Previous research has identified the main predictors of being a victim of school bullying. This study focused on the phenomenon of school bullying and its relationship with self-perceived emotional intelligence. The main aim was to analyze the mediating effect of emotional attention, clarity, and repair in relation to school victimization. The sample was made up of 822 primary school pupils from 10 public schools. Data were collected through self-reports, exploring the profile of victims of school bullying, and the dimensions of self-perceived emotional intelligence (PEI). A multivariate analysis and multinomial regression showed a relationship between the two variables; the probability of being a victim of school bullying was 5.14 times higher among pupils with low clarity, 2.72 times higher among pupils with low repair, and 2.62 times higher among pupils with excessive attention. The results demonstrated that the better their emotional regulation and understanding, the less likely pupils are to be victims of school bullying. This confirmed that adequate emotional attention and excellent emotional clarity and repair are protective factors against victimization. Bullying is acknowledged around the world as a serious problem in educational settings during childhood and adolescence . Due to This phenomenon is defined as a form of abuse perpetrated by peers repeatedly over time ,5 and isSchool bullying gives rise to two profiles: an aggression profile and a victimization profile. The aggression profile is determined by students building an aggressive and generally violent relational dynamic toward those they see as weak, while the victims are usually the target of hostile attacks without any incitement, systematically suffering the situation with a great degree of emotional intensity that can lead to severe states of anxiety or depression and social isolation ,9. A perAdequate interaction with peers in a school setting is usually a source of emotional support , but pupPrevious research has identified a series of predictors of these adverse effects. One study found that the main predictors of being a victim of bullying at primary school were being a boy, being younger, exhibiting internalizing and externalizing problems, having poor academic performance, having parents with a low socioeconomic status and a low education level, and having little family support and affectivity ,23,24,25However, not all victims experience negative consequences: some children respond better to bullying due to the presence of certain protective factors such as resilience , family support, and support from their peers . TherefoAlthough the concept of emotional intelligence has been significantly developed, it is not free from controversy. There are two different concepts for emotional intelligence; one considers it a combination of a series of attributes related to personality , the othSalovey and Mayer’s ability model ,30 consiEmotional intelligence in interactions with peers is considered essential for good social adaptation and positive, mature personal relationships ,39. SeveSome studies have focused on emotional processes as regulators and mechanisms for controlling aggressive behavior and victimization among peers . EmotionStudies analyzing emotional intelligence in the context of school bullying have shown that students who suffer a great deal of intimidating behavior or bullying present low levels of emotional intelligence . The finIn the context of these considerations, this study focused on the phenomenon of school bullying and its relationship with self-perceived emotional intelligence. Drawing on previous research linking a lack of emotional intelligence with bullying, the main aim of the study was to analyze the mediating effect of the dimensions of emotional intelligence—attention, clarity, and repair—in relation to school victimization. As factors of protection against victimization, we expect to feel emotions and express feelings without hypervigilance , to know and understand our emotions, to be able to distinguish one from another, to understand how they evolve and to integrate them into our thinking , and to regulate and control positive and negative emotions, moderating or intensifying them at our convenience . The participants were among 20,000 pupils enrolled in years 5 and 6 at primary schools in the autonomous community of Extremadura, Spain, during the 2018–2019 school year, considering a sampling error of 3.5% and a confidence level of 96%. The total sample was made up of 822 primary school pupils from 10 public and semi-private schools, selected using intentional or convenience sampling; 45% of the sample of primary school pupils were in year 5, and 55% were in year 6. The age range was 10–12 years ; 46% were female and 54% male.The SCQ  is a selTo evaluate self-perceived emotional intelligence, the Spanish version of the Trait Meta-Mood Scale-24 (TMMS-24) questionnaire was used . The queThe authors of the questionnaire classified the scores for the different dimensions in three categories: low, adequate, and excessive or excellent, with different cut-off points for boys and girls. In the emotional attention dimension, the cut-off points are: low attention , adequate attention , and excessive attention . In the emotional clarity dimension, the cut-off points are: low clarity , adequate clarity , and