Thymus quinquecostatus Celak. (Korean name: bak-ri-hyang) is an important medicinal and aromatic herb in Korea, which is named for the spread of its fragrance over a distance of approximately 40 km. In traditional Korean systems of medicine, T. quinquecostatus has been used to treat cancer, constipation, hepatic disease, arteriosclerosis, poor circulation in women, constipation, and menstrual irregularities. At present, T. quinquecostatus is used only for ornamental and ground cover purposes. A literature search was conducted to retrieve information regarding the essential oil composition and biological properties of T. quinquecostatus from PubMed, Science Direct, Wiley, Springer, Taylor and Francis, Wiley, and other literature databases. T. quinquecostatus can be divided into different chemotypes, such as γ-terpinene, thymol, phenol, carvacrol, and geraniol, according to the presence of major components in its essential oil. Further, the essential oil from T. quinquecostatus has been reported to possess various therapeutic properties such as antioxidant, antimicrobial, anticancer, anti-inflammatory, analgesic, sleep prolonging, soothing, skin protection and whitening, anti-aging, anti-obesity, and anti-acne properties. In conclusion, this review will be helpful for utilizing the T. quinquecostatus plant in different industries including food, pharmaceuticals, pesticides, perfumery, and cosmetics. Essential oils are hydrophobic concentrates containing volatile aromatic compounds extracted from plants. Approximately 200 kinds of industrially used essential oils are obtained from the flowers, leaves, roots, stems, bark, fruits, buds, and seeds of various aromatic plants. Several methods are employed to isolate volatile components from medicinal and aromatic plants including hydro-distillation, steam distillation, extraction, supercritical fluid extraction (SFE), organic solvent extraction (OSE), and microwave extraction (AE). Among them, the hydro-distillation and steam distillation extraction methods are the standardized methods to isolate essential oils. Essential oils contain a variety of aromatic components, mainly belonging to monoterpenes and sesquiterpenes due to the differences in their odor characteristics. Essential oils are used in numerous industries to develop perfumery, aromatherapy, cosmetics, food, medicinal, and household cleaning products .Essential oils from aromatic plants mainly contain monoterpenes and sesquiterpenes and their oxygenated derivatives with diverse chemical structures. These aroma components have been reported to possess various biological activities including anti-inflammatory, antispasmodic, analgesic, antioxidant, immunomodulatory, psychotropic, antiviral, antidiabetic, anticancer, and significant antibacterial properties ,3. FurthThymus belongs to the family Lamiaceae with approximately 300 species distributed worldwide [Thymus species have traditionally been used to treat digestive and respiratory diseases such as colds, indigestion, nausea, and dysentery [Thymus, thymol and carvacrol, are classified as Generally Recognized As Safe (GRAS) by the United States Food and Drug Administration (FDA). However, in the United States, the daily allowance of essential oils used in food is stipulated [European Pharmacopoeia, only the thymol chemotype is selectively used among thyme essential oils. Thymol (36.0–55.0%), carvacrol (1.0–4.0%), p-cymene (15.0–28.0%), γ-terpinene (5.0–10.0%), linalool (4.0–6.5%), β-myrcene (1.0–3.0%), and terpinen-4-ol (0.2–2.5%) are the most abundant components in the essential oils of Thymus species. Among them, thymol is considered in pharmacopeias and used as a food preservative in the US, UK, Japan, India, and China [The genus orldwide ,9. Thymuysentery . Thyme sysentery ,12. Thisipulated . In Euronene 5.0–.0%, linaThymus quinquecostatus Celakovsky) are summarized. This review paper provides sufficient knowledge to improve the industrial value of T. quinquecostatus and its cultivation practices on farms.Thyme has been used in Korean oriental medicine for the treatment of upper respiratory tract inflammation. Research on thyme is only fragmentary and sporadic due to the fact of its sluggish industrial use. Hence, the cultivation of thyme is very limited on farms. In this review, the botanical and agronomic characteristics, the chemical composition of its essential oil, and the biological activities of Korean thyme , Mentheae Dumort (tribe) Menthinae Endl. (subtribe) [Thymus have significant morphological variations and do not have clear diagnostic characteristics for plant characteristics. Hence, the total number of Thymus species varies greatly among researchers, making it the most controversial plant among those of European origin [Thyme is a perennial deciduous shrub known to be native to the Mediterranean coast of southern Europe . It is aubtribe) , with 25ubtribe) , and it ubtribe) . Differen origin . T. quinquecostatus has many branches from the stem and the leaves are opposite and egg-shaped, oval, or lanceolate , found throughout the Korean Peninsula; island thyme (T. quinquecostatus var. japonica), found only in island areas including Ulleungdo. Thymol was found to be the most abundant component in the essential oils of bak-ri-hyang (39.8%) and island thyme (54.7%). [T. vulgaris L. is reported to be a completely different species from Korean native thyme. T. quinquecostatus is also distributed in China, but significant variations were observed in their essential oil compositions. Carvacrol (28.54%) is the major component of thyme from the Ningxia Guyuan region, whereas p-cymene (17.39%) is from the Shandong Yimeng region. These data suggest that the main component in the essential oil of thyme remarkably varied according to the region. The difference in the essential oil composition might be due to the differences in environmental conditions, harvesting time, cross-pollination, extraction, and analysis methods of the essential oils [In particular, two varieties of (54.7%). ,28. T. vial oils ,30. TherCurrently, it has been investigated that several types of thyme introduced from foreign countries are being sold as domestic thyme in the private sector in Korea. Further, the correct identification of domestic thyme is too difficult due to the presence of many crossbreeds between native and imported thymes . TherefoT. quinquecostatus can be propagated by seeds, but generally, cuttings are used. This takes advantage of the botanical characteristics of thyme stems that take root in the soil when they grow to a certain extent, but it is not possible to cut them at any time of the year. Choi et al. [v/v). This ratio is suitable for the propagation of thyme cuttings for improving the plant length and width of seedling quality. Sunlight, along with moisture, has a great influence on plant growth. When thyme was grown without shading, the fresh weight was high, and the flowering period was early. Conversely, due to the low root depth of thyme, if periodic irrigation is not performed, it will suffer from drying out. The planting distance affects the overall yield. In general, it is known that an increase in plant spacing is found to increase the yield of the plant. A similar pattern was observed in the case of baechohyang, which is grown as a medicinal plant on domestic farms. As the planting distance of thyme was farther, the fresh weight and dry weight of the plant increased. When the planting distance was 15 × 15 cm, the plant height of thyme was 27.8 cm, and the fresh weight was 48.7 g/plant. However, the planting distance was doubled, and when it was 30 × 30 cm, the plant height was 25.3 cm, and the fresh weight was 156.7 g/plant. From these results, it can be seen that the greater the distance of thyme planting, the higher the yield. The essential oil content was 3.4% in non-forestry cultivation, whereas the oil content was as low as 2.6% in open-field cultivation, which indicates that stable moisture supply and protection from damage caused by pests were effective [Since thyme is an aromatic plant, the standard of cultivation in industrial terms is high yield and high quality of natural essential oil. The soil, light, planting distance, and cultivation methods for cultivating thyme containing high-content and high-quality essential oil have been studied. i et al.  reportedi et al.  reportedffective . Thymus sp. Have long been used for medicinal purposes, perfumery, and in food industries due to the presence of various bioactive components and their unique aroma. Hence, thyme has been of interest to many academic and industrial researchers. The essential oil isolation from T. quinquecostatus and its major components are presented in The essential oils from p-cymene. The study suggested that the chemotype is different from that of Cheongwon and Shandong Yimeng of China [A total of 30 volatile compounds were detected in the steam distilled oil of thyme using the solid-phase microextraction (SPME) technique. The main components were trans-geraniol 36.85%), citral (15.64%), 3-octanone (3.70%), geranyl acetate (3.43%), borneol (2.48%), and nerol (2.25%) . A studyof China . It is r5%, citraof China . Choi etof China  reportedp-cymen-3-ol (50.41%), p-cymen-2-ol (24.06%), and cymene (19.04%). The results demonstrated that the chemical type of Jeju thyme is closer to thyme from Shandong Yimeng in China than thyme from Cheongwon Herbalang in Chungbuk [Oh et al.  reportedChungbuk . From thLee et al.  extracteIn a comparative study on the content of island thyme essential oil, Lee et al.  reportedp-thymol (27.51%). In the thyme collected from Ulleungdo, 41 types of volatile components were detected in the essential oil, and the main component was phenol (13.48%). A total of 54 components were detected in the essential oil of thyme collected in Gapyeong, Gyeonggi-do, and the main component was carvacrol (18.25%).Choi et al.  conductep-thymol, phenol, and carvacrol) for thyme. The fact that the main component, as well as the content of the essential oil, may differ by region, even in the same species of plant, was reported in a study of thyme (T. vulgaris). The essential oil content of Thymus spathulafolia was 3.74% [Thymus capitatus was 6.0% [Thymus linearis was 11.2% [The results of these studies can be summarized as follows. First, the content of thyme essential oil differed by region. Second, it is possible to classify the chemical type as the main component of the essential oil of thyme. Chiang et al.  reportedas 3.74% , Thymus was 6.0% , and Thyas 11.2% . The maias 11.2% , but theas 11.2% . Thymus collected from various regions in Iran. Through cluster analysis, they could be divided into three groups: thymol, geraniol/linalool, and carvacrol. These results indicate that even the same plant (thyme) living in one country may have different main components depending on the habitation area, and this difference is inferred due to the severe morphological variation of plants of the genus Thymus. In the western and central parts of the Balkan Peninsula, 250 taxa were identified [γ-terpinene (16.0%) > p-cymene (13.0%) > β-caryophyllene (4.7%) > carvacrol (4.0%) > β-bisabolene (2.7%) > α-terpinene (2.6%). On