement. Perceived value also mediates the effect of situational involvement on customer loyalty . On the basis of these findings, the following research hypotheses are proposed: Customer involvement positively affects perceived value . Customer involvement positively affects customer loyalty . Perceived value enhances the effect of involvement on customer loyalty .
|
39754370_p14
|
39754370
|
Involvement, Perceived Value, and Customer Loyalty
| 0.999265 |
other
|
Study
|
[
0.0017743435455486178,
0.0003671939775813371,
0.997858464717865
] |
[
0.5744466185569763,
0.391182005405426,
0.029857831075787544,
0.004513539839535952
] |
en
| 0.999997 |
The demographic characteristics examined in this study were sex, age, place of residence, educational level, monthly disposable income, and skin type . Consumption behavior for skin‐care products varies between men and women. Women prefer products with diverse features and are generally less loyal than men. Men repurchase products primarily because of satisfaction with the product's function, whereas women value the interaction with the salesperson during purchase . Men's spending on skin‐care products has been increasing annually, thereby expanding the market . Men are more loyal to high‐priced products than women and associate these products with stable quality, low risk, and high status . Women use a wider variety of skin‐care products, prefer lotions and lip balms, and are more loyal to specific brands . Matić and Puh stated that women care more about function and emotion and have stronger repurchase intention for natural skin‐care products than men .
|
39754370_p15
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 2.24131 |
biomedical
|
Study
|
[
0.5858562588691711,
0.0012932152021676302,
0.412850558757782
] |
[
0.9562088251113892,
0.04121099039912224,
0.0022912239655852318,
0.00028899332392029464
] |
en
| 0.999997 |
Customer age also influences skin‐care product consumption behavior. Older consumers have extensive shopping experience and make decisions according to this experience and safety. By contrast, younger consumers consider satisfaction but might prioritize sales staff information, enjoy change, and value openness . Older consumers are generally more loyal than younger ones. Older consumers, who typically have simpler lifestyles and higher disposable income, have higher demand and loyalty for locally sourced natural skin‐care products .
|
39754370_p16
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.147976 |
other
|
Other
|
[
0.006258541718125343,
0.0005502156564034522,
0.9931913018226624
] |
[
0.004808355122804642,
0.9941588640213013,
0.0006445816834457219,
0.0003882486780639738
] |
en
| 0.999998 |
Place of residence, which is an external factor, also affects skin‐care product purchasing decisions. Because of urban–rural differences in income and price levels, customer loyalty varies between urban and rural areas . Lin and Chuang indicated that people in southern Taiwan are more pragmatic and conservative compared with those in northern Taiwan, whereas people in northern skin‐care product manufacturers often segment the market on the basis of regional characteristics to develop different sales strategies, thereby increasing customer satisfaction and loyalty .
|
39754370_p17
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.243741 |
other
|
Other
|
[
0.012843124568462372,
0.0004389508976601064,
0.986717939376831
] |
[
0.07083145529031754,
0.9261336922645569,
0.0022462133783847094,
0.0007885912782512605
] |
en
| 0.999994 |
Education level also affects customer loyalty, albeit to a lesser extent than other demographic variables. Evanschitzky and Wunderlich found that lower education levels were associated with contextual factors having a stronger effect on loyalty. People with higher education levels tend to collect and process more information and make more cautious consumption decisions . Compared with people with a low education level, highly educated people, who are better at collecting and understanding product information, are expected to have higher repurchase intentions for local PEBSC products, which they recognize as being rich in bioactive substances .
|
39754370_p18
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.246323 |
other
|
Other
|
[
0.01598105952143669,
0.0003323211276438087,
0.983686625957489
] |
[
0.19650432467460632,
0.7992038130760193,
0.0033527854830026627,
0.0009391025523655117
] |
en
| 0.999997 |
Customer loyalty can be influenced by monthly disposable income. Consumers with high disposable income tend to prioritize product quality and after‐sales service but are resistant to sales, promotions, and discount products, which results in higher customer loyalty. Conversely, those with lower disposable income are more likely to be attracted to lower‐priced alternatives, which makes it easier for them to switch products and thus reduces their loyalty .
|
39754370_p19
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.085941 |
other
|
Other
|
[
0.0018366456497460604,
0.0006400373531505466,
0.9975233674049377
] |
[
0.0027791475877165794,
0.99580979347229,
0.0007457441533915699,
0.0006654200260527432
] |
en
| 0.999997 |
Customer loyalty to specific skin‐care products can also be affected by their skin type and condition. The sebum on the skin surface, which regulates skin humidity and protects the skin, can affect skin quality . However, individual skin conditions can vary because of factors such as innate physique, acquired care, nature of work, entertainment orientation, and product attribute requirements. Skin types can be categorized into oily, dry, combination, and normal, and no single skin‐care product can cater to all skin types simultaneously. Different skin types require different treatments and products. Consumers' expectations for skin‐care products vary, including in aspects such as tolerance, safety of use, and pleasure . Therefore, the following hypothesis is proposed: For consumers of Taiwanese PEBSC products, customer loyalty is influenced by factors such as sex, age, place of residence, educational level, monthly disposable income, and skin type .
|
39754370_p20
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.609812 |
other
|
Other
|
[
0.08031895011663437,
0.0005551682552322745,
0.9191258549690247
] |
[
0.3254510760307312,
0.6718025803565979,
0.0020215290132910013,
0.0007248474867083132
] |
en
| 0.999997 |
The research model developed in this study is displayed in Figure 1 .
|
39754370_p21
|
39754370
|
Effects of Various Demographic Characteristics on Customer Loyalty
| 1.9558 |
biomedical
|
Study
|
[
0.982233464717865,
0.002293009078130126,
0.015473509207367897
] |
[
0.9623271822929382,
0.03307395800948143,
0.0036713476292788982,
0.0009275775519199669
] |
en
| 0.999997 |
Taiwanese PEBSC products are uniquely important from agricultural and economic development perspectives . The present study focused on Taiwanese consumers aged over 18 years with experience in using domestic PEBSC products. Of 965 respondents, those with an item variation of below 0.2 were excluded; thus, 920 valid cases remained for further analysis. This study's questionnaire is divided into five sections, namely those related to prior experience, involvement, perceived value, customer loyalty, and demographic characteristics. It comprises 37 items, which are detailed as follows: Prior experience: Two questions were developed with reference to three documents including Hsu et al. , Theopilus et al. , and Zandman‐Goddard et al. . Involvement: Seventeen questions are developed based on the four literatures including Huang , Im and Ha , Wu, Liang, and Ip , and Zaichkowsky . Perceived value: Twelve questions are developed based on four literatures including Kung, Wang, and Liang , Sheth, Newman, and Gross , Sweeney and Soutar , and Zeithaml Customer loyalty: Six questions are developed with reference to three documents including Narayandas , Srivastava and Rai , and Venkateswarlu, Ranga, and Sreedhar . Demographic characteristics: Six questions are developed including sex, age, place of residence, educational level, monthly disposable income, and skin type.
|
39754370_p22
|
39754370
|
Methods
| 1.638498 |
other
|
Study
|
[
0.06417179852724075,
0.0008933873614296317,
0.9349347949028015
] |
[
0.9930645823478699,
0.006340540945529938,
0.00033705876558087766,
0.0002578984131105244
] |
en
| 0.999996 |
The Likert scale is a common attitude measurement tool in social sciences and was used in this study. In accordance with the recommendations of Chomeya and Taherdoost , a 6‐point Likert scale was used in this study to ensure that respondents could clearly express their opinions. The scale endpoints ranged from 1 ( strongly disagree ) to 6 ( strongly agree ). The purpose of the study was clearly communicated to the respondents at the beginning of the questionnaire, and the respondents were explicitly told that the survey was anonymous and that their privacy was protected. This study was conducted on the SurveyCake online platform. The QR code linking to the questionnaire was shared on forums and online groups related skin‐care products. The survey was conducted from July 1 to August 15, 2023. All questionnaire items were single‐choice questions, and no item could be left blank, thereby ensuring that no values were missing.
|
39754370_p23
|
39754370
|
Methods
| 1.998549 |
other
|
Study
|
[
0.4641704261302948,
0.001046743942424655,
0.5347828269004822
] |
[
0.9857150912284851,
0.013740073889493942,
0.0003709888260345906,
0.00017387300613336265
] |
en
| 0.999998 |
Subsequently, confirmatory factor analysis (CFA) was conducted using Amos 25.0 to assess the factor structure of the items. Factor loadings, means, standard deviations, composite reliabilities (CRs), and average variance extracted (AVE) values were obtained. A structural model was then evaluated using the maximum likelihood method. The heterotrait–monotrait (HTMT) ratio of correlations was used to evaluate the discriminant validity between constructs. The model's goodness of fit with the hypotheses was tested in terms of χ 2 , root mean square error of approximation (RMSEA), standardized root mean squared residual (SRMR), comparative fit index (CFI), and Tucker–Lewis index (TLI) . Furthermore, standardized beta values were used to determine whether the hypotheses were supported.
|
39754370_p24
|
39754370
|
Methods
| 4.103396 |
biomedical
|
Study
|
[
0.9850472211837769,
0.0004060646751895547,
0.014546755701303482
] |
[
0.9992434978485107,
0.0004008639371022582,
0.0003232562739867717,
0.000032396223105024546
] |
en
| 0.999998 |
The descriptive statistics are reported in Table 1 .
|
39754370_p25
|
39754370
|
Descriptive Analysis
| 1.579265 |
biomedical
|
Study
|
[
0.9726673364639282,
0.005900487769395113,
0.021432120352983475
] |
[
0.9666465520858765,
0.026995696127414703,
0.005178600549697876,
0.0011791301658377051
] |
en
| 0.999997 |
In this study, maximum likelihood estimation was performed in CFA to determine the factor structures of involvement, perceived value, and customer loyalty. The analysis indicated that involvement can be divided into three factors, namely product, message, and situational involvement; perceived value can be distinguished into three factors, namely functional, emotional, and social value; and consumer loyalty can also be divided into three factors, namely repurchase intention, willingness to receive information, and willingness to pay. The results indicate a satisfactory fit in accordance with the criteria suggested by Hu and Bentler . The factor loadings of the items ranged from 0.53 to 0.88, the AVE values of the constructs ranged from 0.45 to 0.75, and the CRs of the constructs ranged from 0.61 to 0.89; these results indicated that all constructs had acceptable convergent validity (Table 2 ). In Table 2 , “these products” refer to Taiwanese PEBSC products.