excellent clarity . In the emotional repair dimension they are: low repair , adequate repair , and excellent repair . High scores in clarity and repair indicate a good emotional intelligence in these dimensions, but this is not the case for emotional attention, as high scores can indicate an excessive vigilance of emotions and a need to improve this aspect.To carry out this research, the first step was to contact headteachers and teachers from the selected schools to explain the study objectives and to request their collaboration and permission. A consent form was then sent to parents and guardians, and the pupils who were given permission to participate were included in the study. The data collection process involved administering questionnaires by class group during school hours. The questionnaire took approximately 25 min to complete, in a quiet atmosphere to avoid pupils sharing opinions and contaminating the data. The ethical guidelines set out by the American Psychological Association were followed, ensuring the anonymity of the responses, the confidentiality of the data, and the exclusive use of this data for research purposes. The study was approved by the ethics committee of the University of Extremadura, Spain.Reliability analyses  and confirmatory analyses of the instruments were carried out, followed by a multivariate analysis of the mean scores in the different dimensions of emotional intelligence , based on the degree of victimization . Finally, as the authors of the TMMS-24 established three categories  for the different dimensions of emotional intelligence, and the victim scale includes three degrees of victimization based on frequency, it was necessary to conduct a multinomial logistic regression to establish the degree of association between the study variables, calculating the odds ratios and the respective 95% confidence intervals. Statistical analysis was carried out using the SPSS 21.0  package for PC and JASP Free.The victim scale exhibited good internal consistency, with Cronbach’s alpha (α = 0.84) and McDonald’s omega (Ω = 0.856). With respect to the TMMS-24, the reliability of each component was: attention ; clarity ; repair . To determine whether the models found in the original validation study of the questionnaires properly adjusted to our data, we used GFIs (goodness-of-fit indexes) . The adjA correlation analysis of the variables in the study was carried out. Multivariate comparison of the mean scores in the attention, clarity, and emotional repair dimensions of the TMMS-24 was carried out based on the degree of victimization , gender, and the interaction between the two variables .λ = 0.954, F = 6.472, p < 0.001, η = 0.023), but no significant main effect was found for gender  = 0.198, p = 0.898, η = 0.001) or the interaction between the degree of victimization and gender  = 1.904, p = 0.077, η = 0.007).The multivariate analysis (MANOVA) showed a significant main effect of the degree of victimization  and emotional repair  = 10.895, p < 0.001. η = 0.026). No significant differences were found in emotional attention  = 1.647. p = 0.193. η = 0.004). Bonferroni pairwise comparisons showed that: (1) participants in the no victimization category scored significantly higher in emotional clarity than those in the occasional victimization (p = 0.017) and victimization (p = 0.001) categories; (2) participants in the no victimization category scored significantly higher in emotional repair than those in the occasional victimization (p = 0.003) and victimization (p < 0.001) categories, while those in the occasional victimization category scored higher than those in the victimization category (p = 0.027).Univariate contrasts in the degree of victimization showed significant differences in emotional clarity  = 5.853. A multinomial logistic regression analysis was performed to determine which TMMS-24 variables predict victimization in school bullying. The analysis used the TMMS-24 dimensions of attention, clarity, and repair, grouped into three categories as predictor variables, and the degree of victimization, grouped into no victimization, occasional victimization, and victimization, as the dependent variable. The gender of the participants was included in the model as a control variable.2 = 83.304(14), p < 0.001; χ2 Pearson = 135.069(70), p = 0.097; R Nagelkerke = 0.161), allowing 58% of the cases to be classified correctly.The multinomial regression analysis showed satisfactory fit (χp = 0.001), adequate attention , low clarity , adequate clarity , and low repair  were significantly and directly associated with victimization, while adequate attention , low attention , and adequate clarity  were significantly and directly associated with occasional victimization. Meanwhile, being a boy  was directly associated with victimization  was significantly and directly associated with victimization, meaning that probability of being a victim of school bullying was 2.55 times higher among pupils with low repair. Boys were more likely to be involved in processes of victimization .Finally, the predictive model estimating the parameters for the occasional victimization reference category, which allowed a comparison of the victim and occasional victim groups, showed that low repair (Wald = 7.781, To fulfill the study objectives, the reliability and validity of the instruments were evaluated. The