the other hand, island thyme contains thymol (39.8%) > γ-terpinene (9.9%) > p-cymene (5.5%) > camphor (5.0%) > β-caryophyllene (4.7%) > α-pinene (3.5%). However, the most abundant component of both plants was thymol; thus, both plants can be classified as the same chemical type.In addition, Tohidi et al.  extracteentified  and onlyentified . Hence, entified . Paying In a study by Shin and Choi , Korean The structure of the chemical substances contained in thyme essential oil, reported by many researchers to date, is shown in T. quinquecostatus has various biological properties such as antioxidant, antimicrobial, anticancer, anti-inflammatory, analgesic, anti-obesity, and anti-acne activities. It has been reported to have various physiological activities, including sleep prolonging, soothing, whitening, skin protection, skin aging inhibition, and plant growth inhibitory activities. The biological activities reported so far are shown in The US FDA defines antioxidants as substances used to preserve food by delaying deterioration, acid waste, or discoloration caused by oxidation. The oxidation reaction is one of the rancidity pathways of oils and fats. Oxidation products can be toxic when ingested as well as flavor in foods. Thus, the rancidity of oils and fats must be suppressed in terms of food preservation as well as stability. The rash is largely caused by a noncomplex diene compound produced by the reaction of singlet oxygen with unsaturated fatty acids by autoxidation by free radical chain reaction and enzymatic oxidation by lipoxygenase. All antioxidants act to block or delay their oxidation through several pathways . TherefoThe antioxidant effect of solvent extract of thyme has been reported by several researchers. Hyun et al.  reportedThymus lanceolatus, which is related to thyme, contains 74.85% of oxygen-containing monoterpenes and 19.77% of monoterpene hydrocarbons, reported that it is similar to the antioxidant activity of thyme essential oils [Choi et al.  also repial oils .Thymus. Nazzaro et al. [Thymus species on plant morphology due to the breakdown of the fat membrane, inhibition of the protoplast efflux pump, mitochondrial activity inhibition, production of oxygen oxides and nitrogen oxides, and the effects on mitotoxin production. Shin and Kim [Aspergillus niger, Aspergillus flavus, Blastoschyzomyces capitatus, Candida albicans, Candida utilis, Cryptococcus neoformans, Trichosporon mucoides, and Trichophyton rubrum). T. quinquecostatus showed significant inhibition of the growth of the tested fungi with the minimum inhibitory concentration (MIC) in the range of 40–390 µg/mL. In addition, the well-known antibiotic, ketoconazole showed antifungal activity against these pathogens with MIC values between 3.12 and 12.5 µg/mL. In a follow-up study, Kim and Shin [Candida albicans, which causes inflammation in the vagina of Swiss albino female mice. The authors reported that the bacterial growth and the sterilization effect were very high. Thyme essential oil (4%) is expected to be used in the pharmaceutical industry in the future due to the fact of its effective antifungal potential. Further, T. quinquecostatus showed prominent synergistic effects with clotrimazole.Many researchers have reported on the antibacterial action of essential oils from different species of o et al.  explaine and Kim  studied and Shin  investigBotrytis cinerea, which produces disease in cucumbers. This study suggests that the oil can also be used in agriculture. Just as the essential oil of thyme exhibits antimicrobial activity, the extract of Thymus laevigatus, also exhibited antimicrobial activity [Aspergillus fumigatus. The methanol extract contains flavonoids, tannins, anthraquinones, and phenolic compounds, and the dichloromethane extract contains volatile oils, mainly terpenoids. The authors reasoned that antibacterial action would be due to the presence of phenylpropanoids and tannins. Lihyang supercritical extract (SFE) showed antibacterial activity against Ascosphaera apis, which hardens and kills bees because spores invade through the mouth of bee larvae and the mycelium envelops the entire body [Sitophilus zeamais)) [Park et al.  reportedactivity . It was ire body . When theamais)) .Botrytis cinerea), leaf blight (Rhizoctonia solani), red pepper blight (Phytophthora capsici), red pepper anthrax (Glomerella cingulata), apple spot blight , and rice blast (Magnaporthe grisea). Thymol significantly inhibited the growth of these tested pathogens from 7.0% to 20.8% at a concertation of 100 µg/mL. Choi et al.  reportedStaphylococcus pneumoniae was 0.125 to 1.000 mg/mL and the MIC for Salmonella enteritidis was 8 to >16 mg/mL. The thyme oils also exhibited significant antibacterial activity against Staphylococcus aureus and Salmonella typhimurium with MIC values in the range of 1 to 8 mg/mL. Further, the authors compared the antibacterial activity of essential oils with antibiotics such as norfloxacin (MIC at 2 to >64 µg/mL), oxacillin (MIC at 1 µg/mL to >16 µg/mL), and erythromycin (MIC at 0.25 µg/mL to >64 µg/mL). Shin and Kim  reportedEscherichia coli (approximately 50%), which is a contamination indicator and Gram-negative putrefactive bacterium. Products containing these essential oils are already on the market, and “DMC Base Natural”, a food preservative produced by DOMCA S. A. in Spain, contains 50% of essential oils of rosemary, sage, and citrus [Thyme extract was also reported to have antibacterial activity. Choi et al.  reportedd citrus .Thymus exhibited considerable antimicrobial activity [50 value of thyme essential oil for DXR enzyme is 48 μg/mL, showing a moderate inhibitory efficacy. Thus, the authors reported that carvacrol showed an excellent enzyme inhibitory ability even at a low concentration (68.3% at 20 μg/mL).Previously, several authors reported that essential oils obtained from different species of activity ,70,71,72activity  stated tp-cymene [In thyme essential oil, carvacrol (5-isopropyl-2-methylphenol) is a monoterpene isomer of cymene, also known as 2-hydroxycymene. It has been reported that carvacrol disrupts the membrane of microorganisms to cause leakage of intracellular ions and lowers the proton motive force of cells by inhibiting ATPase activity . In addip-cymene , cinnamap-cymene , cinnamip-cymene , and eugp-cymene  are alsoT. laevigatus also exhibited antimicrobial activity [Thymus, including T. quinquecostatus.The essential oil contained in thyme showed antimicrobial activity against food microorganisms, and Burt  reportedactivity , it is iT. vulgaris had a CC50 value of 0.0079% for HSV-1/HSV-2, and an IC50 value of 0.0010/0.0007%, which was effective in treating skin diseases caused by viruses. Thymus essential oil is inferred to have antiviral activity, but scientific proof for this has not been made so far. Antiviral studies of thyme essential oil are expected to be widely applied in the treatment of various diseases.Orchard and van Vuuren  reportedIn an anti-inflammatory study of thyme, Kim and Suk  found th50 values of thymol varied significantly according to the type of cell line tested. The IC50 value of thymol for the breast cancer cell line MCF-7 is 304.81 µg/mL, while for leukemia cell lines, P388 is 0.8 µg/mL, hepatocellular carcinoma cell HEPG2 is 266 mM, and HL-60 is 113.51 µM. In the case of the cervical cancer cell, HeLa, the IC50 value of thymol is 134.29 µg/mL [T. vulgaris essential oil showed antiproliferative and proapoptotic effects in MCF-7 and MDA-MB-231 breast cancer cells. Further, T. vulgaris essential oil at 0.1% and 1% doses reduced the volume of tumors in a syngeneic 4T1 mouse model and also decreased the tumor frequency by 53% compared to the control (at 1%) in the rat model [T. vulgaris prevents colorectal cancer by inhibiting the Wnt/β-catenin pathway in HCT116 and Lovo cells as well as in BALB/c nude mice [T. vulgaris registered the strongest antiproliferative activity against the MCF-7 cell line (IC50: 52.65 μg/mL) followed by the H460 (IC50: 68.59 μg/mL) and MOLT-4 cell line (IC50: 228.78 μg/mL) [The anticancer effect of thymol, one of the main components contained in thyme, is well summarized in the literature by Islam et al. . Thymol 29 µg/mL . In partat model . Anotherude mice . In a re8 μg/mL) .Beer et al.  reportedIn an experiment confirming the analgesic action of thyme essential oil on the central nervous system (CNS), analgesic effects were found at 20, 40, and 80 mg/kg in a hot plate test, and at 80 mg/kg, the analgesic effect was found to be more peripheral than the CNS. It showed a greater effect in the peripheral nervous system (PNS) [T. magnus essential oil  significantly increased the sleep time (222.9 min) when compared to the control group (70.1 min) [Hypnotics refers to drugs that make the user sleepy and promote the onset and maintenance of wavelengths similar to those of natural sleep. Bromide, known as a sedative in 1853, has been used as a sleeping pill since 1864. In addition, chloral hydrate, paraldehyde, urethane, etc., were used before 1900. A variety of barbiturates have been used, but their effects do not last for more than 2 weeks, and safety issues have been raised; thus, they are not currently used. Since chlordiazepoxide appeared in 1961, similar drugs have been produced and used as sleeping pills . In a pe0.1 min) . Kim and Suk  reportedWhitening is classified as a functional cosmetic according to the Cosmetics Act. According to the Ministry of Food and Drug Safety, they are (1) cosmetics that prevent melanin pigment from being deposited on the skin to suppress the formation of spots or freckles and (2) the color of melanin pigment deposited on the skin. It is defined as a cosmetic with the function of lightening the skin by thinning the skin. It has been announced and recognized as a whitening ingredient . In part®, a thymol ester complex , inhibits melanogenesis in melanin-α and α-MSH-stimulated B16 cells. As evidenced by microscopic observation, it was reported that the complex inhibits the migration of melanin to multiple epidermal layers. Summarizing the results of the studies so far, it can be said that thymol is an important functional material that causes whitening activity, although slightly toxic to humans.Choi et al.  reportedA study demonstrated that thymol detected in the hexane solvent fraction of the extract had a high alpha-glucosidase inhibitory activity, and thus had an anti-obesity effect . Lee et Ultraviolet rays (UV) that reach human skin from the sun are a major environmental factor that cause skin aging. In particular, polyphenol-rich compounds are known to prevent skin aging. Ultraviolet rays that reach human skin are mainly UVA (400–315 nm) and UVB (280–315 nm), but when overexposed, it causes retinal destruction of the eyes, erythema, inflammation, and serious consequences for the immune system as well as photoaging and keratinization. The development of cellular malignancies and melanomas has been reported in academia ,95,96,97T. vulgaris, and the thymol contained therein, in a skin aging study was investigated. T. vulgaris extract (1.82 μg/mL) and thymol (1 μg/mL) were used to induce UV-induced skin damage (epidermis). It was