|
39754370_p26
|
39754370
|
Confirmatory Factor Analysis
| 2.222197 |
other
|
Study
|
[
0.06611599773168564,
0.0007257736870087683,
0.9331583380699158
] |
[
0.9957767724990845,
0.0034368648193776608,
0.0005837626522406936,
0.00020252600370440632
] |
en
| 0.999998 |
The obtained HTMT ratios are presented in Table 3 . The recommended HTMT ratio threshold of 0.9 was used to obtain sufficient evidence of discriminant validity .
|
39754370_p27
|
39754370
|
HTMT Ratio of Correlations
| 2.302511 |
biomedical
|
Study
|
[
0.9338352084159851,
0.0010743729071691632,
0.06509039551019669
] |
[
0.9908906817436218,
0.008256598375737667,
0.0006765284924767911,
0.00017619191203266382
] |
en
| 0.999997 |
For consumer loyalty, the hypothetical mediation model achieved a good fit . With regard to repurchase intention, Figure 2 and Table 4 reveal that product and situational involvement had negative direct effects, whereas all three types of perceived value had positive direct effects. In terms of total effects, emotional value exhibited the strongest effect, followed by functional value, product involvement, social value, and situational involvement. The amount of variance explained reached 0.71.
|
39754370_p28
|
39754370
|
Structural Equation Modeling
| 1.120352 |
other
|
Study
|
[
0.008098408579826355,
0.0005268740351311862,
0.9913747906684875
] |
[
0.9315330386161804,
0.06552283465862274,
0.001638274174183607,
0.0013058746699243784
] |
en
| 0.999995 |
With regard to willingness to receive information, the results reveal that product involvement had a negative direct effect, whereas all three types of perceived value had positive direct effects. In terms of total effects, functional value had the strongest effect, followed by product involvement, situational involvement, emotional value, and social value. The amount of variance explained reached 0.51.
|
39754370_p29
|
39754370
|
Structural Equation Modeling
| 1.596898 |
other
|
Study
|
[
0.06277696043252945,
0.0009427533950656652,
0.9362803101539612
] |
[
0.9788403511047363,
0.019838988780975342,
0.0008084767614491284,
0.000512189872097224
] |
en
| 0.999996 |
With regard to willingness to pay, the results reveal that product involvement had a negative direct effect, whereas all three types of perceived value had positive direct effects; these results are similar to those obtained for willingness to receive information. In terms of total effects, functional value had the strongest effect, followed by product involvement, emotional value, situational involvement, and social value. The amount of variance explained reached 0.78.
|
39754370_p30
|
39754370
|
Structural Equation Modeling
| 1.596725 |
other
|
Study
|
[
0.04842530936002731,
0.0008538495749235153,
0.9507207870483398
] |
[
0.978890597820282,
0.01980840414762497,
0.0008104486623778939,
0.0004906023386865854
] |
en
| 0.999996 |
An independent samples t test was conducted to assess the differences induced by sex and place of residence. The results revealed that men exhibited a significantly higher willingness to pay than women (Table 5 ); the remaining results did not exhibit significant differences between respondents with different sexes and places of residence.
|
39754370_p31
|
39754370
|
Difference Analysis
| 2.159086 |
biomedical
|
Study
|
[
0.6430578827857971,
0.0014527086168527603,
0.35548943281173706
] |
[
0.9962928891181946,
0.003336680820211768,
0.0002652722178027034,
0.00010505421232664958
] |
en
| 0.999995 |
Analysis of variance (ANOVA) was performed to evaluate the effects of age, educational level, monthly disposable income, and skin type on customer loyalty. The results indicated that respondents with a postgraduate degree had significantly lower repurchase intention and willingness to receive information than those without such a degree (Table 6 ). The other results did not exhibit significant differences between respondents with different ages, educational levels, monthly disposable incomes, and skin types.
|
39754370_p32
|
39754370
|
Difference Analysis
| 1.335952 |
other
|
Study
|
[
0.028934119269251823,
0.0007576865027658641,
0.970308244228363
] |
[
0.9881207942962646,
0.010838120244443417,
0.0006191795691847801,
0.00042201628093607724
] |
en
| 0.999996 |
Table 7 reports the test results for the hypotheses proposed in this paper.
|
39754370_p33
|
39754370
|
Difference Analysis
| 1.620049 |
other
|
Study
|
[
0.48125872015953064,
0.0017256998689845204,
0.5170155763626099
] |
[
0.8172792196273804,
0.1747540831565857,
0.006664350163191557,
0.0013024118961766362
] |
en
| 0.999997 |
In the factor analysis, prior experience refers to skin‐care products causing allergies or not meeting expectations. Product involvement includes respondent beliefs that Taiwanese PEBSC products are gentle, nonirritating, moisturizing, beautifying, and suitable for sensitive skin. Message involvement refers to respondent interest in product information such as target users, skin types, usage instructions, functions, and ingredient sources. Situational involvement refers to respondents' focus on product packaging design, store decoration style, and shopping website usability. In addition, functional value refers to the novelty, claimed functions, and benefits that the products offered to respondents. Emotional value refers to the comfort and trust that the products provide to respondents. Social value refers to the products' contribution to caring for the Earth and local agriculture and their environmental benefits. Repurchase intention refers to respondents' intention to continue purchasing the products. Willingness to receive information refers to respondent interest in receiving product information from skin‐care product manufacturers or friends and relatives. Finally, willingness to pay refers to respondent tolerance for price fluctuations in these products.
|
39754370_p34
|
39754370
|
Constructs and SEM
| 2.806438 |
biomedical
|
Study
|
[
0.8253219127655029,
0.001137316576205194,
0.17354074120521545
] |
[
0.9043592810630798,
0.09331651031970978,
0.002028439659625292,
0.0002957600518129766
] |
en
| 0.999998 |
The results of SEM indicated that perceived value significantly influenced respondent loyalty to Taiwanese PEBSC products, thereby supporting the mediation model hypothesized in this study. Customer loyalty, particularly willingness to pay, was most strongly affected by functional value, followed by emotional value and social value. This finding suggests that marketing efforts for increasing customer loyalty toward Taiwanese PEBSC products should focus on providing customers with diverse and novel values.
|
39754370_p35
|
39754370
|
Constructs and SEM
| 1.106505 |
other
|
Study
|
[
0.0049337889067828655,
0.00038273248355835676,
0.9946834444999695
] |
[
0.8198248147964478,
0.17610421776771545,
0.0022654400672763586,
0.0018056306289508939
] |
en
| 0.999997 |
Emotional value had the strongest effect on repurchase intention, which indicates that emotional appeals to comfort and trust can profoundly enhance the repurchase rate of Taiwanese PEBSC products. Functional value and product involvement (mediated by perceived value) also had significant effects on repurchase intention. These constructs are related to usefulness, suggesting that the products should meet customers' expectations in the initial purchase. By contrast, social value and situational involvement had relatively weak effects on customer loyalty, which indicates that although environmental benefits, product packaging, and purchasing atmosphere have positive effects on repurchase motivation, they are not the key drivers of it. Prior experience and message involvement did not have significant effects on customer loyalty, even when the mediation by perceived value was considered. This result might be attributable to the fact that PEBSC products are still new in Taiwan and have a low market share; thus, advertisers might struggle to highlight their key selling points.
|
39754370_p36
|
39754370
|
Repurchase Intention
| 1.131371 |
other
|
Study
|
[
0.006725360173732042,
0.00042979809222742915,
0.9928448796272278
] |
[
0.8549584746360779,
0.14147810637950897,
0.001985794398933649,
0.001577681745402515
] |
en
| 0.999996 |
Functional value had the strongest effect on willingness to receive information, which indicates that novelty and benefits should be the focus of product advertising. In addition, product involvement and situational involvement had a strong influence on willingness to receive information through perceived value, suggesting that functional descriptions that meet customer needs and an appealing presentation, including attractive packaging design and store decoration, can attract customers; the description should be prominently displayed in product advertising. Emotional value and social value had minor effects on willingness to receive information, which possibly indicates that appeals related to comfort, trust, and environmental benefits should not be the focus of product advertising. Message involvement and prior experience did not have significant effects on willingness to receive information. This result might be attributable to the fact that PEBSC products are not yet popular in Taiwan or that people who are already interested in these products do not need to receive the product information.
|
39754370_p37
|
39754370
|
Willingness to Receive Information
| 1.3103 |
other
|
Study
|
[
0.01574893854558468,
0.0004232914070598781,
0.9838278293609619
] |
[
0.7467584013938904,
0.24986669421195984,
0.002099055564031005,
0.0012759091332554817
] |
en
| 0.999997 |
Functional value had the strongest effect on willingness to pay, which suggests that novelty and benefits can drive premium purchasing behavior. Moreover, product involvement (mediated by perceived value) and emotional value had significant effects on willingness to pay, indicating that functions meeting customer needs and feelings of comfort and trust can encourage premium purchasing behavior. Situational involvement (mediated by perceived value) and social value had weak effects on willingness to pay, which possibly suggests that an appealing presentation, including attractive packaging design and store decoration, and environmental appeals do not significantly encourage premium purchasing behavior. Neither prior experience nor message involvement had a significant effect on willingness to pay, even when the mediation effect of perceived value was considered. This result might be attributable to the fact that PEBSC products are not yet widespread in Taiwan, and people who are familiar with such products might not engage in premium purchasing behavior.
|
39754370_p38
|
39754370
|
Willingness to Pay
| 1.270485 |
other
|
Study
|
[
0.011970484629273415,
0.00048427245928905904,
0.9875451922416687
] |
[
0.8978855609893799,
0.09963793307542801,
0.00135497294832021,
0.0011215570848435163
] |
en
| 0.999996 |
Male respondents were more willing to pay a premium for PEBSC products than were female respondents. This result supports the conclusion of Duesterhaus et al. that men believe high‐priced products symbolize high quality and low risk and consequently exhibit higher customer loyalty compared with women. Furthermore, respondents with a postgraduate degree were less likely to repurchase and receive information about the products than were those without such a degree. This result might be attributable to the fact that highly educated consumers are more budget‐conscious than less educated consumers, obtain information in diverse and rapid ways, and tend to believe that advertising content is biased .
|
39754370_p39
|
39754370
|
Demographic Differences
| 1.209499 |
other
|
Study
|
[
0.01232966035604477,
0.0003836973919533193,
0.9872866272926331
] |
[
0.8044013977050781,
0.19268737733364105,
0.0017396050971001387,
0.0011716819135472178
] |
en
| 0.999997 |
This study contributes to the fields of cosmetics, agriculture, and marketing in several ways. First, Taiwanese PEBSC products were identified as a promising avenue for development by considering global trends, and the causes of customer loyalty were deconstructed. This unique approach lays a solid foundation for future research. Second, a prediction model mediated by customers' perceived values was constructed as a novel framework for advancing academic understanding of customer loyalty toward skin‐care products. This model also serves as an empirical platform that can adapt to changes in plants and demographic variables in the future. Third, given Taiwan's considerable agricultural polarization, advanced food processing techniques, and external political threats, this study highlights the effects of local people's involvement on perceived value and customer loyalty for PEBSC products. The insights from this study can guide the development of relevant domestic policies, regulations, measures, and strategies for the agricultural and cosmetic industries.