factorial models found in the original studies of the instruments ,52 displThe aim of this study was to investigate the relationship between emotional intelligence and victimization in school bullying. The results of the multivariate analysis confirmed the existence of an association between the two variables: pupils who struggled to understand and regulate their emotional states were more likely to be involved in school bullying. Other studies have indicated significant differences between those involved and those not involved in bullying, with those involved displaying lower emotional repair. Victims in particular are characterized by low clarity and repair .A detailed analysis of the results confirmed the relevance of self-perceived emotional intelligence as a predictor of victimization. Typically, the lower the excessive attention and the greater the clarity and repair among pupils, the less likely they were to be victims of school bullying ,42,43. IOther studies have also revealed associations between emotional intelligence and interpersonal relationships. Low emotional intelligence scores have been positively correlated with low scores in empathy, self-control in social situations, social skills, cooperation with peers, and affective relationships with others , while lOur findings raised an interesting question: Why does clarity have stronger predictive power than emotional repair or attention? The results showed that the probability of being a victim of school bullying was 5.14 times higher among pupils with low clarity, 2.72 times higher among pupils with low repair, and 2.62 times higher among pupils with excessive attention. A limited ability to understand emotions makes it more difficult to interpret others’ intentions, potentially giving rise to errors in assessing certain behaviors . This goFinally, our results showed that being a boy is directly associated with victimization, i.e., boys are more likely to be involved in processes of victimization than girls. More boys than girls said they had been victims of verbal aggression, hitting, threats, and blackmail. Our findings echo those of other studies, which indicate that boys are more frequently involved in bullying as victims ,63,64,65Some studies have shown that women are more sensitive than men. Generally, women are also more expressive than men. Some authors ,67 have This study has several important limitations, including the use of self-reports as a data collection method for evaluating emotional intelligence. Pupils may have underestimated or exaggerated their perceptions of their emotional competence when completing the self-reports. Other tools for measuring emotional skills are available, which evaluate participants’ ability to complete a task . When asThis study has made a valuable contribution to understanding the links between emotional intelligence and school bullying. The findings showed that the lower their excessive attention and the higher their emotional regulation and understanding, the less likely pupils are to be victims of school bullying. This confirms that adequate emotional attention and excellent emotional clarity and repair are protective factors against victimization.Bullying at school is a topic of great social concern and the source of significant financial costs to the public health system. With the relevance of emotional intelligence skills as a protective factor, we recommend that emotional education is included in any actions taken to prevent or reduce school bullying. Schools are ideal settings for encouraging the development of emotional skills to allow pupils to manage their feelings and emotions, as well as those of others, and to respond appropriately to bullying . As scho


Artemisia absinthium—wormwood (Asteraceae)—is a very important species in the history of medicine, formerly described in medieval Europe as “the most important master against all exhaustions”. It is a species known as a medicinal plant in Europe and also in West Asia and North America. The raw material obtained from this species is Absinthii herba and Artemisiae absinthii aetheroleum. The main substances responsible for the biological activity of the herb are: the essential oil, bitter sesquiterpenoid lactones, flavonoids, other bitterness-imparting compounds, azulenes, phenolic acids, tannins and lignans. In the official European medicine, the species is used in both allopathy and homeopathy. In the traditional Asian and European medicine, it has been used as an effective agent in gastrointestinal ailments and also in the treatment of helminthiasis, anaemia, insomnia, bladder diseases, difficult-to-heal wounds, and fever. Today, numerous other directions of biological activity of the components of this species have been demonstrated and confirmed by scientific research, such as antiprotozoal, antibacterial, antifungal, anti-ulcer, hepatoprotective, anti-inflammatory, immunomodulatory, cytotoxic, analgesic, neuroprotective, anti-depressant, procognitive, neurotrophic, and cell membrane stabilizing and antioxidant activities. A. absinthium is also making a successful career as a cosmetic plant. In addition, the importance of this species as a spice plant and valuable additive in the alcohol industry (famous absinthe and vermouth-type wines) has not decreased. The species has also become an object of biotechnological research. Artemisia