shown to have a protective effect on cell morphology, proliferation, cytotoxicity, and genotoxicity [The effect of toxicity . Thyme aUVB is known to induce oxidative stress in human skin and induce transient or persistent genetic damage, increase in activation factors, and expression of aging factors such as matrix metalloprotease (MMP). Exposure to UVB increases the expression of MMP protein, a type of collagenase that promotes skin aging and, as a result, collagen, a major protein constituting the skin dermis, is degraded or production is reduced . Jung etT. vulgaris extract showed an anti-aging effect [T. vulgaris extract and thymol inhibited the production of reactive oxygen species in keratinocytes cell lines treated with UVA/UVB. However, MDA formation was reduced only in UVA-treated cells, suggesting that T. vulgaris extract and thymol acted as antioxidants and scavengers of free radicals but did not directly reduce or prevent DNA damage. The anti-aging research results of thyme suggest that thyme essential oil can be applied as a good material for the development of anti-aging cosmetics.Another study reported that thymol from g effect . Calo etg effect  reportedPropionibacterium acnes in hair follicles when pores are clogged due to the excessive sebum production [Acne is a chronic inflammatory skin disease that is caused by excessive sebum secretion, stress, hormone imbalance, misuse of cosmetics, and internal diseases. It is also called folliculitis because of irritation caused by the process of decomposing sebum and producing free fatty acids by breeding oduction .Melaleuca alternifolia) [Eucalyptus globulus), guava (Psidium guajava) [Abies koreana [Citrus obovoides and Citrus natsudaidai [Cryptomeria japonica [Cymbopogon nardus) [Mentha spicata), thyme (T. vulgaris), cinnamon (Cinnamomum zeylanicum) [Ocimum basilicum) [Citrus aurantium), eucalyptus , juniper (Juniperus communis), rose geranium (Pelargonium asperum), patchouli (Pogostemon cablin), and benzoin (Styrax benzoe) [Many researchers reported that essential oils are effective in treating acne such as tea tree (nifolia) , eucalypguajava) , Abies k koreana , Jeju cisudaidai , Cryptomjaponica , citrone nardus) , mint (Mlanicum) , sweet bsilicum) , bitter  benzoe) . These eP. acnes and Propionibacterium granulosum. However, it is suggested that the efficacy is not very high.Oh et al.  reportedEchinochloa crus-galli and Lemna minor. Since these results have been studied only in vitro, additional tests should be conducted to determine whether they are effective even under in vivo conditions.Kim and Hong  found thThymus genus has been widely used for strengthening memory and concentration and calming nerves [Aromatherapy is a technique or practice to improve the psychological and physiological functions of humans using essential oils obtained from various medicinal and aromatic plants . Currentg nerves . AlthougThyme has a cover effect due to the fact of its nature of spreading and growing along the ground surface; thus, it is planted under street trees in Jeju Island. Bang et al.  experimeThymus vulgaris L.) that are sold as thyme on the market. T. quinquecostatus has antioxidant, antimicrobial, anticancer, anti-inflammatory, analgesic, anti-obesity, and anti-acne activities. Various physiological activities, such as sleep prolonging, soothing, whitening, skin protection, skin aging inhibitory, and plant growth inhibitory properties have been reported, but industrial application of T. quinquecostatus is insufficient. Thyme is expected to be actively utilized in various industries such as food, pharmaceuticals, pesticides, and aromatherapy; thus, the total area of thyme cultivation should be expanded.Thyme is an aromatic medicinal plant and is widely distributed in Korea. At present, thyme is used only as an ornamental and ground cover plant. There are several kinds of foreign thymes (thyme,


In order to better understand the link between High-Performance Human Resource Practices (HPHRPs) and outcomes, this study examines the mediating roles of person–job fit (PJ fit) and person–organization fit (PO fit) using congruence theory. Through a survey questionnaire, data were gathered from 296 people who work at educational institutions in China. The results demonstrated that the association between HPHRPs and outcomes is mediated by both PJ fit and PO fit. We observed theoretical implications and discovered that HPHRPs are an important antecedent that builds congruence among employees' values and goals and organizational values and goals, as well as their job goals, which in turn prevents employees from experiencing stress and developing intentions to leave their workplace. The current study adds to extant literature on education and HPHRPs by identifying PJ fit and PO fit as mechanisms through which HPHRPs demonstrate their authority on employee outcomes. The managerial implications, limitations, and directions for future studies are included in detail at the end. In contemporary work environments, the ability to attract, recruit, and retain talented employees are a prerequisite for a company's success. These factors also form employee perspectives, influencing their selection of an appropriate profession and employer, which are crucial for achieving a higher quality of work life . It also helps the manager understand the role of HPHRPs in an organizational setting and their impact on job outcomes such as employee TOIs and stress. It provides insights into the role of PO fit and PJ fit in an organizational setting.We contribute to the existing body of knowledge by identifying two important mediators between HPHRP-outcome relations and explaining this relationship with the help of congruence theory. This theory emphasizes the need to increase congruence among employees and their organizations and jobs to yield positive outcomes. In other words, HPHRPs give employees the feeling that their goals are congruent with organizational goals and their job. Employees who feel this alignment in values and goals are less likely to experience stress and tend to stay with the organization.The current study was conducted in accordance with person–environment congruence theory Holland, . The conHolland  also sugThe privatization/deregulation scenarios, the competitive climate, and technological advancements have forced management to recalibrate numerous HR and other management practices in the context of the rapidly changing global economy. Organizations are now required to use HPHRPs that increase competitive advantages due to environmental changes Gurbuz, . Many scThe current research used five HR practices in order to measure the employee's sensitivity to HPHRPs. The practices used are the most popular while analyzing the relationship between HPHRPs and employees' job-related outcomes . Demographics included age, gender, and education. Most respondents were below the age of 36 (80%), 71 % were male, and 58 % had a master's degree.**) and job stress (−0.62**) and positively correlated with the PO fit (0.68**) and PJ fit (0.66**). TOI was positively correlated with job stress (0.65**) and negatively correlated with the PO fit (−0.68**) and PJ fit (−0.63**). Job stress negatively correlated with the PO fit (−0.66**) and the PJ fit (−0.62**). Lastly, the PO fit positively correlated with the PJ fit (0.84**). The reliability of scales was examined through Cronbach's alpha. Reliability above 0.70 was considered significant . Thus, H1 was substantiated. Similarly, according to H6, HPHRPs were positively related to the PJ fit. The result showed that the HPHRPs positively affect PJ fit . Thus, H6 was also substantiated.To test the mediation effect, we employed Preacher and Hayes  process p = 0.000, beta −0.57) negatively impacted job stress through PO fit, confidence interval values also validate the significance of the indirect effect . Thus, H2 and H3 were substantiated. The results revealed that under HPHRPs, employees' levels of PO fit increased, and their level of job stress decreased.The result showed that entering PO fit mediates HPHRPs and job stress. Because HRPs  negatively impacted TOI through PO fit, confidence interval values also validated the significance of the indirect effect . H4 and H5 were substantiated and the results revealed that under HPHRPs, employees' levels of PO fit increased, and their turnover intention reduced.We found that the PO fit mediates between HPHRPs and TOIs. Because HR practices  negatively impact job stress through the PJ fit, confidence interval values also validate the significance of the indirect effect . So H7 and H8 were substantiated. Thus, the results reveal that under HPHRPs, employees' levels of PJ fit increased, and their job stress decreased.Results also showed that the PJ fit mediates HPHRPs and job stress. Because HPHRPs  negatively impact TOI through PJ fit, confidence interval values also validate the significance of the indirect effect . Thus, H9 and H10 were substantiated. The results reveal that under HPHRPs, employees' levels of PJ fit increased, and their leaving intentions were reduced.According to the study results, the PJ fit mediates the HPHRPs and TOIs. Because HPHRPs  somewhat (but considerably).Our investigation revealed a significant positive relationship between the PO fit and HPHRPs. This proves that HPHRPs share company values, goals, and aspirations with employees, energizing greater harmony between employees and groups (Boon et al., via PO fit, indicating that PO fit is a crucial mediator in these links.The outcomes presented in the present investigation indicate that HPHRPs shape the qualities and goals of employees, as HPHRPs caused major variations in the PO fit for employees in the Netherlands and Japan. The PO fit partially mediated the relation between HPHRPs and job stress/TOIs. Moreover, the PO fit had a similar effect on the two outcome variables. For job stress and TOIs, the change resulting from HPHRPs and the PO fit was 6 and 20%, respectively. The majority of the shift was brought about indirectly by HPHRPs As far as the links between PJ fit and employee outcomes are concerned, the results are in accordance with our hypotheses and previous studies (Jin et al., This investigation concentrated on PO fit, which is a popular and important fit type (Kristof-Brown et al., The findings of this study have significant practice-related ramifications. Generally speaking, achieving alignment between employees' and business values is vital if companies are motivated to improve employees' work experiences. The research demonstrated that HPHRPs, like training opportunities, elevated job security, promotion from the inside, and working independently, are compelling in this respect. Supervisors, in this way, should utilize the authoritative mission and objectives as the premise on which HPHRPs are planned. This will expand the arrangement of employee objectives and those of the association. Supervisors ought to exercise cautious thoughtfulness regarding the implementation and correspondence of HPHRPs to positively impact how employees see these practices. This will help strengthen employees' relationships with the association's way of life and