|
39754370_p40
|
39754370
|
Contributions and Suggestions
| 2.319923 |
other
|
Study
|
[
0.11717872321605682,
0.0005562478327192366,
0.8822649717330933
] |
[
0.9795446991920471,
0.01896490715444088,
0.0012177854077890515,
0.0002725707308854908
] |
en
| 0.999998 |
Three recommendations are proposed for the Taiwanese government on the basis of the findings of this study. First, to ensure that Taiwanese PEBSC products remain innovative and diverse, companies should use a wider range of botanical ingredients. These ingredients, which can be derived from agricultural by‐products such as peels, seeds, and leaves, can be used to extract bioactive substances, fibers, and enzymes for product manufacturing. The government should continue to invest in the industrialization of agricultural science and technology, strengthen research and development for emerging ingredients, and enhance related production processes. Second, the safety of these skin‐care products can be addressed from two perspectives: raw materials and manufacturing processes. The presence of pesticide residues on crops is a common agricultural problem. Guiding farmers to use pesticides economically, rationally, and safely is a critical task for the government. Quality and hygiene depend on process management. Therefore, promoting compliance with best‐practice industrial standards for cosmetics at manufacturing sites can effectively improve process management and ensure consumer safety. Third, consumers view claims that a product is organic and natural as indicators of environmental friendliness, which can increase their willingness to purchase and pay a premium. To prevent false claims from misleading consumers, the government must enforce suitable regulations for organic and natural claims to protect consumers and legitimate businesses.
|
39754370_p41
|
39754370
|
Contributions and Suggestions
| 2.956177 |
biomedical
|
Other
|
[
0.5307432413101196,
0.001318325288593769,
0.4679383635520935
] |
[
0.09366727620363235,
0.9010942578315735,
0.004947487264871597,
0.00029103353153914213
] |
en
| 0.999997 |
Moreover, two strategies for domestic agriculture are suggested. First, local farmers can collaborate to inventory their agricultural by‐products (including goodwill products) that require appropriate disposal. They can partner with nearby agricultural research institutes to identify items and ingredients with high extraction value. Through systematic coordination with local cooperatives, marketable products (such as skin‐care products or healthy foods) can be jointly developed. Second, farmers must understand that the circular economy is an effective strategy for preventing waste and reusing or recycling natural resources and agricultural by‐products. They should also focus on the rational and safe use of pesticides as a foundation for promoting the circular economy because pesticide residues can lead to unsellable agricultural products, cause safety issues, and affect the subsequent value‐added applications of agricultural by‐products.
|
39754370_p42
|
39754370
|
Contributions and Suggestions
| 1.225694 |
other
|
Other
|
[
0.008142123930156231,
0.0005700494511984289,
0.991287887096405
] |
[
0.004334526136517525,
0.9947172999382019,
0.0005912625347264111,
0.00035688362549990416
] |
en
| 0.999996 |
Four strategies are also suggested for the cosmetic industry. First, when marketing Taiwanese PEBSC products, companies can highlight aspects such as gentleness, nonirritating nature, moisturizing ability, skin‐beautifying ability, and antiaging effect of these products to attract consumer attention. Emphasizing the novelty, diversity, and environmental friendliness of the natural, safe plant‐extracted ingredients can further enhance perceived value. Second, although consumers consider applicable targets, skin types, usage instructions, functions, and ingredient sources, establishing a positive user experience can be more impactful and credible than simply providing information. Experiential marketing is recommended to engage target audiences more effectively and increase their interest in the product information. Third, visual presentation is crucial for piquing people's interest. Excellent design can enhance a product's value. Companies can influence consumer perceptions regarding products directly and quickly through suitable packaging design or store decoration. Fourth, different marketing plans should be developed for different target groups. For example, high‐priced, high‐quality Taiwanese PEBSC products can be developed for men, appealing packages with diverse products can be developed for women, and authoritative product information can be used to win the trust of highly educated consumers.
|
39754370_p43
|
39754370
|
Contributions and Suggestions
| 2.18381 |
other
|
Other
|
[
0.16174589097499847,
0.0013997547794133425,
0.8368543386459351
] |
[
0.013523820787668228,
0.979468047618866,
0.006661700084805489,
0.00034648572909645736
] |
en
| 0.999994 |
This study has three limitations. First, skin‐care products in different categories, such as essences, moisturizers, hand creams, sunscreens, and face masks have different functions. Consumption behavior may vary depending on product attributes. However, this study did not conduct a detailed classification of product attributes, which might have biased the results. Second, only two questionnaire items evaluated prior experience, which might be insufficient for comprehensively measuring this construct. In addition, other variables affecting customer loyalty for PEBSC products can be investigated in future research. Third, sex significantly affects premium consumption, and education level significantly affects purchase intention and willingness to receive information. These results indicate that moderating effects might exist in the developed research model.
|
39754370_p44
|
39754370
|
Contributions and Suggestions
| 2.809472 |
biomedical
|
Study
|
[
0.6986997127532959,
0.0015225481474772096,
0.2997777760028839
] |
[
0.9984001517295837,
0.0012672790326178074,
0.00024196297454182059,
0.00009058999421540648
] |
en
| 0.999995 |
Future research should consider the following directions to address the aforementioned limitations. First, when consumer behavior research is conducted regarding Taiwanese PEBSC products, product type can be investigated in more detail. Moreover, specific plants (or plant families) can be studied separately, thereby reducing the potential bias caused in the results by differences in plant attributes. Second, prior experience can include various aspects, such as beauty, emotion, enjoyment, and relationship. Relevant questionnaire items can be developed to gain a deeper understanding of the relationship between prior experience and customer loyalty. Additional variables from different academic theories can also be included to supplement the results of the present study. Third, sex and education level can be considered moderating variables and included in the SEM model to gain a deeper understanding of the effects of demographic characteristics on consumption behavior.
|
39754370_p45
|
39754370
|
Contributions and Suggestions
| 1.573226 |
other
|
Study
|
[
0.021305026486516,
0.00029291558894328773,
0.9784020781517029
] |
[
0.5240234136581421,
0.4715133607387543,
0.0035415594466030598,
0.0009216595208272338
] |
en
| 0.999995 |
The authors confirm that they obtained oral informed consent from participants.
|
39754370_p46
|
39754370
|
Consent
| 1.03959 |
biomedical
|
Other
|
[
0.8084651231765747,
0.007277424912899733,
0.18425753712654114
] |
[
0.02607392705976963,
0.970430850982666,
0.0012795126531273127,
0.0022156836930662394
] |
en
| 0.999995 |
The authors declare no conflicts of interest.
|
39754370_p47
|
39754370
|
Conflicts of Interest
| 0.866279 |
other
|
Other
|
[
0.0576341487467289,
0.002869163639843464,
0.9394966959953308
] |
[
0.01143918838351965,
0.9847283959388733,
0.002433478832244873,
0.001398958032950759
] |
en
| 0.999996 |
Recurrent nonmetastatic hormone-sensitive prostate cancer (nmHSPC) is defined by increasing prostate-specific antigen (PSA) levels while naive or responsive to androgen deprivation therapy (ADT), and without evidence of metastasis on conventional imaging. In the setting of biochemical failure after definitive primary therapy, androgen receptor pathway inhibitors have shown clinical utility in both metastatic and chemotherapy-naive disease. 1 , 2 , 3 The EMBARK (A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy) trial is a randomized, phase 3 study that evaluated the effect of enzalutamide plus ADT and enzalutamide monotherapy on patients with high-risk nmHSPC with increasing PSA concentrations after definitive therapy. 4 Patients who received either enzalutamide plus ADT or enzalutamide monotherapy showed a significant increase in metastasis-free survival compared with those who received ADT plus placebo. 5 Patients who qualified for the EMBARK trial were classified through negative results on conventional imaging, which underdetects metastatic disease in comparison with prostate-specific membrane antigen–positron emission tomographic (PSMA-PET) imaging. 6 In this study, we aimed to describe the PSMA-PET findings in a cohort of patients from 4 prospective studies who met the inclusion criteria for the EMBARK trial.
|
39752157_p0
|
39752157
|
Introduction
| 4.168972 |
biomedical
|
Study
|
[
0.9925152659416199,
0.007113044150173664,
0.00037160675856284797
] |
[
0.988781750202179,
0.009628080762922764,
0.0009238581988029182,
0.0006662171799689531
] |
en
| 0.999998 |
This retrospective cross-sectional study was approved by the University of California, Los Angeles (UCLA) institutional review board and followed the principles outlined in the Declaration of Helsinki. 7 We screened 2002 patients from 4 prospective study databases who were enrolled at UCLA from September 15, 2016, to September 27, 2021, to derive a cohort of patients with high-risk nmHSPC who underwent PSMA-PET imaging for increasing PSA levels. Patients provided oral and written informed consent to take part in these studies. Key inclusion criteria to reflect the EMBARK trial were increasing PSA level above 1.0 ng/mL (after radical prostatectomy [RP] and salvage radiotherapy [SRT]) or 2.0 ng/mL above the nadir value (after definitive radiotherapy [dRT]) (to convert to micrograms per liter, multiply by 1.0), PSA doubling time of 9 months or less, and serum testosterone level of 150 ng/dL or more . Exclusion criteria similarly followed the EMBARK trial, defined as distant metastatic (M1) disease detected by any conventional imaging, prior hormonal neoadjuvant or adjuvant therapy at the time of dRT for more than 36 months, more than 6 months of short-course ADT with less than 9 months of washout before randomization, or advanced systemic therapy for prostate cancer. Clinical characteristics, including primary therapy, initial PSA, biopsy Gleason score (describing a composite of histopathologic patterns with 1 = small, uniform glands; 2 = more stroma between glands; 3 = distinctly infiltrative margins; 4 = irregular masses of neoplastic glands; and 5 = only occasional gland formation; the biopsy Gleason score is the sum of the most predominant and the worst patterns and ranges from 2 to 9, with 2 being associated with the best and 9 with the worst prognosis), RP pathologic findings, ADT history, most recent PSA levels, and PSA doubling times, were collected from electronic medical records and existing databases from the previously listed prospective clinical trials. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for cross-sectional studies.