species. This is undoubtedly connected with the awarding of the Nobel Prize in Medicine in 2015 for the discovery of artemisinin―a sesquiterpenoid lactone effective in the treatment of malaria, found in Artemisia annua . A commonly known species of the genus Artemisia, with an important place in the history of medicine, is Artemisia absinthium L.Over the past few years, there has been an increase in interest in research on the chemistry and biological activities of A. absinthium in order to evaluate the importance of this species in the traditional phytotherapy, as well as in the modern medicine. The emphasis was put on the latest biological activities confirmed by scientific studies. The applications in the cosmetology and in the food industry were also announced. Moreover, the studies on the safety of use as well as the biotechnological researches were reported.The aim of this work was the review of the latest literature reports on A. absinthium was collected collected from various sources such as official websites e.g., The Plant List, GBIF , WHO , FDA (Food and Drug Administration), EFSA (European Food Safety Authority), EMA (European Medicines Agency), CosIng (Cosmetic Ingredient database), classical books, databases of scientific journals , on-line books, and pharmacopoeias. In addition, professional historical descriptions of this species were also analyzed.The information about A. absinthium has its natural habitats in Europe, West Asia, and North Africa. The species has been used for centuries as effective in various gastrointestinal ailments and in the treatment of helminthiases. Contemporary pharmacological studies have focused on confirming and determining the mechanisms of these traditional directions of activity. They have also demonstrated new, previously unknown possible therapeutic applications resulting from proven antiprotozoal, antibacterial, antifungal, anti-ulcer, hepatoprotective, anti-inflammatory, immunomodulatory, cytotoxic, analgesic, neuroprotective, anti-depressant, procognitive, neurotrophic, cell membrane stabilizing, and antioxidant effects.A. absinthium has today an important place in the production of cosmetics. It also has an established position in the food industry, as a base for alcoholic beverages and as a spice. It has also become an object of biotechnological research.Furthermore, Recent years have seen publication of review articles on this species. However, they present the existing, broad knowledge on its therapeutic values in a very general way ,2.While compiling this review, every effort was made to present in detail the qualities of this species, with particular emphasis on the current work on the chemistry of the plant, on the chemistry of its essential oil, its variability in chemical composition, mechanisms of action in the traditional applications and new directions of biological activities confirmed by scientific research, as well as current views on the safety of using this plant species. Additionally, the position of the plant in food industry and cosmetic industry was underlined and biotechnology investigations were presented.Artemisia absinthium L.—wormwood (Asteraceae), is an herbaceous plant. This species has numerous (about 20) synonymous Latin names. The most common synonyms are: Absinthium majus Garsault -(N)-nicotine and [3H]-(N)-scopolamine from the receptors was determined. The results of the study showed that A. absinthium had significant affinity for both muscarinic and nicotinic receptors, meaning that preparations from the plant can show procognitive effects ..ArtemisiLactobacillus sp.Raw materials obtained from the plant are used as components of cosmetic products such as shampoos, face serums, masks, essences, tonics, moisturizing creams with an SPF filter, and under-eye patches. These forms of cosmetics are used to protect, cleanse, and moisturize the skin, as well as to remove skin imperfections. They are produced mainly with extracts of the herb of the plant or distilled oil; also included is the filtrate obtained after fermentation of the leaves by A. absinthium can be found in the offers of foreign companies worldwide. South Korean, Russian and American cosmetics producers are leaders among them.Products containing A. absinthium is the main ingredient in absinthe, which is a high-proof alcoholic beverage that was particularly popular in the 19th and 20th centuries because of its psychoactive properties due to the high α- and β-thujone content [ content ,111. InfDried aerial parts of the plant are used to produce absinthe. In a traditional recipe, wormwood, along with other herbs, is macerated. The obtained macerate of a greenish colour with a slightly stinging, strongly bitter taste is subjected to distillation, leading to a reduction in the amount of bitter compounds. In the last stage, the distillate is diluted with water and the product has a characteristic light green colour .