reinforce their bonds with the association, which will thus make it more unlikely that they feel stressed and need to leave. Overall, this study contributed to the literature, particularly in the education sector, by identifying the ways in which TOIs and job stress can be reduced in the education sector. An important takeaway from this study is the crucial role of congruence. Employees show positive outcomes only when they think that their job and organization are aligned with them and are not moving in the opposite direction. One of the biggest lessons practitioners can take from this study is that they must adopt HPHRPs in the education sector, as it will make employees, whether they are nurses, doctors, or administrative staff, feel that their organization and jobs are in congruence with them. We can apply this concept of congruence to the whole society, especially in relationships. This means that individuals are more likely to show positive behavior when they believe they are fully aligned with others regarding goals, objectives, and much more. We tend to develop strong relationships with those who show higher congruency with us.The discoveries of this examination ought to be interpreted in light of various constraints. For instance, the present study employed a cross-sectional design, and thus, no conclusions regarding causality can be established. For instance, it is conceivable that the degree of PO fit affects how employees see HPHRPs. Employees who successfully fit in with their organizations may have a favorable opinion of HPHRPs. Additionally, it is conceivable that individuals with low levels of work-related stress believe that their companies' opinions of them are predictable. More research with longitudinal or experimental designs is necessary to address the problem of causation. Second, common method bias may have inflated the associations since self-reported data from a single source was used. Third, it is unclear which set of procedures should be used to examine the correlation between HPHRPs and employee performance. The five practices used in the current analysis may not be an accurate representation of all HPHRPs used by companies; however, they need to be. In any event, the practices included in this analysis are among those that are most frequently used in studies linking HPHRPs and employee outcomes. Lastly, for the investigation, data were gathered from employees, and a convenience sample was utilized. Thus, the findings of the current study cannot be generalized to the current environment as a whole and are limited to the sample under consideration. Future studies might want to investigate whether the findings can be generalized across organizations and other geographical regions. Despite these limitations, our analysis confirms the significance of PJ fit and PO fits public links since the effects of HPHRPs depend on how well-employees get along with their companies. Fairness and social support have also been suggested as variables that may predict stress and turnover objectives (Leiter and Maslach, via fits among employees in the education industry was well-supported by the findings of this study. The suggested links were tested in the education sector, an understudied area where research interest is growing. Thus, the work of this study strengthened the generalizability of ideas and policies in the countries examined. This is crucial since the investigation's contributing variables will significantly impact employees everywhere (Akhtar et al., In conclusion, this study provided valuable insights into analyzing how HPHRPs provide beneficial results. The impact of HPHRPs as significant drivers of employee outcomes The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of South China Normal University, China. The patients/participants provided their written informed consent to participate in this study.CY: investigation, writing—review and editing, and conceptualization. FY: investigation, methodology, software, formal analysis, and writing—original draft. Both authors contributed to the article and approved the submitted version.


Non-paroxysmal (NPAF) forms of atrial fibrillation (AF) have been reported to be associated with an increased risk for systemic embolism or death.Comparison of procedural details and long-term outcomes in patients (pts) with paroxysmal AF (PAF) against controls with NPAF in the prospective, multicentre observational registry of patients undergoing LAAC (LAARGE).p = 0.066). The total CHA2DS2-VASc score was lower in the PAF group , while HAS-BLED score  was comparable. The rate of successful implantation was equally high . In the three-month echo follow-up, LA thrombi  and peridevice leak > 5 mm  were numerically higher in the NPAF group. Overall, in-hospital complications occurred in 15.0% of the PAF cohort and 10.7% of the NPAF cohort (p = 0.12). In the one-year follow-up, unadjusted mortality  and combined outcome of death, stroke and systemic embolism  were significantly higher in the NPAF cohort. After adjusting for CHA2DS2-VASc and previous bleeding, NPAF was associated with increased death/stroke/systemic embolism .A total of 638 pts  were enrolled. In both groups, a history of PVI was rare (4.0% vs 1.6%, Atrial fibrillation type did not impair periprocedural safety or in-hospital MACE patients undergoing LAAC. However, after one year, NPAF was associated with higher mortality.The online version contains supplementary material available at 10.1007/s00392-021-01874-3. Atrial fibrillation (AF) is the most common arrhythmia with more than 33 million people affected worldwide . The risThe prospective, real world Left Atrial Appendage Occluder Registry Germany (LAARGE) is a non-randomized and independently funded registry of LAAC in Germany. This study aims to investigate if paroxysmal vs non-paroxysmal forms of AF influence safety and long-term outcomes of LAAC.The multicenter LAARGE registry is a prospective, non-randomized study with 38 participating centers. Patients were enrolled from July 2014 to December 2015. The registry is managed by the non-profit organization “Institut für Herzinfarktforschung” . There was no funding by industry. Selection of closure devices were left at the operator’s discretion. Written informed consent was obtained from all patients. The privacy measures and data collection have been described previously [2DS2-VASc and previous bleeding.The detailed procedural methods have been described previously . Patient2DS2-VASc score and previous bleeding in a multiple Cox regression model and visualized by direct-adjusted survival curves computed in a stratified Cox model, where the expected survival curves are averaged over all patients in the analysis population. All statistical comparisons were two-sided, and P values < 0.05 were considered statistically significant. Analyses were performed using the Statistical Analysis System .Normally distributed continuous data and risk scores are given as means ± standard deviation (SD), otherwise shown as medians with interquartile ranges (25th and 75th percentiles). Categorical data are presented as relative percentages and absolute values. Statistical differences between both groups were compared using either Pearson’s Chi-squared test or Mann–Whitney–Wilcoxon test. Fisher’s exact test was used for rates of in-hospital and follow-up complications. The 12-month event-rates of death, composite outcome of death and stroke, and composite of death, stroke and systemic embolism were calculated by the Kaplan–Meier method. Long-rank test was used to compare the outcomes between the groups. Hazard-ratios (HR) with 95% confidence intervals (CI) were estimated using Cox regression. Adjustment of the composite outcome was done for CHAp = 0.099) and percentage of female patients  were similar. Overall, a history of catheter ablation (CA) with pulmonary vein isolation was rare . The PAF group had significantly less history of congestive heart failure  while the left ventricular ejection fraction (LVEF) (median 60% vs 60%) and the percentage of patients with reduced ejection fraction (LVEF < 40%) were similar. Median heart rate was significantly higher in the NPAF cohort, but still adequately rate controlled.A total of 638 patients were included in the analysis. The group with paroxysmal AF (PAF) included 274 patients, while the non-paroxysmal AF (NPAF) group included 364 patients Table . The NPA2DS2-VASc score was lower in the PAF group  but the percentage of patients with a CHA2DS2-VASc score > 2 was statistically similar . There was no difference in the HAS-BLED score . An overview of indications for LAAC is given in the supplemental Table 1.The CHAp < 0.001) and LA volume  were significantly smaller in the PAF cohort compared to the NPAF cohort . The prevalence of LAA thrombus  and LAA sludge  was similar in both groups. Acute implantation success of LAAC devices was equally high  in both groups (Table p < 0.001) and significantly less in AF . Most procedures were done under conscious sedation , followed by general anesthesia . There was no difference in device selection. The number of device-retractions and repositioning  was comparable in both groups but skewing towards the NPAF group. The PAF cohort had significantly longer procedural  and fluoroscopy  times. There was no significant difference in peridevice leak  or left-to-right shunts  after the procedure.The LA diameter  in both groups (Table p = 0.55), including severe bleeding and AV-Fistula, were similar. Moderate complications were similar in both groups  as well as minor complications . The overall incidence of combined severe and moderate complications was numerically higher in the PAF cohort .Incidences of MACCE  were equally rare . Single antiplatelet therapy (SAPT) was significantly higher in the PAF cohort compared with the NPAF cohort . At discharge, dual antiplatelet therapy (DAPT) was the main antithrombotic therapy in both groups . There were no significant differences in the antithrombotic therapy at discharge or at the one-year follow-up  and peridevice leak > 5 mm  were numerically higher in the NPAF group. Overall device dislodgment was rare . Groin complications  were rare in both cohorts. Pericardial effusion was numerically higher in the PAF cohort ). There was no difference in stroke  or TIA , however, MI occurred significantly less often  in the PAF cohort compared with the NPAF cohort. In the unadjusted outcomes, the PAF cohort demonstrated significantly lower all-cause mortality , combined death and stroke  and combined outcome of death, stroke and systemic embolism  (Table 2DS2-VASc and previous bleeding) outcome of event-free survival NPAF was associated with increased composite outcome of death/stroke/systemic embolism   vs 97d 54d, 186d)), LA thrombi 2DS2-VASc score. Complications are comparable between patients with paroxysmal or non-paroxysmal AF, though procedure and fluoroscopy times are longer in the former.Among patients undergoing LAAC, non-paroxysmal forms of AF are associated with higher rates of death, stroke or systemic embolism after one year in a prospective real-world setting regardless of the CHApost-hoc analysis of the ACTIVE-W trial