|
39752157_p1
|
39752157
|
Study Design, Setting, and Participants
| 4.208075 |
biomedical
|
Study
|
[
0.9983574748039246,
0.0014198067365214229,
0.0002226412034360692
] |
[
0.998547375202179,
0.0007023055222816765,
0.0005585412145592272,
0.00019173980399500579
] |
en
| 0.999997 |
All patients underwent 68 Ga-PSMA-11 PET/computed tomography (CT) at UCLA. Imaging acquisition was performed as previously described. 8 After injection of a median of 5.0 mCi of 68 Ga-PSMA-11, PET images were recorded at a median uptake time of 61 minutes (IQR, 57-68 minutes). A total of 178 of 182 patients (98%) received a CT contrast agent. PSMA PET/CT images were interpreted in consensus by a board-certified nuclear medicine physician and a board-certified radiologist with access to all patient medical information. PSMA PET/CT findings (Prostate Cancer Molecular Imaging Standardized Evaluation [PROMISE] miTNM stage, lesion location, number of lesions) were collected from the clinical imaging reports and existing databases from the previously listed prospective clinical trials.
|
39752157_p2
|
39752157
|
PSMA-PET/Computed Tomography Scan
| 4.091465 |
biomedical
|
Study
|
[
0.9889698028564453,
0.010715393349528313,
0.00031481319456361234
] |
[
0.9957213401794434,
0.003091842867434025,
0.0004931834409944713,
0.0006935796118341386
] |
en
| 0.999997 |
Statistical analysis was performed from January 2023 to July 2024. Patient baseline characteristics and scan findings are provided with summary statistics. Comparison of populations was used to evaluate the relative distribution (in percentages) of disease within groups. The Pearson χ 2 test was used to assess the association between primary treatment groups and PSMA-PET–based staging categories as well as to compare the distributions in the patient cohort of this analysis with the original EMBARK study population. All statistical tests were 2-sided, and a threshold of P < .05 was considered to be statistically significant for rejection of the null hypothesis. Statistical analyses were performed using IBM SPSS Statistics, version 29 (IBM Corp).
|
39752157_p3
|
39752157
|
Statistical Analysis
| 4.006129 |
biomedical
|
Study
|
[
0.9988184571266174,
0.0009526284411549568,
0.00022885954240337014
] |
[
0.9987922310829163,
0.0008722040220163763,
0.00021556571300607175,
0.00012004127347609028
] |
en
| 0.999997 |
From the cohort of 2002 patients screened, 1033 were excluded: 176 at initial staging, 385 with castration-resistant disease, 137 with known metastatic disease, 102 who received nonstandard initial therapy (cryotherapy or high-intensity focused ultrasound), and 233 with missing data required for analysis. Of the remaining 969 patients, 322 had a PSA doubling time of more than 9 months, 398 had increasing PSA values less than 1.0 ng/mL (after RP and SRT) or less than 2 ng/mL above the nadir value (after dRT), and 67 had recent ADT or a washout period of 6 months or fewer; these patients were also excluded .
|
39752157_p4
|
39752157
|
Patient Population
| 4.11713 |
biomedical
|
Study
|
[
0.9875475168228149,
0.011963099241256714,
0.0004894202575087547
] |
[
0.9954591989517212,
0.002945797750726342,
0.0009052787208929658,
0.0006897418643347919
] |
en
| 0.999998 |
A total of 182 patients (median age at PET/CT scan, 69 years [IQR, 64-73 years]) with nmHSPC who met the EMBARK inclusion criteria were included in the analysis: 91 (50%) underwent RP, 39 (21%) received dRT, and 52 (29%) received SRT after RP.
|
39752157_p5
|
39752157
|
Patient Population
| 3.634509 |
biomedical
|
Study
|
[
0.9513694643974304,
0.04761933162808418,
0.001011135522276163
] |
[
0.988692045211792,
0.008956452831625938,
0.0004350132658146322,
0.0019165296107530594
] |
en
| 0.999997 |
The median time from primary therapy to PSMA-PET was 28 months (IQR, 8-62 months). The median time from primary therapy to biochemical recurrence (BCR) was 60 months (IQR, 19-250 months). Median prescan PSA levels were 2.4 ng/mL (IQR, 1.4-4.8 ng/mL) after RP, 6.9 ng/mL (IQR, 3.5-18.5 ng/mL) after dRT, 2.6 ng/mL (IQR, 1.6-5.2 ng/mL) after RP and SRT, and 2.8 ng/mL (IQR, 1.7-6.6 ng/mL) overall ( Table 1 ). The median PSA doubling times were 3 months (IQR, 1.9-5.4 months) after RP, 3.3 months (IQR, 2.2-4.9 months) after dRT, 4 months (IQR, 2.6-5.5 months) after RP and SRT, and 3.6 months (IQR, 1.9-5.4 months) overall. The Gleason scores at diagnosis were 8 or higher for 35 of 91 patients (38%) after RP, 18 of 39 patients (46%) after dRT, 13 of 52 patients (25%) after RP and SRT, and 66 of 182 patients (36%) patients overall.
|
39752157_p6
|
39752157
|
Patient Population
| 4.166474 |
biomedical
|
Study
|
[
0.9909757971763611,
0.00870771799236536,
0.00031653090263716877
] |
[
0.9968999624252319,
0.0017973665380850434,
0.0006822384893894196,
0.0006204356905072927
] |
en
| 0.999997 |
Compared with the original EMBARK study cohort of 1068 patients at 244 sites, 5 we included significantly fewer patients treated with combined RP and SRT (29% vs 49%; P < .001) and significantly more patients treated with RP alone (50% vs 25%; P < .001). Patients in our study had a lower median PSA doubling time compared with the EMBARK study population (3.6 vs 4.9 months) and a lower median serum PSA level at enrollment (2.8 vs 5.2 ng/mL; patient-individual PSA-related values of the EMBARK trial were not available for statistical comparison).
|
39752157_p7
|
39752157
|
Patient Population
| 4.139457 |
biomedical
|
Study
|
[
0.9966050386428833,
0.003067879006266594,
0.0003270385495852679
] |
[
0.9977874755859375,
0.001653884188272059,
0.00035285059129819274,
0.0002057964011328295
] |
en
| 0.999996 |
Table 2 provides an overview of PSMA-PET results. The metastatic burden classification by PSMA-PET is shown in Table 3 . The disease distribution by primary treatment as depicted by PSMA-PET is shown in Figure 2 . PSMA-PET findings were positive in 80% of patients (73 of 91) after RP, 92% of patients (36 of 39) after dRT, 85% of patients (44 of 52) after RP and SRT, and 84% of patients (153 of 182) overall. PSMA-PET–detected disease was localized only to the prostate fossa (mi T+N0M0) in 7% of patients (6 of 91) after RP, 23% of patients (9 of 39) after dRT, 2% of patients (1 of 52) after RP and SRT, and 9% of patients (16 of 182) overall, and T+ status was significantly more frequent in the dRT group (23% [9 of 39] vs 7% in the RP group [6 of 91], 2% in the RP and SRT group [1 of 52], and 9% overall [16 of 182]; P < .001). PSMA-PET detected pelvic nodal disease (miTxN1M0) in 40% of patients (36 of 91) after RP, 13% of patients (5 of 39) after dRT, 23% of patients (12 of 52) after RP and SRT, and 29% of patients (53 of 182) overall. PSMA-PET detected any distant metastatic disease (miTxNxM1) in 34% of patients (31 of 91) after RP, 56% of patients (22 of 39) after dRT, 60% of patients (31 of 52) after RP and SRT, and 46% of patients (84 of 182) overall, and M1 status was significantly less frequent in the RP group (34% [31 of 91] vs 56% in the dRT group [22 of 39], 60% in the RP and SRT group [31 of 52], and 46% overall [84 of 182]; P = .005). PSMA-PET detected metastatic nodal only disease (N1 and/or M1a) in 44% of patients (40 of 91) after RP, 15% of patients (6 of 39) after dRT, 44% of patients (23 of 52) after RP and SRT, and 38% of patients (69 of 182) overall and osseous disease (M1b) in 18% of patients (16 of 91) after RP, 36% of patients (14 of 39) after dRT, 31% of patients (16 of 52) after RP and SRT, and 25% of patients (46 of 182) overall. Polymetastatic disease (≥5 lesions) was found in 19% of patients (17 of 91) after RP, 36% of patients (14 of 39) after dRT, 23% of patients (12 of 52) after RP and SRT, and 24% of patients (43 of 182) overall.
|
39752157_p8
|
39752157
|
PSMA-PET Findings
| 4.265196 |
biomedical
|
Study
|
[
0.9974086880683899,
0.002307073911651969,
0.000284254492726177
] |
[
0.9983839988708496,
0.0007020245539024472,
0.000706654682289809,
0.00020737758313771337
] |
en
| 0.999997 |
In this study, we aimed to contextualize how PSMA-PET may influence the interpretation of the EMBARK trial results. 5 In this retrospective study of 182 patients with nmHSPC eligible for the EMBARK trial (based on conventional imaging), we demonstrated that PSMA-PET detected metastatic disease in 46% of all patients, suggesting that a significant number of patients have disease that is understaged by conventional imaging.
|
39752157_p9
|
39752157
|
Discussion
| 4.093102 |
biomedical
|
Study
|
[
0.997972309589386,
0.0017858442151919007,
0.0002418195945210755
] |
[
0.998838484287262,
0.0006231926381587982,
0.0003590811393223703,
0.0001792059774743393
] |
en
| 0.999997 |
The EMBARK trial demonstrated a significant survival benefit. Numerous studies have demonstrated the association of PSMA-PET findings with management decisions across multiple disease stages; however, there are limited data to support the benefit of management alterations. 9 , 10 , 11 The ARCHES (A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy [ADT] Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer [mHSPC]) trial is a randomized phase 3 clinical trial of enzalutamide that reported outcomes similar to EMBARK in the metastatic hormone-sensitive prostate cancer setting. 12 The trial stratified patients based on disease burden using conventional imaging and demonstrated the potential to use enzalutamide in the treatment of patients with low-volume disease. 12 Additional consideration should be given to the eligibility of these patients for metastasis-directed therapy as an adjunct or predecessor to systemic androgen receptor pathway inhibitor therapy. The EMBARK trial selected patients meeting high-risk criteria by the European Association of Urology (EAU) BCR risk grouping, given a mandatory PSA doubling time of less than 9 months. 13 The EAU BCR risk groupings were derived from patient cohorts evaluated using conventional imaging techniques. 14 Integrating the EAU risk grouping with PSMA-PET, in 2023, Leplat et al 15 reported significantly higher positivity rates in patients with high-risk BCR (59% vs 36%; P < .001), with 49% of cases with metastatic disease vs 31% in patients with low-risk BCR, all of which were oligometastatic in patients with low-risk BCR. In 2024, Scharl et al 16 reported PSMA-guided SRT outcomes based on EAU BCR groupings, with a 3-year metastasis-free survival of 94.4% in patients with low-risk BCR vs 87.6% in patients with high-risk BCR ( P = .005). Conversely, an analysis by Dong et al 17 suggested that BCR risk groups define patients who benefit most from a PSMA-PET/CT scan in the case of BCR. In this context, a potential clinical benefit associated with PSMA-PET could be the identification of patients to be safely treated with local radiotherapy or stereotactic body radiotherapy, including a potential curative perspective in some cases. The implications of the EMBARK trial regarding the choice for metastasis-directed therapy or SRT vs enzalutamide in patients with increasing PSA levels are further discussed in a comment by Einstein et al, 18 enlightening the approaches of metastasis-free survival vs treatment-free survival.