α- and β-thujone content in alcoholic beverages, including absinthe, must not exceed 10 mg/kg for spirits with an ethanol content higher than 25%, or it must not exceed 35 mg/kg in bitter spirits [The European Food Safety Authority (EFSA) states that in the European Union, the  spirits .A. absinthium. The whole herb together with A. absinthium roots is used for their production; also used are other aromatic or bitter herbs  and spices . In the United States, vermouths are used to make cocktails, while in Europe they are served without any admixtures [Wormwood is also added to wines to give them aroma and bitterness. Vermouths are a popular type of wine containing mixtures .A. absinthium is recommended for seasoning meat, vegetable soups and fresh vegetables. It is also used as a dye and flavouring in the traditional Korean rice cake “green songpyeon”, which is an integral part of the celebration of the “chuseok” thanksgiving festival. In Morocco, A. absinthium is added to mint tea [In small quantities, mint tea .It is worth pointing out the dangers of drinking absinthe. Its consumption initially causes the feeling of well-being and hallucinations, slowly leading to a depressive stage. Chronic abuse of the spirit has been described as absinthism, characterized by blindness, tremors, hallucinations, and significant deterioration of the mental state. The degeneration that is observed in the advanced stage causes convulsions and can even lead to death.A. absinthium herb on the development of absinthism is being questioned. The most probable hypothesis is that absinthism is misdiagnosed alcoholism because all the symptoms characteristic of absinthism can be attributed to ethanol itself [Currently, however, the influence of the substances present in l itself .A. absinthium is a species rich in compounds that show toxic effects. These are α- and β-thujone, with α-thujone being thought to be two to three times more harmful. The likely mechanism of action of these compounds is interaction with the GABA receptor of chloride channels [α-thujone into rodents induced tremors. Convulsions did not occur if diazepam or phenobarbital was administered prophylactically [channels . The comchannels . These sctically .α- and β-thujone content in the essential oil of the plant ranges from 0% to 70.6%, which will also result in the occurrence or absence of side effects [EFSA emphasizes, however, that the  effects .Absinthii herba hinders embryo implantation and reduces the number of births. An overdose of preparations containing the plant may result in vomiting, diarrhoea and urinary retention [Wormwood should not be used if the patient has gastric or duodenal ulcers, biliary obstruction, liver disease, or if he is allergic to plants of the family Asteraceae. This species should not be used during pregnancy and breastfeeding because, as shown in experiments on pregnant rats, etention ,30.A. absinthium oil. Acute toxicity tests in a group of mice did not show increased animal mortality after oral application of the essential oil; however, neurological, muscular and gastrointestinal problems were observed [The potential effect of skin irritation and potential acute toxicity of the essential oil of the plant were investigated in 2014. After testing in healthy volunteers, researchers found no skin irritation after applications of undiluted α- and β-thujone, absinthin, and anabsinthin. The summarizing conclusions regarding A. absinthium contain the information that the plant can be safely used as a basic substance. It has a known toxicological profile, and the compounds that were previously considered harmful are currently being investigated as medicinal substances [As potentially dangerous compounds, EFSA lists bstances .A. absinthium as an allergenic species. The source of allergens is the pollen, which can also be present in extracts of the plant [The FDA (U.S. Food and Drug Administration) lists he plant .A. absinthium from natural habitats or by cultivation, attempts are being made at finding biotechnological solutions. They can undoubtedly bypass the problems associated with the chemical variability of the raw materials derived from the plant—the herb and the essential oil. Biotechnological research to date has been concerned with endogenous production of secondary metabolites and the development of micropropagation protocols.Although there are no problems with obtaining A. absinthium secondary metabolites by cultures in vitro. In the first stage aimed at establishing the cultures, they tested the Murashige-Skoog (MS) medium enriched only with the addition of 0.5–5.0 mg/L thidiazuron (TDZ), or a combination of TDZ with 1.0 mg/L naphthalene-1-acetic acid (NAA), or with 1.0 mg/L indole-3-acetic acid (IAA). Thus prepared substrates were used to initiate cultures from leaf explants. Callus obtained on MS media supplemented with 1.0 mg/L TDZ and 1.0 mg/L NAA was passaged for biomass growth. Further experiments on the growth and production of secondary metabolites involved the use of suspension cultures established from 35-day callus cultures. Biomass was grown in Erlenmeyer flasks containing MS medium with 1.0 mg/L TDZ and 1.0 mg/L NAA. The biomass was taken for analysis at 3-day intervals during 42-day cultivation cycles. Phytochemical analysis was performed by HPLC. Seedlings from germinating seeds constituted the control sample. The amount of phenolic acids in the suspension was 3.57 mg/g (control: 2.75 mg/g), and the amount of flavonoid compounds was 1.77 mg/g (control: 1.20 mg/g). The results of the study showed that A. absinthium suspension cultures might be a good potential source of phenolic acids and flavonoids [In 2013, one of Pakistani research groups proposed a method of producing A. absinthium suspension cultures. The cultures were grown on MS medium supplemented with 