found no association of AF type on thromboembolic events. However, differences in anticoagulation between PAF and persistent AF and low CHADS2 scores were a major limitation [post-hoc analysis of the ROCKET-AF trial, persistent AF was significantly associated with higher systemic embolism, stroke and all-cause mortality [p < 0.0001) and follow-up encompassed only 58 days [Recently, a case series showed that LAAC is associated with acute brain lesion in MRI of unknown clinical relevance . The impmitation . In a poortality . Recentlortality . Interesortality , 14. Theortality , 14. How 58 days , 14. Whi2DS2-VASc scores (PAF: 4.4 ± 1.5 vs NPAF: 4.6 ± 1.5) to other registries such as the European EWOLUTION registry (4.5 ± 1.6). While the one-year mortality in EWOLUTION was 9.8% and thus comparable to the PAF cohort (8.4%), the NPAF cohort demonstrated a higher mortality of 14% [Our cohort had comparable CHAy of 14% , 17. Oury of 14% . We alsoWhat is more, there is evidence that NPAF is associated with larger LAA volume as well as non-chicken-wing LAA morphologies . These mWhile we could observe increasing volume of LA and LAA ostia in the NPAF cohort, this was not associated with more residual leaks in the follow-up. We observed longer fluoroscopy and procedure times in PAF patients, which might be explained by the higher rate of sinus rhythm during implant and thus potentially more challenging LAA movement.2DS2-VASc score, underlining the effect NPAF may have on outcomes after LAAC. Future studies are needed and, ultimately, randomized trials to evaluate different antithrombotic strategies after LAAC depending on AF patterns observed.Our data shows numerically higher incidences of LA thrombus in the NPAF cohort. In an analysis of 1739 patients in prospective trials or registries in the US receiving a Watchman device, DRT was significantly associated with large LAA diameter and permanent atrial fibrillation and higher risk of stroke . LikewisConfounding factors cannot be excluded due to the observational registry format. Additionally, there was no standardized process for patient screening, device selection and LAAC procedure.There may have been significant differences between the operators’ experience as well as the center volume of procedures. Also, increased experience and technical improvements may lead to more favorable outcomes in a contemporary study. Newer devices such as the Watchman FLX were not included in this study. Furthermore, we lack sufficient follow-up echocardiography data to report three-month and one-year incidences of DRT and peri-device leak. Centers were encouraged to enroll patients consecutively but not obligated; therefore, a selection bias cannot be excluded. There was no monitoring of AF burden or changes of AF pattern during follow-up but since most patients in the NPAF cohort were in longstanding persistent or permanent AF, the AF burden is unlikely to have changed during follow-up.Centers were also encouraged to report adverse events which may include a certain reporting bias.Patients with non-paroxysmal forms of atrial fibrillation undergoing LAAC are more likely to have larger LA volume as well as larger LAA size and orifices. This did, however, not impair periprocedural safety or in-hospital MACE. After one year, NPAF was associated with higher mortality, stroke or systemic embolism.Supplementary file1 (DOCX 49 KB)Below is the link to the electronic supplementary material.


Cerebrospinal fluid (CSF) and serum tau  are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear.The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them.CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM  diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software.Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment.The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS. Tau protein is one of the main types of proteins in the microtubule-associated protein family. It is a soluble protein and widely expressed in neurons . Tau proclinically definite or clinically probable ALS according to the modified EI Escorial criteria  and AM  were selected as control who were from inpatients in the same periods. A total of 90 patients who were first diagnosed with criteria  and who criteria . The patcriteria  at the tcriteria  was defin = 38; 79%), hypokalemic paralysis , low intracranial pressure , and CSF leakage  were selected as the control group. This group of OND mainly consisted of non-degenerative diseases. 25 men (52%) and 23 women (48%) with a mean ± SD age of 55.42 ± 11.83 years.A total of 48 age-and sex-matched patients with OND, including tension-type headache (Twenty patients with ALS mimic (AM) diseases served as disease control group, including two patients (10%) with multifocal motor neuropathy, 3 patients (15%) with hereditary spastic paraparesis, and 15 patients (75%) with cervical spondylotic myelopathy. The diagnosis of AM is made by the examination of cervical magnetic resonance imaging, electromyography, cerebrospinal fluid, relative gene detection and so on. All patients were interviewed and examined by neurologists from the study group who had experience with motor neuron diseases.A blood and CSF sample was collected from the same patient in the control group. All participants enrolled in this study received routine examinations on admission, including hepatic and renal functional assessments. Patients with severe cardiac, liver, or renal dysfunction were excluded.Blood samples were drawn from all study participants and centrifuged at 3,000g at 4°C for 10 min within 2 h of collection. Supernatants were stored at −80°C until the beginning of the experiment. The mean ± SD time from blood draw to centrifugation was 89.26 ± 32.59 min. The CSF samples were obtained from 48 patients with ALS, 40 patients with OND, and 20 patients with AM disease at the time of diagnosis in our department after lumbar puncture for CSF analysis, the samples were immediately centrifuged at 800g at 4°C for 5 min. Supernatants were stored at −80°C until the beginning of the experiment. The mean ± SD time from lumbar puncture to centrifugation was 85.24 ±17.82 min.The ELISA protocol used in this study is as follows: The p-tau181 original Standard reagent was diluted into 0, 0.5, 1.0, 2.5, 5.0, and 10 μg/ml. After preparing reagents, samples and standards, p-tau was added into monoclonal antibody Enzyme wells which are pre-coated with p-tau antibody: 100 μl/well of the standards and 50 μl/well of enzyme conjugate were added into the Standard wells, while 100 μl/well of the samples and 50 μl/well of enzyme conjugate were added into the test wells. After incubated for 60 min at 37°C, the plates were washed five times with the wash solution to remove the uncombined enzyme and then incubated with 50 μl/well of chromogen solution A and 50 μl/well of chromogen solution B for 10 min at 37°C away from light. After incubation, 50 μl/well of stop solution was used to stop the reaction and visualize the reaction products. And the optical density (OD) was measured at a wavelength of 450 nm by a BioTek Synergy 2 microplate reader  within 10 min. According to standards' concentrations and the corresponding OD values, the standard curve linear regression equation was calculated out, and then the corresponding samples' concentrations were obtained by applying the OD values of the samples on the regression equation. ELISA for t-tau is the same as p-tau, except the original Standard reagent was diluted into 0, 50, 100, 200, 400, and 800 μg/ml. Non-measurable p-tau or t-tau samples were reported as 0 μg/ml. If required, samples were appropriately diluted to be within the range of the standard curve.t-test or Mann-Whitney U test when two sets of data are compared. Pearson correlation test was used for statistical correlations between CSF and serum p-tau level, t-tau level, and either MMSE, MoCA, ECAS, UMN, or ALSFRS-R scores, time onset, or the DPR. Statistical data were expressed as the mean ± SE. All P-values were 2-sided, and statistical significance was set at P < 0.05. Data were analyzed from May 15, 2019, to March 05, 2020.All graphs were generated using GRAPHPAD PRISM, version 7 . Normal distributions of data sets were checked using quintile-quintile (Q–Q) plots. One-way ANNOVA analysis were conducted when compared among ALS, OND and AM. Whereas, the results were compared after testing for normal distribution using either the Student There were no significantly differences in age, gender, BMI, BG, Chol, TG, LDL-c, HDL-c and education among ALS, OND, and AM. Details of the patients and controls are summarized in P = 0.8720) and AM , data shown in P = 0.7989; and AM, 341.9 ± 10.44 pg/mL, P = 0.9731), data shown in P < 0.0001), the CSF p-tau levels in patients with OND (23.64 ± 1.49 pg/mL) were significantly higher than AM . There was no significant differences in CSF p-tau between ALS (4.19 ± 0.32 pg/mL) and AM . In addition, The serum p-tau level in ALS (51.61 ± 2.32 pg/mL) was lower than that in the OND , differences were not found in serum p-tau levels between patients with ALS (51.61 ± 2.32 pg/mL) and AM , data shown in We first examined the levels of p-tau and t-tau in both the CSF and serum. Results indicated that there was no significant difference in CSF t-tau level between patients with ALS (101.30 ± 5.33 pg/mL) and control patients  in the ALS patient group and AM group  was significantly lower than that in the OND group (9.31 ± 1.49). In addition, there was no significant difference in serum p-tau:t-tau ratio among patients ALS (15.3 ± 0.37), OND (16.8 ± 0.63) and AM (15.26 ± 0.52); data shown in The ratio of CSF p-tau:t-tau  was higher than that of patients without cognitive impairment . There was no significant difference in the CSF t-tau level between patients with ALS and cognitive dysfunction  and patients with ALS and no cognitive dysfunction , MoCA score (r = −0.4906 P = 0.0004); data shown in r = −0.5502; P = 0.0009), and ALS-specific score , especially in excutive function  and verbal fluency in patients with cognitive impairment . However, there was no correlation between CSF p-tau level and language score  or ALS non-specific score . In addition, CSF p-tau level in patients with ALS were negatively correlated with UMN score changes at 6 months  in a broader ALS population could not be established. Future studies should be well designed and include a higher number of ALS patients with defined categories in the EI Escorial criteria from multiple centers. In addition, further genotyping of ALS will help to explore the value of CSF p-tau.In this study, we found that the CSF p-tau level and the p-tau:t-tau ratio were lower in patients with ALS. In patients with cognitive impairment, CSF p-tau was negatively correlated with MMSE scores, MoCA scores, total ECAS score, and specific ECAS score, particularly in executive function and verbal fluency. However, there was no correlation found between CSF p-tau level and language score. In brief, the results of this study suggest that CSF p-tau may be considered a potential index of cognitive impairment in patients with ALS. However, several limitations of this study must be kept in mind. Firstly, serum tau levels varied greatly between our study and other studies; our study includes ALS patients from China, and so the natural history and clinical features are quite different between China and Western countries . SecondlThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee from Tianjin First Central Hospital. The patients/participants provided their written informed consent to participate in this study.ZG contributed to the conception of the study and performed the data analyses and wrote the manuscript. LG performed the experiment. YL contributed significantly to analysis and manuscript preparation. ZW helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.This work was supported by the Tianjin Health Committee  and the Chun Technology Fund CF201806 from Tianjin First Central Hospital.