|
39752157_p10
|
39752157
|
Discussion
| 4.291477 |
biomedical
|
Study
|
[
0.9965628981590271,
0.003032993758097291,
0.00040419382276013494
] |
[
0.9516295790672302,
0.006007601507008076,
0.04155009984970093,
0.0008127327309921384
] |
en
| 0.999995 |
In addition, PSMA-PET/CT may lead to downstaging compared with conventional imaging. In a study including 167 patients across disease stages, bone scans were shown to have a high rate of false-positive results compared with PSMA-PET. 19 Another retrospective study at 4 international sites comparing high-volume and low-volume disease as defined by the CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) criteria with PSMA-PET–based disease load similarly found that stage migration from conventional imaging to PSMA-PET occurs both by upstaging and by downstaging in patients with metastatic hormone-sensitive prostate cancer. 20 , 21 The actual significance of such upstaging or stage migration on treatment outcomes and appropriate treatment management is difficult to assess and not yet known.
|
39752157_p11
|
39752157
|
Discussion
| 4.045066 |
biomedical
|
Study
|
[
0.9993901252746582,
0.0003972045669797808,
0.00021266892144922167
] |
[
0.9876656532287598,
0.0004984652623534203,
0.011703478172421455,
0.00013232896162662655
] |
en
| 0.999996 |
Prospective studies investigating the association between PSMA-defined risk groups and patient outcomes are warranted. PSMA-PET was highly associated with response to SRT and was associated with 3-year freedom from progression more accurately than clinical factors such as PSA level or Gleason score. 22 In the ORIOLE (Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer) phase 2 randomized study, radiotherapy coverage of PSMA-positive disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). 23 In a large cohort of 1612 patients with prostate cancer including all disease stages, Karpinski et al 24 reported that PSMA-PET standardized PROMISE criteria were accurate for estimation of overall survival, outperforming major established clinical risk tools. Efforts to prospectively analyze the benefit associated with PSMA-PET vs traditional imaging include an ongoing prospective multicenter study that plans to include 448 patients, randomized 1:1 to either traditional imaging or PSMA-PET/CT. The study aim is to assess whether PSMA-PET/CT increases progression-free survival and quality of life.
|
39752157_p12
|
39752157
|
Discussion
| 4.106484 |
biomedical
|
Study
|
[
0.9990591406822205,
0.0006940210005268455,
0.0002469395403750241
] |
[
0.9940164089202881,
0.0010218160459771752,
0.004819255322217941,
0.0001425272785127163
] |
en
| 0.999997 |
The analysis performed in this study has limitations in its design and comparability with the EMBARK trial. Our analysis included significantly fewer patients undergoing SRT and more patients undergoing RP alone compared with the EMBARK trial. In our study, the SRT group most frequently showed metastatic disease according to results of PSMA-PET/CT: TxNxM1 in 60% of cases in the SRT group. Thus, our results may underestimate the actual proportion of patients with PSMA M1 disease in the EMBARK trial.
|
39752157_p13
|
39752157
|
Limitations
| 4.006949 |
biomedical
|
Study
|
[
0.9987481832504272,
0.0009909998625516891,
0.00026069546584039927
] |
[
0.9989253878593445,
0.0007409569225274026,
0.0002187518257414922,
0.00011492681369418278
] |
en
| 0.999996 |
Furthermore, the lower median serum PSA level at enrollment translates to a lower disease burden in our cohort, indicating that our results may further underestimate the actual disease burden of patients included in the EMBARK trial, as PSMA-PET detection rates significantly increase in association with the PSA level. 25 This was a cross-sectional analysis with no longitudinal follow-up. Further studies are needed to understand the association of PSMA-PET upstaging with clinical outcomes. The retrospective nature of this study precluded systematic baseline imaging as would be standard for true clinical trial enrollment.
|
39752157_p14
|
39752157
|
Limitations
| 3.994214 |
biomedical
|
Study
|
[
0.9990548491477966,
0.0007594354683533311,
0.00018567935330793262
] |
[
0.9990164041519165,
0.0005089837941341102,
0.00035188623587600887,
0.00012267104466445744
] |
en
| 0.999998 |
Finally, even if PSMA-PET is the imaging modality with the best diagnostic accuracy for prostate cancer staging, it can lead to false-positive metastasis findings (positive predictive value in BCR, 0.84% 25 ), especially in the bone. Here, we cannot estimate the rate of false-positive findings nor its association with patient outcomes.
|
39752157_p15
|
39752157
|
Limitations
| 3.729713 |
biomedical
|
Study
|
[
0.9994219541549683,
0.00034285589936189353,
0.0002351542643737048
] |
[
0.9930474162101746,
0.0038110946770757437,
0.002915410790592432,
0.00022612289467360824
] |
en
| 0.999997 |
In this cross-sectional study of patients with high-risk nmHSPC and PSA doubling time of less than 9 months who were eligible for the EMBARK trial, PSMA-PET findings were positive in 84% of patients, detected M1 disease in 46% of patients, and found polymetastatic disease (≥5 lesions) in 24% of patients. PSMA-PET provides novel additional risk stratification for patients with high-risk nmHSPC without distant metastasis based on conventional imaging. Further studies are needed to assess its potential independent prognostic value and its use for treatment guidance. Integration of PSMA-PET in major industry-sponsored clinical trials for secondary end points analyses is warranted.
|
39752157_p16
|
39752157
|
Conclusions
| 4.133129 |
biomedical
|
Study
|
[
0.9977510571479797,
0.0020612929947674274,
0.00018765653658192605
] |
[
0.9977948665618896,
0.001295876456424594,
0.0006528830854222178,
0.0002563835878390819
] |
en
| 0.999996 |
Out-of-hospital-cardiac arrest (OHCA) is a significant health concern with approximately 275,000 annual cases in Europe and 420,000 in the United States. 1 Immediate recognition of cardiac arrest, initiation of cardiopulmonary resuscitation (CPR) and early defibrillation are key factors to improve survival. 2 However, bystander CPR are only reported on average in 58 % (range 13 % to 83 %) of episodes. 2 In addition, there is considerable variation in the quality of bystander CPR, with only a minority demonstrating high quality CPR. 3 Simulation studies have shown that video assisted CPR (V-CPR) may improve cardiac arrest recognition, improve the quality of basic CPR and that it can be performed in a real-life setting. 4 , 5 In OHCA, clinical studies show promising results of V-CPR on CPR quality, return-of-spontaneous-circulation (ROSC) rates and survival to hospital discharge. 6 , 7 , 8 , 9 However, there are considerable knowledge gaps regarding possible benefits of applying this technology in patients with cardiac arrest. 10 We present a case with witnessed OHCA, where dispatcher V-CPR was initiated early and considered essential to provide a tailored approach to a complex OHCA.
|
PMC11699598_p0
|
PMC11699598
|
Introduction
| 4.166028 |
clinical
|
Clinical case
|
[
0.35613080859184265,
0.6411226987838745,
0.002746491227298975
] |
[
0.0364178791642189,
0.028666028752923012,
0.008731850422918797,
0.9261842370033264
] |
en
| 0.999997 |
A 58-year-old male with known paroxysmal atrial fibrillation (AF) sustained an OHCA at 9:47 a.m. while changing tires on his jacked-up car together with his son. An emergency call was received at 9:48 a.m. The patient was reported unconscious with agonal respiration and no CPR was performed. Guided by the Norwegian Index for Medical Emergency Assistance, a stepwise tool for decision-making and to guide callers in emergency medical situations by the Emergency Medical Coordination Centre (EMCC), the patient was identified as unresponsive and not breathing normally. 11 The medical dispatcher immediately instructed the two laypersons on-scene to perform CPR, which they did without hesitation. None had previous CPR experience. Emergency medical services (EMS) and the on-call general practitioner were also immediately dispatched. No other emergency resources (e.g. volunteer first responders) were available during the incident. Since there were two persons on-scene, the medical dispatcher decided to initiate a video call (VC) to better guide the ongoing layperson CPR. The video transmission was initiated two minutes after the emergency call and showed high-quality chest compressions, and a patient with apparent spontaneous respiration and limb movements. After three minutes, they paused compressions according to Norwegian CPR guidelines. 12 The medical dispatcher then observed that the patient‘s breathing pattern changed into agonal respiration. When compressions were continued, the respiration was again considered normal. Because the breathing pattern was deemed normal due to well performed chest compressions, the medical dispatcher decided not to instruct in mouth-to-mouth ventilations according to standard CPR guidelines. The patient therefore received compression-only CPR until arrival of EMS at 10.21 am, 33 min after start of bystander CPR, at which point V-CPR was discontinued. The two laypersons alternated in performing CPR during the whole incident prior to EMS arrival.
|
PMC11699598_p1
|
PMC11699598
|
Case Description
| 3.772897 |
clinical
|
Clinical case
|
[
0.03768649697303772,
0.9582487344741821,
0.004064769484102726
] |
[
0.008062503300607204,
0.01464895810931921,
0.005135905928909779,
0.9721526503562927
] |
en
| 0.999997 |
On EMS arrival, the patient was still in cardiac arrest and presented with ventricular fibrillation (VF). A direct current (DC) defibrillation with 200 Joule was delivered by EMS personnel before they continued CPR. The patient obtained ROSC at 10:23 am. However, the ROSC only lasted for 30–40 s, and the patient resumed to VF. Another two DC 200 J defibrillations were delivered, but the patient remained with VF. A physician-staffed air ambulance helicopter arrived on-scene at 10:30 am. With ongoing CPR with the patient in VF, the patient showed signs of life with head and limb movements, verbal sounds and a normal respiration pattern with a respiration rate of 12 breaths per minute during chest-compressions. A fourth DC 200 Joule defibrillation was delivered which resulted in sustained ROSC with AF rhythm at 10:33, 46 min after the time of cardiac arrest. Before transportation a rapid sequence induction with intravenous (iv) analgesia (fentanyl 0.2 mg iv), sedation (ketamine 75 mg iv), muscle relaxation (rocuronium 50 mg iv) and endotracheal intubation was performed without any complications. An arterial line was inserted and an intravenous ketamine infusion (1.5 mg/kg/hour) was started for maintenance of sedation during transport to hospital. The patient was hemodynamically stable in-flight with a blood pressure of 150/80 and a pulse rate of 70–90/min, except a brief period of ventricular tachycardia during take-off from the scene. A dose of intravenous amiodarone 100 mg was administered, and the patient converted to AF. The measured oxygen saturation level was 98 % and the patient was normothermic. Transport to the nearest university hospital was uneventful and he was admitted to hospital at 11:59 a.m.