1 mg/L TDZ and 1 mg/L NAA. The dynamics of biomass growth were measured during 39-day cultivation cycles. Cultures grown in the presence of continuous artificial light with a radiation intensity of 40 mol·m−2·s−1 reached their maximum, 3.9-fold, increase in dry biomass on day 30, whereas cultures grown in the dark, a 3.7-fold increase, on day 27 of cultivation. In addition, in vitro cultures grown in the presence of light were found, using UV-VIS spectroscopy methods with the addition of Folin-Ciocalteu reagent, to have elevated levels of phenols, while those with the addition of aluminium chloride—elevated levels of flavonoids. The results of the study showed that appropriate lighting conditions for A. absinthium cultivation had a positive effect on the efficiency of secondary metabolite production [Scientists from the same research group also studied the effect of light and its absence on the accumulation of secondary metabolites in oduction .A. absinthium by indirect organogenesis. The most effective for callus growth was MS medium with 0.5 mg/L 2,4-dichlorophenoxyacetic acid  and 0.5 mg/L kinetin (Kin). Maximal induction of shoots from callus was found on a medium containing 4.5 mg/L BAP (6-benzylaminopurine) and 0.5 mg/L NAA. With a different quantitative combination of growth regulators, i.e., 1.5 mg/L BAP and 0.5 mg/L NAA, a pronounced induction of many shoots from nodal explants was observed. The most beneficial medium promoting rhizogenesis was one with the addition of 0.5 mg/L indole-3-butyric acid (IBA) [A Hindu research group has developed a protocol for micropropagation of id (IBA) .A. absinthium is a species with a very important position in the history of Asian and European medicine; described in medieval Europe as “the most important master against all exhaustions”, it was mainly used to treat digestive tract diseases and worm infestations.Nowadays, this species has the status of a pharmacopoeial species in the European allopathic as well as homeopathic therapies. Currently the species occupies an important place in the traditional European and Asian medicine.A. absinthium has been the object of numerous studies on the chemistry of raw materials derived from it—the herb and the essential oil, as well as numerous studies on the biological activity of extracts.In modern times, Research on the chemistry of the plant has identified a large number of compounds in the herb, including most of all the presence of essential oil with a very rich but variable chemical composition, bitter sesquiterpenoid lactones, flavonoids, other bitterness-imparting compounds, azulenes, phenolic acids, tannins and lignans.Research on biologically active extracts from the herb and/or individual isolated compounds and/or essential oil has drawn attention to the mechanism of action of these raw materials in known classical applications. It has also provided evidence for numerous, very valuable, previously unknown, new directions of biological activity of the raw materials—antiprotozoal, antibacterial, antifungal, anti-ulcer, hepatoprotective, anti-inflammatory, immunomodulatory, cytotoxic, analgesic, neuroprotective, antidepressant, procognitive, neurotrophic, cell membrane stabilizing, and antioxidant effects.Both phytochemical and pharmacological tests are carried out by research centres located all over the world.The species is also used with great success as a source of cosmetic raw materials, in Southeast Asia, North America (USA) and Europe, in particular. The long-known significance of the species in the food industry, as a base in the production of alcoholic beverages (absinthe and vermouth wines) and as a valuable spice, is not decreasing. The species has also become the subject of biotechnological research on the production of bioactive compounds and the possibility of micropropagation using established in vitro cultures.Artemisia absinthium is: “the most important master against all exhaustions”.The proven new directions of the biological activity of extracts from the herb and of individual isolated compounds and the essential oil of wormwood substantiate the medieval claim that


For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly, approval varies in many countries and this permits a large spectrum for evaluation. Thus, BoNT is used for patients with Parkinson’s disease (PD) and other Parkinson’s syndromes (PS) in varying degrees of frequency. We have to distinguish between (1) indications that are either approved or (2) those not approved, (3) indications that might be a result of PS and (4) finally those which appear independent of PS. The most important indication for BoNT in PS patients is probably sialorrhea, for which approval has been granted in the majority of countries. Cervical dystonia is a frequent symptom in PS, with anterocollis as a specific entity. A further indication is blepharospasm in the different forms, especially the inhibition of eyelid opening in atypical PS. The use of BoNT in cases of camptocormia, the Pisa syndrome and neck rigidity is still a matter of debate. In dystonia of the extremities BoNT can be recommended, especially in dystonia of the feet. One well-known indication, for which however sufficient data are still lacking, involves treating tremor with BoNT. As to autonomic symptoms: Focal hyperhidrosis and detrusor hyperactivity can be mentioned, in this last