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques—dissimilar to SCS—mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted. With the first successful transplantation of a whole liver, donated after circulatory death (DCD), Starzl et al. launched the era of liver transplantation (LT) in 1963 . Based oOne direct consequence appears with an ever-increasing number of candidates listed for transplantation, along with a growing acceptance of new indications, including primary and secondary liver tumors. To serve this large pool of recipients, clinicians accept livers from donors with a completely different risk profile today compared to previous decades. Donor livers with increased risk are classified as ECD today. Although a few “classic” risk factors, such as donor age or DCD, are considered by many, this group of livers is the most heterogenous cohort identified .Of note, regulations and ethical considerations in countries, regions, centers and even among individual surgeons impact the definition of organ marginality. The best example appears with donor age. While DCD livers with an age beyond 50 y are considered as extended risk in the United States (US), such grafts are routinely transplanted with standard cold storage (SCS) in experienced centers in some European countries ,7. SimilWith increasing experience, the criteria of acceptable donor quality were stretched and balanced with the recipient risk factors in several prediction models ,10,11,12The underlying mechanisms of injury described after the reperfusion of cold-stored ECD livers point to a high relevance of the mitochondrial metabolism, which is directly linked to the overall metabolic situation in the donor ,18,19. TSuch concepts of dynamic organ preservation provide the additional opportunity to test organ viability before implantation to safely increase the use of ECD organs ,22.This review provides an overview on the various types of ECD livers and related classifications used today. Mitochondria are another focus, and their role as key instigators of the inflammatory IRI cascade and as targets for dynamic preservation strategies is highlighted. Finally, the clinical outcomes achieved with different perfusion strategies are described and challenged among each other together with a future perspective and remaining challenges in this interesting field.While regulations and center policies certainly impact decision making, the classification of a donor liver, as ECD is frequently based on the surgeon’s experience or “gut feeling” ,23. DespThe heterogenous group of ECD livers covers two main groups: first, livers with the risk for poor graft function, and second, livers from donors with a specific disease with the potential for transmission to the recipient. With the increasing experience with donor infections and tumors, fairly clear guidelines on what to accept are available and widely respected ,25,26,272; liver steatosis of >40% and elevated serum sodium, transaminases and bilirubin ..8].Additional risk may be conveyed through past medical donor history, which may have a negative impact on arterial vessels, the subsequent donor cannulation and may appear with suboptimal liver perfusion before and during donation. Such features may be related to donor arteriosclerosis, arterial hypertension, cardiomyopathy, right heart failure with the need for cardiac-assist devices or diabetes ,100. DueSplit liver transplantation, introduced in the eighties, appears as the key to reduce waiting list mortality, together with living-related liver transplants. One deceased donor liver is shared between two recipients, and the split procedure can be performed in- or ex situ, with inherent benefits to both approaches. The smaller left lateral segment is often used for children and the larger extended right lobe for an adult or adolescent candidate . The theA suitable vascular anatomy for later reconstruction and age/weight-related donor recipient size matching are routinely considered . A recenConsidering the current logistic challenges and the frequent traveling of grafts from the donor to the split and recipient center, a CIT of 6 h is a significantly limiting factor. The better understanding of risk factor boundaries, along with increasing experience  and the introduction of a mandatory split policy, as, for example, in Italy, can increase the utilization. DCD livers are rarely considered for splitting due to an overall too-high risk. More recently, MP techniques are used for these organs during and also after the split procedure, which will be presented in more detail below ,103.Donors and grafts are always accepted in the context of the overall recipient status and risk. The entire spectrum, including recipient age, BMI, lab MELD and the medical history, is considered together with the technical risk parameters, such as advanced portal vein thrombosis or a candidate listed for retransplantation, are of particular importance . Such fa2. Values above >29.9 kg/m2 were linked with significantly more infections and a prolonged hospital stay when compared to recipients with a normal body weight [2 [A team from Leeds found an additional increasing number of complications with an elevated recipient BMI of >24.9 kg/my weight ,105. Theeight [2 .The recipient disease severity is another contributor, and patients with a lab MELD of >30 points are known for their higher risk of intra- and postoperative complications with prolonged ICU and hospital stays. In combination with advanced age, an elevated recipient lab MELD of >25 points was linked to higher early posttransplant mortality rates, when, for example, combined with DCD grafts or an otherwise elevated donor risk and in the context of SCS ,68.Of additional impact is the underlying recipient liver disease, with a general reluctance to allocate ECD livers to candidates with non-alcoholic steatohepatitis (NASH), a recipient cohort known for their relevant comorbidities being prone to cardiovascular complications .During ischemia, cellular hypoxia leads to an invisible instigation of the rather complex IRI cascade. The key players here are mitochondria—the powerhouse and energy provider in all sorts of mammalian cells. The most exclusive mitochondrial function is cellular respiration, with the final product crucial to the survival of all cells: adenosine triphosphate (ATP). A cascade of enzymatic reactions of the tricarboxylic acid (TCA) cycle generates reducing metabolites to transfer electrons across the mitochondrial respiratory chain, where electrons are funneled through complex proteins I–IV to generate potential across the inner mitochondrial membrane, which is required to produce ATP. This process is strictly oxygen-dependent ,108.One important enzyme, participating in both the TCA-cycle and the electron transport chain, is succinate dehydrogenase (SDH). During ischemia and with the lack of oxygen, cellular respiration switches from aerobic to anaerobic. Molecules, including NADH and succinate, and other precursors of the TCA cycle accumulate, and the cells suffer a lack of energy with steadily decreasing ATP with prolonged ischemia and due to nonfunctioning cellular respiration ,110. In The functions of the respiratory chain are reactivated, and the electron flow is immediately restored. As a result, and with the proper function of a major proportion of the mitochondria in a cell, the levels of ATP increase and may fuel the augmenting metabolic demand at higher temperatures ,108,110.The higher the injury  with high succinate levels, the more ROS molecules are released from complex-I and pass through the inner mitochondrial membrane to cause injury to other cellular components, initiating a downstream cascade of tissue injury and inflammation. The first wave of IRI is the hyperacute injury, where the ROS and DAMPs (damage-associated molecular patterns) are released from all cell types and contribute to the acute inflammation of the overall tissue, characterized by type modifications of macrophages and their additional contribution to the cascade. This scenario is followed by the chronic phase, where circulating recipient immune cells, e.g., monocytes, are recruited and infiltrate the newly implanted organ to further enhance the injury.Various cytokines and chemokines are released and recirculate to enhance and endure the ongoing inflammation. Once prolonged, ongoing inflammation leads to the development of tissue fibrosis and stiffness with clinical signs of example biliary complications, such as ischemic cholangiopathy.The impaired capability of cells to regenerate, e.g., hepatocytes and cholangiocytes further aggravates this. The extent of this IRI tissue injury is ultimately associated with posttransplant complications, including early allograft dys- or nonfunction. The level of IRI is directly linked with the donor quality, and every manipulation and additional injury between the donor and recipient contributes further. Key interventions should therefore target the mitochondria as the main initiators of this injury and reduce or ideally prevent the accumulation of succinate with the subsequent reduction of ROS release. Despite the general awareness of such mechanisms for many decades, novel treatments are being increasingly developed to block downstream inflammation instead of preventing such an injury in the mitochondria right at the root of IRI. Cytosorb filters are one example of an expensive add-on during MP with a still not well-described effect but high contributions to the cost ,112.Based on the above-described mechanisms, a detailed plan was recently provided on how to prevent significant IRI features. Two main options to prevent succinate accumulation and engery loss were evaluated: first, in the donor, or early during the donation. The second option implies a continuous metabolism of succinate together with ATP-reloading, a mechanism requiring the reintroduction of oxygen (reperfusion), which should, however, be achieved without the “price” of ROS release .Currently explored dynamic preservation concepts span the same goal to provide oxygen to preinjured ischemic tissues and to avoid additional injury, e.g., further succinate accumulation. Such concepts are increasingly well-explored in DCD grafts, while the impact on outcomes with the transplant of other ECD liver types requires further studies. This last subsection will highlight the current