|
PMC11699598_p2
|
PMC11699598
|
Case Description
| 3.684611 |
clinical
|
Clinical case
|
[
0.026439858600497246,
0.9696873426437378,
0.0038727682549506426
] |
[
0.005772227421402931,
0.013164939358830452,
0.00569886714220047,
0.9753639698028564
] |
en
| 0.999997 |
The first arterial blood gas showed a metabolic acidosis with pH 7.20, pCO2 5.7 kPa, pO2 12.2 kPa, base excess −11.2 mmol/L, lactate 5.5 mmol/L, bicarbonate 17 mmol/L and glucose 13.6 mmol/L. Other values were normal. A percutaneous coronary intervention was performed with a successful revascularisation and stent implementation of partly occluded left anterior descending and circumflex arteries. A one-chamber cardioverter-defibrillator was implanted and he was discharged to a local hospital for follow-up on day 11, with full neurological recovery.
|
PMC11699598_p3
|
PMC11699598
|
Case Description
| 3.75312 |
clinical
|
Clinical case
|
[
0.07935022562742233,
0.9173555970191956,
0.0032941503450274467
] |
[
0.0062730032950639725,
0.011012709699571133,
0.003127487376332283,
0.9795868992805481
] |
en
| 0.999997 |
Access to timely EMS response in time-critical situations (e.g. cardiac arrest) is a vital factor to improve patient outcome. 13 The EMS response time in this case was 33 min, which is often the case in sparsely populated areas, such as rural Norway. 14 However, the massive development of smartphone technology during the last two decades has opened new telemedicine possibilities in modern healthcare. 15 The use of VC to assist callers and EMS has the potential to compensate for longer response and travel times. However, despite considerable interest in this technological development, the evidence of effect on patient survival and outcome in real-life OHCA is limited as the specific effect of V-CPR has been difficult to isolate. Other promising technological developments, such as the use of drones carrying defibrillators in OHCA, have shown the potential for increased access to advanced devices and additional decision-making, especially in rural areas. 16 , 17 However, like V-CPR, there is a need for further testing in real-life situations to evaluate efficiency and how these interventions impact final outcome. 16 , 17 A recent meta -analysis found that V-CPR can improve bystander CPR during simulated cases, but that the process is substantially affected by poor video signals and lack of guidance procedures. 18 Several studies have found improvements in specific items of the CPR process, with better compression rates and hand placement. 10 , 5 , 6 , 7 In our opinion, the main effect of V-CPR in this case was a more tailored approach and thorough guidance of laypersons without previous CPR experience in a complex setting with long-lasting CPR without back-up of present EMS, resulting in high-quality CPR, CPR induced consciousness (CPRIC) and a good neurological outcome.
|
PMC11699598_p4
|
PMC11699598
|
Discussion
| 4.196712 |
biomedical
|
Study
|
[
0.9477912783622742,
0.05172973871231079,
0.0004790016100741923
] |
[
0.9137605428695679,
0.023556530475616455,
0.024347230792045593,
0.0383356474339962
] |
en
| 0.999996 |
VCs were introduced in 2020 in Norwegian EMCCs for the use at the medical dispatcher’s discretion, in order to increase dispatcher situational awareness and improve the quality of care given by lay persons. 19 Currently, no specific guidelines exist on how VC can be used in the most appropriate way. The solution used in this case was developed by the Norwegian Air Ambulance Foundation and implemented in EMCC nationally in collaboration with the Norwegian Directorate of Health in 2020. 20 The EMCC sends a link to the caller’s mobile phone after approval by the caller, and the video link allows the medical dispatcher to use the available mobile phone camera. 20 , 21 Preliminary evaluations pertaining to general use have described high user-friendliness and that the medical dispatcher’s perception of patient’s acuity was affected in about half of the cases. 19 We strongly believe that video assistance by trained medical personnel has future unsolved potential. However, it is important to recognize the need for 1) clear guidance protocols 2) training in video-assisted dispatch and 3) training in the ability to instruct lay rescuers in psychological distress. It is also important to keep in mind, that the availability of live video transmission from scenes may expose the EMCC dispatchers to unpleasant visual impressions. 22 .
|
PMC11699598_p5
|
PMC11699598
|
Discussion
| 3.598329 |
biomedical
|
Other
|
[
0.8443105816841125,
0.11823952198028564,
0.037449926137924194
] |
[
0.24070532619953156,
0.7489057183265686,
0.004416997544467449,
0.005971986334770918
] |
en
| 0.999997 |
Apparent signs of life (i.e. breathing and head/limb movements) were observed in this case during compressions by the laypersons and after arrival of EMS personnel. This situation added extra complexity, which potentially could have affected the decision to continue or stop ongoing CPR. In case reports and a systematic review describing the phenomena, the observation of breathing efforts has been inconsistently reported. 23 , 24 Agonal gasps or breathing efforts also may be present in patients with cardiac arrest not receiving CPR, so this sign may be less sensitive on CPRIC than movements. Increasing number of CPRIC events are reported, most likely due to a combined effect of community CPR responder programs, improved CPR quality and increased focus on the chain of survival. 25 A noteworthy point is that in a prospective study focusing on cognitive experiences in cardiac arrest survivors, only 2 % of patients retrieved visual or auditory awareness following their incident and no patients remembered any experience of pain. 26 In the described case, the patient could not recall any memory of the incident.
|
PMC11699598_p6
|
PMC11699598
|
Discussion
| 4.200608 |
biomedical
|
Study
|
[
0.9094264507293701,
0.09007115662097931,
0.000502389797475189
] |
[
0.6910701990127563,
0.04443003609776497,
0.021442396566271782,
0.24305738508701324
] |
en
| 0.999995 |
The case represents a complex cardiac arrest with long-lasting CPR, signs of life and no previous CPR experience in lay persons, where V-CPR was instrumental in providing on-scene guidance and decision-making.
|
PMC11699598_p7
|
PMC11699598
|
Conclusion
| 2.030858 |
clinical
|
Clinical case
|
[
0.12163804471492767,
0.8680789470672607,
0.01028300542384386
] |
[
0.0019136517075821757,
0.02678610198199749,
0.0015387962339445949,
0.9697614312171936
] |
en
| 0.999996 |
Steinar Einvik: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Ole Erik Ulvin: Writing – review & editing. Trond Nordseth: Writing – review & editing. Oddvar Uleberg: Writing – review & editing, Writing – original draft, Supervision, Investigation, Data curation, Conceptualization.
|
PMC11699598_p8
|
PMC11699598
|
CRediT authorship contribution statement
| 0.964205 |
other
|
Other
|
[
0.14209312200546265,
0.0034172493033111095,
0.8544896841049194
] |
[
0.003202282590791583,
0.9960166811943054,
0.00038638434489257634,
0.00039468088652938604
] |
en
| 0.999997 |
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
|
PMC11699598_p9
|
PMC11699598
|
Declaration of competing interest
| 0.981821 |
other
|
Other
|
[
0.004888119176030159,
0.0006584168877452612,
0.994453489780426
] |
[
0.0019688550382852554,
0.9968124032020569,
0.0006366009474731982,
0.0005821678787469864
] |
en
| 0.999997 |
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia among the elderly. Clinical manifestations of AD include memory impairment, difficulties in abstract thinking and computational abilities, and alterations in personality and behavior . The characteristic pathological changes in AD involve the excessive deposition of Aβ plaques, hyperphosphorylated tau protein forming neurofibrillary tangles, and neuroinflammatory responses due to overactivated microglia . In 2019, the International Alzheimer’s Association estimated that over 50 million people worldwide suffer from AD, with projections indicating a doubling of cases by 2050, significantly escalating the socio-economic burden . Despite being identified over a century ago, the precise pathogenesis of AD remains incompletely understood.
|
39754224_p0
|
39754224
|
Introduction
| 4.190527 |
biomedical
|
Review
|
[
0.9960118532180786,
0.001949116587638855,
0.002039015991613269
] |
[
0.013759780675172806,
0.006049910560250282,
0.9795787334442139,
0.0006115014548413455
] |
en
| 0.999995 |
Traditionally, the brain was considered a sterile environment due to the presence of the blood-brain barrier. However, recent studies have revealed the presence of bacterial communities in post-mortem human brain tissues, suggesting that microorganisms may directly affect the brain . There is substantial evidence linking AD with various pathogens, including human herpesviruses, Chlamydia pneumoniae, Helicobacter pylori, and several periodontal pathogens . Emerging research indicates that β-amyloid protein may serve physiological roles, acting as a defense mechanism against potential AD-inducing infections by viruses, bacteria, and fungi. It functions as a natural antimicrobial peptide and can directly kill pathogens . Patients infected with herpes simplex virus have a twofold increased risk of developing dementia in old age compared to controls . Active antiviral treatment in HSV-infected individuals can prevent AD onset up to 10 years later. Another study demonstrated that populations successfully eradicating H. pylori exhibited improved cognitive function after a 2-year follow-up . Animal experiments also revealed increased astrocyte numbers in the brains of Hp-infected mice, indicative of neuroinflammation . Although multiple studies have established a connection between pathogen infection and AD, the specific causal relationship remains contentious. Therefore, understanding the potential causal relationship between pathogen infection and AD is crucial for the prevention and treatment of AD.
|
39754224_p1
|
39754224
|
Introduction
| 4.483671 |
biomedical
|
Review
|
[
0.9974828362464905,
0.0013913902221247554,
0.001125809969380498
] |
[
0.15832507610321045,
0.001639424473978579,
0.8392968773841858,
0.0007385878707282245
] |
en
| 0.999997 |
To address the inherent potential confounding factors in observational studies, MR provides an effective method. This approach introduces intermediate variables, namely instrumental variables (IVs), to analyze the causal relationship between exposure factors and outcomes. Utilizing publicly available genome-wide association studies GWAS data, our study aims to investigate the potential role of antibody-mediated immune responses to infectious agents in the pathogenesis of AD. We employed a two-sample MR analysis to assess this relationship. Additionally, we evaluated the association between genetic predisposition to AD and antibody-mediated immune responses to infectious agents, thereby gaining a clearer understanding of the interplay between AD and these immune responses.