concepts of MP, with a focus on the clinical results after transplantation, considering the initial donor/recipient risk and the underlying mechanism of protection or injury.Human beings naturally expect the superiority of normothermic perfusion techniques over every other strategy performed in the cold due to the “healthy” appearance of organs during a perfusion at 37 °C with a blood-based perfusate . Organs This is in clear contrast to the metabolism seen in mitochondria with very minimal ROS production and injury when tissues receive oxygen under hypothermic temperatures below the Arrhenius break point of 15 °C  72,110,,110,114.Two main normothermic perfusion concepts are currently applied to human organs before implantation. First, normothermic regional perfusion (NRP), where the donor blood is reoxygenated and recirculated after canulation, and when the donor WIT and stand-off periods have passed . This apThe leading countries using this technique routinely for DCD liver procurement are Spain, France, Italy and the United Kingdom (UK) ,118,119.The results after transplantation are available from multiple local or national case–control studies demonstrating the superiority of NRP combined with cold storage compared to the standard cold storage alone. Based on the opportunity for donor cannulation prior to treatment withdrawal in Spain, the duration of functional DWIT appears rather short, with 10–14.4 min in the recent series .A large Spanish series of 545 controlled DCD livers procured with NRP showed excellent outcomes, provided the cold storage after NRP and the recipient risk was controlled . Such reOf great interest is also the recent comparative study from Cambridge. Watson et al. analyzed the outcomes after DCD LT comparing NRP with normothermic machine perfusion (NMP) . In contIn contrast, an early reoxygenation with NRP after DWIT and before 6.7 h of cold storage achieved better outcomes with less biliary complications and better graft survivals . Of inteBased on the current literature, normothermic reperfusion seems more efficient when done instead or before cold storage, e.g., in the donor, with additional advantages conveyed by “natural” liver positioning and the contribution from other abdominal organs. Such results are further supported by a recent matched cohort study where NMP after short cold storage achieved similar results as DCD transplantation with NRP  123,126126,127. One remaining challenge to compare and identify the most beneficial MP techniques in the “jungle of literature” is inconsistent risk reporting. DCD livers with extended donor risks are routinely transplanted in Italy, where a 20-min stand-off period contributes to a prolonged functional DWIT of 40–43 min ,42. Most2: 20 kPa) was used, the importance of a high-perfusate oxygen concentration has become increasingly understood [Hypothermic perfusion techniques are routinely applied after standard procurement and transport in the recipient center. While, in the first clinical study, reported in 2010, an artificial perfusion solution without additional oxygenation (pOderstood . When oxderstood ,114,132.The reason behind this is the slow restart of aerobe oxygenation with a forward electron flow, the subsequent slow and steady metabolism of accumulated NADH and succinate and effective ATP-reloading. These mechanisms were demonstrated in various solid organs, not only in ECD livers ,135,136.In addition to NMP, hypothermic concepts are also increasingly used to prolong the overall preservation with prospective ongoing studies to safely move transplantation into the daytime ,145,146.To identify the best combination of viability markers, which enable the reliable outcome prediction during MP is another key target today. To achieve this high-end goal, the underlying mechanisms of IRI and their instigators should be considered. Biochemical molecules are quantified in perfusates and bile during all sorts of MP with controversial results, however, and modifications of the suggested parameters with threshold shifts, presented by the same groups, are ongoing ,151,152.To establish improved preservation protocols of ECD organs with reliable assessment tools to understand the metabolic risk and to predict posttransplant outcomes is the holy grail of organ transplantation today. Despite the large body of literature presented in the last decade, the implementation of MP in routine practice appears slow, which is based on various challenges previously described. The heterogenous experience of transplant surgeons with donor risk profiles in different countries and centers contribute to the difficulties for the routine adoption of new MP techniques worldwide. Based on the lack of cost analyses, only a few techniques have already been commissioned, and further progress depends on convincing data obtained from regional cost–benefit analyses. Another hurdle appears with the frequent need to locally confirm excellent outcomes shown in another region or center with one specific perfusion technique. Additional work is required to establish more uniform guidelines for the donor risk, utilization rates, trial endpoints and perfusion techniques to enable the standardized use of MP for ECD organs and the comparison of risk factors and related outcomes . Despite


Hemorrhagic Fever with Renal Syndrome (HFRS) is the most frequently diagnosed zoonosis in Asia. This zoonotic infection is the result of exposure to the virus-contaminated aerosols. Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability. Several species of orthohantaviruses were identified as causing infection, where Hantaan, Puumala, and Seoul viruses are most common. Orthohantaviruses are endemic to several Asian countries, such as China, South Korea, and Japan. Along with those countries, HFRS tops the list of zoonotic infections in the Far Eastern Federal District of Russia. Recently, orthohantavirus circulation was demonstrated in small mammals in Thailand and India, where orthohantavirus was not believed to be endemic. In this review, we summarized the current data on orthohantaviruses in Asia. We gave the synopsis of the history and diversity of orthohantaviruses in Asia. We also described the clinical presentation and current understanding of the pathogenesis of orthohantavirus infection. Additionally, conventional and novel approaches for preventing and treating orthohantavirus infection are discussed. Orthohantavirus family Hantaviridae [Orthohantavirus are human pathogens: Hantaan virus (HNTV), Seoul virus (SEOV), Puumala virus (PUUV), and Dobrava-Belgrade virus (DOBV). Presently, 38 orthohantavirus species have been identified [Orthohantaviruses, are zoonotic pathogens belonging to the genus aviridae ,2. Multientified , out of entified ,5. HFRS entified . The groentified ,7,8.Orthohantaviruses have a negative sense single-stranded RNA genome, which is organized into three segments: small (S), medium (M), and large (L) . These ROrthohantaviruses are endemic in many Asian countries, with the largest number of cases reported in China, South Korea, and the Far Eastern Federal District of Russia . This reIn China, febrile disease with renal dysfunction was documented as early as 1931 . Since tStill, HFRS is endemic in the Far Eastern Federal District of Russia, where 3145 cases were reported in 15 of the 29 regions of Asian Russia between 1978 and 1995 . It was Symptoms like HFRS were also described in approximately 1700 US soldiers during the Korean War 1950–1953), with less than 5% resulting in deaths . Later, 50–1953, Apodemus agrarius lung tissue, which reacted with convalescent serum from HFRS patients [Hantaan virus, was identified as a member of the family Bunyaviridae [The identity of an infectious agent was revealed several years after, following a retrospective study of clinical cases. In 1978, Dr. Lee isolated the etiologic agent of hemorrhagic fever from the patients . The moraviridae .Hantaan virus, now known as SEOV, which caused severe HFRS in Seoul city residents [In 1980, antibodies to the causative agent of epidemic nephropathy (NE) were detected in the bank vole . Later aesidents .Orthohantavirus named Thottapalayam virus (TPMV) [Suncus murinus) [Orthohantavirus of the family Hantaviridae, later, TPMV was shown to form a phylogenetically distinct genus [Thottapalayam thottimvirus, which is a proto-type shrew-borne orthohantavirus that belongs to the genus Thottimvirus. In addition to Vellore, a high rate of orthohantavirus seropositivity was reported in healthy individuals from the Cochin and Chennai regions of India [The first cases of suspected orthohantavirus infection in India were reported in 1964 in Vellore . Investis (TPMV) ,27. Initmurinus) . Althougof India . Analysiof India . In anotof India . These rRattus norvegicus was the most common rodent species captured in that region, and these rodents were major contributors to orthohantavirus circulation in small mammals in the region. Using reverse transcriptase polymerase chain reaction (RT-PCR), SEOV was detected in Rattus norvegicus in lung tissues. As a result of further analyses, it was discovered that almost all orthohantavirus infections in Taiwan were caused by SEOV [Hantavirus-reactive antibodies were found in serum samples from 5461 small mammals belonging to 16 different species in Taiwan . It was  by SEOV .Bandicoot indica species. It was shown that these rodents were carrying the Hantaan-like virus [Thailand orthohantavirus (THAIV).Also, 3.8% of rodents captured in the Nakhon Pathom region were seropositive for orthohantavirus antigens . All theke virus . Antibodke virus . Later tFor the first time after the detection of hantaviruses, the prevailing opinion was that their carriers were rodents; however, later studies have identified hantavirus antigen (virus) or/and specific antibodies in domestic animals, such as cats, rabbits, and dogs . A case More than 38 orthohantavirus species are known to cause human disease worldwide. While 20 are associated with the disease in Asia, the spectrum ranges from acute febrile illness with or without renal impairment, fever with shock, and multi-organ failure to hemorrhagic illness such as HFRS. Hemorrhage and acute renal injury (AKI) are common clinical manifestations in severe HFRS cases .Nephropathia epidemica (NE), a mild form of HFRS linked to PUUV infection, is diagnosed in Russia [Clinical presentation of HFRS may range from subclinical, mild, and moderate to severe. HTNV, DOBV, and AMRV are more often cause severe HFRS, while the moderate form is frequently diagnosed in SEOV causes. Also, n Russia .The incubation period of HFRS generally ranges between two and four weeks; however, in some cases, it could be as long as six weeks . ClinicaThe febrile phase usually lasts three to seven days and is characterized by high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. Symptoms are non-specific, making orthohantavirus infection diagnosis challenging during this phase. By day three to four post-onset, hemorrhagic manifestations appear in the forms of diffuse petechiae on the conjunctiva and the palate. AKI symptoms of hematuria and proteinuria become evident by day seven of the disease .Shock