|
39754224_p2
|
39754224
|
Introduction
| 4.091548 |
biomedical
|
Study
|
[
0.9996017813682556,
0.0002323735534446314,
0.0001658736146055162
] |
[
0.9991787075996399,
0.00026690284721553326,
0.00048641307512298226,
0.00006795590161345899
] |
en
| 0.999997 |
In the current study, pooled data from the published genome-wide association studies (GWASs) of 46 antibodies and AD were utilized. Firstly, genetic variants associated with each antibody were selected to identify the causal relationship of each antibody with AD. Secondly, AD-associated genetic variants were employed to infer causality between AD and antibodies, respectively. The MR approach relied on three key assumptions: (1) Strong association of genetic variants used as instrumental variables with exposure; (2) No association of genetic variants with any confounders; (3) Absence of a direct correlation between genetic variation and the outcome, except through exposure . As all data used were publicly available, no additional ethical approval was required. The specific study design is depicted in Fig. 1 .
|
39754224_p3
|
39754224
|
Study design
| 4.109723 |
biomedical
|
Study
|
[
0.9995647072792053,
0.0002484059950802475,
0.00018682073277886957
] |
[
0.9992806315422058,
0.0001768047659425065,
0.00048209665692411363,
0.00006043430767022073
] |
en
| 0.999998 |
Fig. 1 The mendelian randomization study design
|
39754224_p4
|
39754224
|
Study design
| 2.485653 |
biomedical
|
Study
|
[
0.9963762164115906,
0.0011766627430915833,
0.0024471194483339787
] |
[
0.9028860926628113,
0.09263599663972855,
0.0032766014337539673,
0.001201312872581184
] |
en
| 0.714284 |
The GWAS statistics of AD were also derived from the FinnGen consortium R11, with 11,755 cases and 441,978 controls, which were defined as Alzheimer’s disease . The exposure data source for this MR study is the UK Biobank, which recruited over half a million British adults between 2006 and 2010. Among these, a subsample of 9,724 participants provided serum samples for serological measurements of 20 different microorganisms. These samples were tested for total antibody levels against multiple antigens .
|
39754224_p5
|
39754224
|
GWAS sources
| 3.952375 |
biomedical
|
Study
|
[
0.9995518326759338,
0.00016277344548143446,
0.0002853987680282444
] |
[
0.999332845211029,
0.00037986322422511876,
0.00023521944240201265,
0.00005209041773923673
] |
en
| 0.999996 |
In our Mendelian randomization analysis, we employed IVs as tools to discern the causal relationships between exposure factors and outcomes. IVs are typically genetic variants, with SNPs being the variant of choice for their commonality. To ensure an adequate number of SNPs for further MR analysis, a significance threshold of P < 5 × 10 − 6 was selected when screening for SNPs related to each antibody and AD. a substantial clumping window over 10,000 kb, and minimal linkage disequilibrium ( r 2 < 0.001), as these measures ensure the SNPs’ independence . Moreover, to affirm the robustness of the association between IVs and the exposure, we utilized the F statistic as a gauge of validity . In this study, the inclusion criteria for SNPs demanded F values exceeding 10, thus minimizing the risk of weak instrument bias. Palindromic SNPs, specifically those with A/T or G/C alleles, were systematically identified and excluded to prevent the ambiguity they can cause regarding the effect allele in GWAS studies of both exposure and outcome. To address and rectify the presence of horizontal pleiotropy, we employed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tool for both global and outlier analyses, rooting out SNPs exhibiting such effects .
|
39754224_p6
|
39754224
|
The selection of IVs
| 4.216725 |
biomedical
|
Study
|
[
0.9994633793830872,
0.00029694847762584686,
0.00023968835012055933
] |
[
0.9992744326591492,
0.00021318583458196372,
0.00043921510223299265,
0.00007317208655877039
] |
en
| 0.999997 |
To estimate the causal effect, we utilized the inverse variance weighted (IVW) method as our primary analytical approach. The IVW model is particularly potent for detecting causality within the framework of two-sample MR analysis . We translated our findings into odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Heterogeneity within the IVW estimates was evaluated using Cochran’s Q test, where a p-value less than 0.05 signified heterogeneity. Nevertheless, heterogeneity does not inherently invalidate the IVW model. Given the diversity in causal estimates from different variants, the multiplicative random effects model was deemed preferable to the fixed effects model, and was therefore adopted for our main analysis.
|
39754224_p7
|
39754224
|
Statistical analysis
| 4.090603 |
biomedical
|
Study
|
[
0.9995063543319702,
0.0002853302867151797,
0.00020832690643146634
] |
[
0.9992444515228271,
0.00029419740894809365,
0.00039756708429194987,
0.00006373956421157345
] |
en
| 0.999996 |
Furthermore, we employed the MR-PRESSO method to identify and correct for outliers in the IVW linear regression . The MR-Egger method, which accommodates non-zero intercepts, was applied to check for the presence of directional pleiotropy. We also conducted leave-one-out analyses to determine the influence of individual SNPs on our results. Using MR-PRESSO, we were vigilant in detecting and excluding outliers promptly. Following outlier removal, the MR analyses were revisited. All computations and statistical analyses were facilitated by the R software (version 4.3.2), utilizing the TwoSampleMR package. We applied a significance threshold of P < 0.001 to account for multiple testing, ensuring a stringent control of type I error given the 46 antibodies analyzed. This adjustment minimizes the likelihood of false-positive results and enhances the robustness of the causal inferences drawn. In cases where IVW analysis yielded a significant result ( P < 0.001) and no evidence of horizontal pleiotropy or heterogeneity was found, the result could be considered positive, even if other methods did not yield a significant result, as long as the direction of the beta remained consistent.
|
39754224_p8
|
39754224
|
Statistical analysis
| 4.113965 |
biomedical
|
Study
|
[
0.999509334564209,
0.00023676833370700479,
0.0002539501874707639
] |
[
0.9992448091506958,
0.00025760673452168703,
0.0004384864296298474,
0.00005916377995163202
] |
en
| 0.999999 |
The causal relationships of 46 antibodies associated with antibody-mediated immune responses to infectious disease agents on AD are depicted in Fig. 2 and detailed in Tables S3 . Using the IVW method, we tested the 46 antibodies and identified 2 that showed a causal association with AD. The specifics of the SNP information (SD, R 2 , F) for the 2 significant antibodies in the MR analyses are provided in Tables S1 - 2 .
|
39754224_p9
|
39754224
|
Causal impact of antibodies on AD
| 4.03939 |
biomedical
|
Study
|
[
0.9995982050895691,
0.00021180813200771809,
0.00019000396423507482
] |
[
0.9993752837181091,
0.00018602519412524998,
0.00037884950870648026,
0.0000598920087213628
] |
en
| 0.999998 |
Fig. 2 Causality of 46 antibodies on AD. The red color shows that there is statistical significance with a p-value less than 0.001. IVW, the inverse variance weighted method.The concentric circular heatmap displays the results of various analytical methods from the outermost to the innermost layer, in the following order: IVW, MR-Egger, weighted median, simple mode, and weighted mode
|
39754224_p10
|
39754224
|
Causal impact of antibodies on AD
| 3.28253 |
biomedical
|
Study
|
[
0.9986960291862488,
0.00023845866962801665,
0.001065484364517033
] |
[
0.955390453338623,
0.04125107452273369,
0.002935713389888406,
0.00042279393528588116
] |
en
| 0.999996 |
Varicella zoster virus glycoproteins E and I antibody, Epstein-Barr virus EBNA-1 antibody showed causal association with AD . The risk of AD may be inversely linked to [Varicella zoster virus glycoproteins E and I antibody levels and positively associated with Epstein-Barr virus EBNA-1 antibody levels . In summary, Varicella zoster virus glycoproteins E and I antibody functioned as protective factors; however, EBNA-1 antibody functioned as an anti-protective factor.
|
39754224_p11
|
39754224
|
Causal impact of antibodies on AD
| 4.019159 |
biomedical
|
Study
|
[
0.9997022747993469,
0.0001104589318856597,
0.00018724906840361655
] |
[
0.995383083820343,
0.0012141000479459763,
0.0033063713926821947,
0.00009634756861487404
] |
en
| 0.999997 |
Fig. 3 Association of antibody-mediated immune responses to infectious diseases agents with AD using Mendelian randmization
|
39754224_p12
|
39754224
|
Causal impact of antibodies on AD
| 3.113951 |
biomedical
|
Study
|
[
0.9990572333335876,
0.00028134038439020514,
0.0006614898447878659
] |
[
0.8689799904823303,
0.12482958287000656,
0.005113260820508003,
0.0010771784000098705
] |
en
| 0.999998 |
We also analysed the causal effect of AD on antibodies, the insufficiency of robust IVs impeded the establishment of conclusive causal inferences.
|
39754224_p13
|
39754224
|
Influence of AD on 46 antibodies
| 2.333204 |
biomedical
|
Study
|
[
0.9964290261268616,
0.0008186050108633935,
0.002752304542809725
] |
[
0.9880071878433228,
0.00988434161990881,
0.0016412015538662672,
0.00046718178782612085
] |
en
| 0.999999 |
Heterogeneity was observed in the two antibodies. The MR Egger regression intercept did not identify any SNP pleiotropy (Table 1 ). The scatter plot indicates that Varicella zoster virus glycoproteins E and I antibodies may have a protective effect on AD, while Epstein-Barr virus EBNA-1 antibody levels may increase the risk of AD. MR analysis includes the IVW method, MR Egger method, weighted median method, and simple mode, all represented in scatter plots with specified weights. An upward sloping line indicates a positive correlation between infectious disease antibodies and AD, while a downward sloping line indicates a protective association . No outliers were detected between infectious disease antibodies and AD using the retention method analysis , indicating that the revealed causal relationship is not influenced by instrumental variables. Furthermore, the funnel plots of all results confirm the absence of horizontal pleiotropy .
|
39754224_p14
|
39754224
|
Influence of AD on 46 antibodies
| 4.145596 |
biomedical
|
Study
|
[
0.9995822310447693,
0.00025296214153058827,
0.00016481878992635757
] |
[
0.9991323351860046,
0.00025117796030826867,
0.0005439315573312342,
0.00007254430238390341
] |
en
| 0.999999 |
Table 1 Heterogeneity and pleiotropy analysis of mendelian randomization analysis Exposure MR-Egger intercept Cochrane’s Q IVW Cochrane’s Q IVW Egger intercept value P Value Q Value P Value Q Value P Value Varicella zoster virus glycoproteins E and I antibody levels -0.0071 0.4291 91.9067 <0.001 90.7297 <0.001 Epstein-Barr virus EBNA-1 antibody levels(EBV-EBNA-1) 0.0071 0.3341 169.6140 <0.001 167.7068 <0.001
|
39754224_p15
|
39754224
|
Sensitivity analysis
| 4.116651 |
biomedical
|
Study
|
[
0.9995750784873962,
0.00017038827354554087,
0.0002544998424127698
] |
[
0.9970301389694214,
0.0022605143021792173,
0.000630100374110043,
0.0000792230130173266
] |
en
| 0.999997 |
Fig. 4 Scatter plots of each antibody associated with the risk of AD. ( a ) Anti-varicella, Anti-varicella zoster virus IgG seropositivity; ( b ) EBNA-1, Epstein-Barr virus EBNA-1 antibody levels(EBV-EBNA-1)
|
39754224_p16
|
39754224
|
Sensitivity analysis
| 2.911169 |
biomedical
|
Study
|
[
0.9989203214645386,
0.0003057351568713784,
0.0007739977445453405
] |
[
0.9804192185401917,
0.018350781872868538,
0.000918753445148468,
0.00031119733466766775
] |
en
| 0.999996 |
Fig. 5 Leave-one-out analysis of each antibody associated with the risk of AD. ( a ) Anti-varicella, Anti-varicella zoster virus IgG seropositivity; ( b ) EBNA-1, Epstein-Barr virus EBNA-1 antibody levels(EBV-EBNA-1)
|
39754224_p17
|
39754224
|
Sensitivity analysis
| 2.878845 |
biomedical
|
Study
|
[
0.9988057613372803,
0.0003341910778544843,
0.0008599924040026963
] |
[
0.9873335361480713,
0.011670045554637909,
0.0007072029984556139,
0.00028912301058880985
] |
en
| 0.999993 |
Fig. 6 Funnel plots of each antibody associated with the risk of AD. ( a ) Anti-varicella, Anti-varicella zoster virus IgG seropositivity; ( b ) EBNA-1, Epstein-Barr virus EBNA-1 antibody levels(EBV-EBNA-1)
|
39754224_p18
|
39754224
|
Sensitivity analysis
| 2.98215 |
biomedical
|
Study
|
[
0.9990053772926331,
0.00023502085241489112,
0.0007596571813337505
] |
[
0.9837577939033508,
0.013395950198173523,
0.002572608646005392,
0.00027364547713659704
] |
en
| 0.999997 |
This study employed Mendelian randomization to explore potential associations between antibody-mediated immune responses to infectious disease agent and the risk of AD. Our findings indicate that varicella zoster virus glycoproteins E and I antibodies are linked to a reduced risk of AD. Conversely, elevated levels of Epstein-Barr virus EBNA-1 antibodies are associated with an increased risk of AD. These insights highlight the intricate interplay between immune responses and neurodegenerative diseases.
|
39754224_p19
|
39754224
|
Discussion
| 4.098402 |
biomedical
|
Study
|
[
0.9996472597122192,
0.0002267194795422256,
0.00012592380517162383
] |
[
0.9986422657966614,
0.00027311319718137383,
0.0009848132031038404,
0.00009981784387491643
] |
en
| 0.999997 |
This study, through Mendelian randomization, found that Varicella zoster virus glycoproteins E and I antibody levels are associated with a reduced risk of AD.The presence varicella zoster virus glycoprotein E and I antibodies typically indicates that an individual has acquired immunity to varicella zoster virus, either through previous infection or vaccination . Varicella zoster virus infection, particularly shingles, has been linked to an increased risk of AD and other dementias [ 23 – 25 ]. Some studies have also found that the level of anti-herpes simplex virus IgM is negatively correlated with the level of amyloid protein in plasma . The currently widely accepted view is that lower levels of amyloid protein in plasma are a possible short-term risk factor for the development of dementia, while accelerated deposition of amyloid protein in the brain occurs in parallel with a decrease in the level of amyloid protein in plasma. Therefore, this evidence also indirectly suggests that the body may accelerate the production of amyloid protein in the brain while resisting the production of IgM by the virus. Although varicella zoster virus itself does not directly cause the hallmark pathologies of AD, such as β-amyloid and tau protein accumulation, it may contribute indirectly by inducing neuroinflammation and reactivating latent herpes simplex virus type 1 in the brain, which is strongly associated with AD pathogenesis . Vaccination against shingles and antiviral treatments have been shown to decrease the risk of dementia, further supporting the potential involvement of varicella zoster virus in AD development .Therefore, controlling active herpesvirus infections may be more critical for reducing AD risk than merely increasing antibody levels .This finding underscores the potential role of varicella zoster virus vaccination in mitigating the risk of AD.
|
39754224_p20
|
39754224
|
Antibody-mediated immune responses to varicella zoster virus infections reduced AD risk
| 4.358156 |
biomedical
|
Study
|
[
0.9994021654129028,
0.0004266773466952145,
0.00017118678078986704
] |
[
0.9974480867385864,
0.000495392014272511,
0.0018744245171546936,
0.0001821487967390567
] |
en
| 0.999998 |
Epstein-Barr virus (EBV) is a widely spread herpesvirus that infects over 90% of adults worldwide for a long time . EBNA-1 antibody levels can evaluate the immune status and past infection status of the body. A cohort study report suggests that the use of antiviral drugs in herpesvirus patients is associated with a reduced risk of dementia . Currently, the specific mechanism linking EBV infection and AD is not clear, but existing research has proposed several possible mechanisms. Continuous EBV infection and repeated reactivation may promote the formation of protein plaques in the brain . The study by Carbone et al. showed that the duration of the EBV incubation period may exacerbate the systemic immune response and induce changes in the inflammatory process, leading to a decrease in cognitive ability during aging . Our MR analysis found that Epstein-Barr virus EBNA-1 antibody levels increase the risk of AD, suggesting potential effects of immune mechanisms. Further research is needed to determine whether EBV reactivation is involved in triggering the onset or progression of AD.
|
39754224_p21
|
39754224
|
Antibody-mediated immune responses to epstein-barr virus infections increased AD risk
| 4.190794 |
biomedical
|
Study
|
[
0.999647855758667,
0.00020468098227865994,
0.0001473870943300426
] |
[
0.9975284934043884,
0.0003029620856977999,
0.0020733391866087914,
0.0000951486945268698
] |
en
| 0.999997 |
This study employs a Mendelian randomization approach to uncover the potential associations between antibody-mediated immune responses to infectious diseases agents and the risk of AD, yet it acknowledges several limitations.
|
39754224_p22
|
39754224
|
Limitation
| 3.546488 |
biomedical
|
Study
|
[
0.9994271993637085,
0.0002416101924609393,
0.0003312491171527654
] |
[
0.9983634352684021,
0.000998809584416449,
0.0005085055599920452,
0.0001292246743105352
] |
en
| 0.999996 |
Firstly, The results exhibit heterogeneity in antibody levels for Varicella zoster virus glycoproteins E and I, and Epstein-Barr virus EBNA-1. This variability may arise from population differences and co-infections, potentially affecting the accuracy and generalizability of our findings. Secondly, the data are primarily derived from the UK Biobank and FinnGen consortium, predominantly consisting of individuals of European ancestry, which may limit the generalizability of the findings. Additionally, the constraints related to the database and sample size, along with the inability to validate findings across multiple databases, impact the robustness of the study. Our study did not exclude SNPs from the HLA region, which is associated with the immune system and exhibits linkage disequilibrium, potentially influencing AD risk.
|
39754224_p23
|
39754224
|
Limitation
| 4.07299 |
biomedical
|
Study
|
[
0.9994781613349915,
0.00020774964650627226,
0.0003140865301247686
] |
[
0.9994807839393616,
0.00017328390094917268,
0.00029998162062838674,
0.000045903401769464836
] |
en
| 0.999996 |
While the study offers new insights into the potential causal relationships between viral infections and AD, these results do not directly establish causality. Further epidemiological research, laboratory studies, and clinical trials are necessary to validate these findings, with large-scale, multi-ethnic population studies required to confirm and extend these observations.
|
39754224_p24
|
39754224
|
Limitation
| 3.674453 |
biomedical
|
Study
|
[
0.999567449092865,
0.00012862280709668994,
0.00030398464878089726
] |
[
0.9811398983001709,
0.009420267306268215,
0.009236539714038372,
0.00020327925449237227
] |
en
| 0.999997 |
This study, employing Mendelian randomization, discovered that antibody-mediated immune responses to infectious diseases agents, such as anti-varicella zoster virus antibodies, are associated with a decreased risk of AD, while antibodies against Epstein-Barr virus, correlate with an increased risk. These findings highlight the complexity of immune system responses and lay the groundwork for future research to further explore the role of immune modulation in the pathogenesis of AD. Although the study provides significant insights, broader epidemiological and experimental research is necessary to validate these conclusions.
|
39754224_p25
|
39754224
|
Conclusion
| 4.077877 |
biomedical
|
Study
|
[
0.9996836185455322,
0.00018362757691647857,
0.00013270102499518543
] |
[
0.9984184503555298,
0.0003034247783944011,
0.0011912285117432475,
0.00008683472697157413
] |
en
| 0.999997 |
Below is the link to the electronic supplementary material.
|
39754224_p26
|
39754224
|
Electronic supplementary material
| 0.976989 |
other
|
Other
|
[
0.10020256042480469,
0.003312709741294384,
0.8964846730232239
] |
[
0.006335775833576918,
0.9910769462585449,
0.0016435992438346148,
0.0009437996195629239
] |
en
| 0.999998 |
Supplementary Material 1
|
39754224_p27
|
39754224
|
Electronic supplementary material
| 1.299746 |
biomedical
|
Other
|
[
0.8858742117881775,
0.0030190381221473217,
0.1111067607998848
] |
[
0.1275506466627121,
0.8626377582550049,
0.0076365359127521515,
0.002175003755837679
] |
en
| 0.857142 |
Supplementary Material 2
|
39754224_p28
|
39754224
|
Electronic supplementary material
| 1.281604 |
biomedical
|
Other
|
[
0.8673255443572998,
0.003014425979927182,
0.12966004014015198
] |
[
0.13567572832107544,
0.8551348447799683,
0.007180076092481613,
0.002009304240345955
] |
en
| 0.999997 |
Subsets and Splits
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Retrieves 100 samples of clinical cases, providing a basic overview of this specific document type.
High-Score Clinical Cases
The query retrieves a limited set of clinical case documents with a high educational score, providing a basic filtered view of the dataset.