is typical for the severe form of HFRS. Approximately 11–40% of febrile patients develop hypotension, and one-third have a shock . The hypThe oliguric phase lasts three to seven days. Patients are at risk of hypotension, severe pulmonary edema, and AKI, as symptoms of oliguria, anuria, proteinuria, hematuria, and azotemia are commonly described. The severe form of HFRS could require hemodialysis at this phase. This is the critical phase, as half of the total fatalities occur during this phase. Typical laboratory findings are elevated serum creatinine and urea ,55. The Convalescence is usually extended and could last up to six months. Recovery is complete, though sequelae of chronic renal failure and hypertension have been reported ,57. The It is believed that orthohantavirus infection results from inhaling virus-contaminated aerosol or other forms of contact with the virus ,62. The Infection of respiratory epithelial cells and dissemination of orthohantavirus happens early before clinical symptoms can be identified . SeveralSlow virus replication capacity could contribute to delayed symptom development after the beginning of viremia .Infection of endothelial cells is the next crucial step in orthohantavirus pathogenesis. Orthohantavirus most likely reaches the endothelial cells of the respiratory tract at the gas exchange membrane site first. Then, viremia follows, making endothelial cells of the small vessels the main target of infection . EndotheInfection and replication in endothelial cells appear essential for the pathogenesis of orthohantavirus disease. There are three main consequences of orthohantavirus infection of endothelial cells: (a) loss of the endothelium barrier integrity, (b) activation of coagulation, and (c) release of cytokines and activation of the immune response. The loss of the blood tissue barrier function will increase vascular permeability leading to edema and hemorrhages . OrthohaLoss of endothelium barrier function: Orthohantaviruses endemic in Asia use beta integrin receptors to adhere to and penetrate endothelial cells [al cells . Virus ral cells ,68,80. Tal cells . In anotal cells . This coal cells , was foual cells . Anotheral cells . Krautkral cells . Recentlal cells  and Jangal cells . Its invData in vivo supports increased endothelial permeability in orthohantavirus-infected patients. These include finding a decreased serum level of the glycocalyx in HFRS . Also, aActivation of coagulation: Decreased expression of von Willebrand (VW) factor in HNTV-infected endothelial cells was demonstrated by Cho et al. [o et al. . Also, wo et al. . Our dato et al. . Thromboo et al. , can diro et al.  and cleao et al. . In the o et al. .There is evidence of disturbed hemostasis in orthohantavirus-infected patients. Thrombocytopenia is an early and most consistent sign of HFRS, indicating disturbed hemostasis ,96. It aCoagulation is activated in the acute phase of the infection ,100. An Blood coagulation is a process where dynamic and complex interactions between platelets and endothelial cells lead to the formation of the initial platelet plug ,105 Fig. TypicalAdditionally, an increased activity level of the circulating extracellular vesicle tissue factor was shown in HFRS . More prRelease of cytokines and activation of the immune response: Human endothelial cells are mainly targeted by orthohantaviruses. Infections of these cells appear to be essential for compromised endothelium barrier function. Endothelial cells were also shown to produce and release cytokines, which was demonstrated in vitro [in vitro ,114. Aftin vitro   approved vaccine to prevent orthohantavirus infection. Likewise, local authorities do not approve the orthohantavirus vaccine in endemic areas such as Europe and North and South America [ America . However America . Inactiv America ,174. In  America . Since t America . Started America . Since t America . The vac America .During the 30 years of the HFRS vaccine development, novel approaches were developed to improve the delivery, orthohantavirus antigens expression, the efficacy of the immune system activation, and reducing side effects.Inactivated vaccines: These were the first type of vaccines containing inactivated orthohantavirus virion [s virion . HNTV was virion . In 1990s virion ,180. Neus virion . Lesser s virion . Studiess virion ,182. Alss virion . Later ss virion . In anots virion . Also, ts virion .Inactivated hantavirus vaccines in South Korea demonstrated controversy regarding their effectiveness . In contBivalent, HNTV, and SEOV inactivated orthohantavirus vaccines were manufactured in China . The perVirus-like particle (VLP) vaccine: Inactivated vaccines effectively activate the humoral immune response. However, these vaccines had substantial limitations, such as failure to induce long-term antibody response, multiple immunizations, and potential side effects. Therefore, there was still an interest in developing vaccines that could address these obstacles. VLP vaccine could provide a solution to some of these limitations. Several VLP is nano-sized self-assembly competent structures made by viral proteins [proteins . They haproteins ,193. Theproteins . As a reThe efficacy of the VLP containing HNTV N and Gn/Gc proteins was tested in a mouse model . To enhaProduction of anti-orthohantavirus antibodies was evidenced after immunization with chimeric hepatitis B virus (HBV) particles containing PUUV N protein polypeptide . These cDNA vaccine: DNA vaccines have multiple advantages as compared to inactivated vaccines. DNA vaccines are safe, as they are replication defective. They are also non-virulent and fail to produce clinical symptoms of the disease. As early as 1992, the HNTV DNA vaccine expressing N and G proteins was developed using the vaccinia virus as a vector [a vector . This vaa vector .Interestingly, anti-HNTV neutralizing antibodies were detected in immunized animals. In contrast, there were no antibodies to the SEOV virus. In clinical trials phase I, neutralizing antibodies was demonstrated in immunized individuals. However, previous exposure to the vaccinia virus appears to interfere with the efficacy of developing neutralizing antibodies in volunteers .DNA vaccines appear to be immunogenic and induce neutralizing antibody responses. For example, two DNA vaccines, HTNV and PUUV, were tested in phase I clinical trials . Both vaSubunit vaccines: Orthohantavirus Gn/Gc and N proteins could elicit a strong humoral immune response [response ,208,209.response , while Nresponse . Additioresponse ,213. N presponse ,214. Simresponse . In anotresponse . Recentlresponse . Howeverresponse .There are no specific post-exposure therapeutics for HFRS. Therefore, treatment may differ between healthcare facilities adapting to patient management protocols based on local regulatory authority’s recommendations. Therapeutics to treat HFRS could be classified as targeting viruses, immune response, and supportive therapy.Therapeutics targeting viruses could block virus entry and replication. Neutralizing antibodies can bind to surface glycoproteins, preventing binding to integrin receptors. Transfer of orthohantavirus convalescent serum containing neutralizing antibodies was shown to have a protective effect in the non-randomized multi-center trial . Also, tNovel therapeutic approaches targeting orthohantavirus entry are still in the development stage. One is based on the peptides binding to αvβ3 integrin receptors . OrthohaAnother approach targets virus replication. One of the earliest drugs tested for its therapeutic efficacy against the orthohantavirus infection is Ribavirin. Ribavirin is a nucleotide analog  used to treat HFRS ,227. TheTargeting the immune response: Activation of the kinin–kallikrein system and liberation of bradykinin were shown in endothelial cells infected by HNTV and ANDV [and ANDV . This brand ANDV . Similarand ANDV  in anothCorticosteroids are most commonly used for treating orthohantavirus infection for their anti-inflammatory effect . Also, dSupportive therapy: Supportive therapy is fundamental for HFRS management. Fluid and electrolyte replacement therapy maintains blood pressure [pressure . Thrombopressure . Additiopressure .Orthohantavirus diagnosis is based on clinical presentation, epidemiological data, and detection of serum antibodies. The diagnosis in endemic areas is often based on clinical symptoms and the presence of IgM. However, the expertise of a healthcare provider is essential for early diagnosis and appropriate treatment. Kim and Han reported that 54% of HFRS patients were misdiagnosed at admission  due to uAnother challenge could be HFRS diagnosis in children. This is mainly because the disease is commonly mild at this age . Zhang eOrthohantavirus infection is an endemic zoonosis in Asia. Several serotypes, such as HNTV, PUUV, and SEOV, were identified as causing HFRS in China, South Korea, and Japan. China remains the most active HFRS epidemic region, where 90% of all orthohantavirus infections diagnosed worldwide are documented. HFRS clinically is characterized by AKI and increased vascular permeability. There are limited specific treatment options. Therefore, the most effective approach for HFRS management is to prevent infection. Recently, novel orthohantavirus serotypes have been isolated from small animals habituating in India and Thailand. These data provide evidence for the emergence of new genotypes of orthohantaviruses in Asia.HFRS management remains challenging due to limited therapeutic options specifically targeting orthohantavirus entry and replication. Therefore, the treatment protocol is mainly symptomatic. In this view, the measures to prevent orthohantavirus infection appear essential to control outbreaks. Currently, the only vaccine approved for the prevention of orthohantavirus infection is Hantavax, which could protect against HNTV and SEOV, the orthohantaviruses endemic in Asia. These vaccines could induce long-term immune response with antibodies detected 33 months post-immunization.Among the novel approaches in treating orthohantavirus infection is using monoclonal antibodies with neutralizing activity against HNTV. These antibodies demonstrated therapeutic efficacy in the I and II phases of clinical studies in the early stage of HFRS. Another novel therapeutic approach is targeting orthohantavirus via αvβ3 integrin receptors.The emergence of orthohantavirus infection could impact the healthcare system in many Asian countries that have limited experience in diagnosing and treating emerging infections. Therefore, awareness of the circulation of orthohantaviruses and associated healthcare burdens is essential for developing prevention measures. One approach could be integrating screening small mammals for orthohantavirus antibodies and antigens using ELISA or PCR methods into epidemiological surveys. Also, serological testing of febrile patients for anti-orthohantavirus IgM could facilitate early diagnosis of orthohantavirus infection in non-endemic countries. Additionally, analysis of the seroprevalence in the human population could provide a better understanding of orthohantavirus infection prevalence, especially in non-endemic regions.