case BoNT has already been approved. A number of further but rare indications such as freezing-of-gait, dyskinesia, and dysphagia will be discussed and evaluated. IConsidering the use of BoNT in Parkinson’s syndrome (PS), we can distinguish between: (1) uses in indications independent of the underlying disease (co-morbidities); (2) indications induced by the primary disease and of course (3) indications which represent symptoms of PS. Within symptoms of PS, we can further distinguish between motor und non-motor ones . In thisIn blepharospasm, we can distinguish between an orbital and a palpebral type . A speciBlepharospasm of the eyelid-opening inhibition type frequently occurs in cases of atypical PS (APS), but also in Parkinson’s disease (PD). According to Lepore and coworkers it is characterized by transient inability to initiate lid opening, no overt orbicularis oculi spasm, vigorous frontalis contractions, and absence of oculomotor or ocular sympathetic nerve dysfunction or ocular myopathy .Differential diagnosis for these various forms can be achieved with electromyography (EMG) . DivergiIn 1995, Lepore et al. already published a larger collection of case studies describing good success . In a fuThis apraxia also occurs frequently in patients with APS, but in these cases, therapy with BoNT is not indicated. The question is still subject to debate as to whether this is apraxia in the narrow sense or rather involves the eyelid-opening inhibition type Clinical consequence: In blepharospasm, the injection of BoNT can be viewed as the therapy of choice. Injecting is done in the routine way. In the eyelid-opening inhibition type a therapeutic trial is well justified, whereby an injection in the tarsal section of the orbicularis oculi muscle is recommended, and where required, with a somewhat higher dose than usual, for example 5 U inco-/onaBoNT/A or 20 U aboBoNT/A per site.In PS, cervical dystonia (CD) frequently occurs, which is usually treated exactly as spasmodic torticollis. Concrete data on the frequency of CD in PS are not available—there are merely smaller reports and single case studies. Thus, for example, in one study on 74 PD patients, 33.9% presented with CD . In addiIn anterocollis, we have to distinguish whether it is a dystonic activation of the ventral musculature or whether proper differential diagnostic work would reveal merely a weakness in the neck extensors . The dystonic form can be viewed as basically similar to camptocormia see . A cliniClinical consequence: In cases of CD, injection with BoNT may well be seen as the therapy of choice, and this holds true of course for CD in PS, whereby the injection is conducted according to routine protocols. A distinctive case is found in anterocollis, in which an examination for each individual patient must be made to establish whether dystonia or muscle weakness pertains. Of course, in the case of muscle weakness, an injection would be rejected. Anterocollis is more difficult to treat than the other forms of CD .The most important indication for BoNT in PS is sialorrhea, or drooling . PD pati®]. The groundwork for approval was the so-called SIAXI study, a large controlled study that confirms the efficacy and safety of incoBoNT/A for the treatment of sialorrhea due to PD and APD [In 2019, the FDA (US Food and Drug Administration) approved incoBoNT/A and rimaBoNT/B for chronic sialorrhea in adults [SPC Xeomin and APD . The stu and APD .In the approval study with rimaBoNT/B 122 PD patients  were randomized to 2500 U, 3500 U rimaBoNT/B or placebo. Treatment with both doses significantly reduced uSFR at week four vs. placebo. The CGI-C scores were also significantly improved at week four for both treatment groups vs. placebo. Treatment benefits were seen as early as one week after injection and were maintained over the treatment cycle of approximately 13 weeks. The most common adverse events were mild to moderate dry mouth, dysphagia, and dental caries .In the meantime, BoNT has been approved for this indication in many further countries. The recommended dose is a total of 100 units (U) incoBoNT/A, 60% parotid gland, and 40% submandibular gland, for rimaBoNT/B 500–1500 U per parotid gland and 250 U per submandibular gland . As frequent side effects dry mouth and dysphagia were detailed ,29,30,31Clinical consequence: Sialorrhea injections of BoNT are now seen as the therapy of choice, and this holds for PD and APS patients. BoNT is safe and efficacious.The injection is conducted under ultrasonic control see  into theParkinson patients, both PD and APS, present with a preponderance for an overactive bladder (OAB) ,35,36,37Giannantoni and coworkers demonstrated  that a dImprovement was described in 19 of 24 (79.2%) patients with OAB in an open label, retrospective study . A totalClinical consequence: In cases of detrusor overactivity or OAB, injection with BoNT can be taken into consideration to treat extensive symptoms when oral medication proves insufficient. This therapy is traditionally conducted by urologists under endoscopic control. In PD patients lower doses are recommended .BoNT is indicated for muscular overactivity, and for this reason its use for tremor and in particular for Parkinson-tremor suggested itself early on . FurtherUnfortunately the previous results published to date were not convincing ,41,42,43A recent study that treated 30 PD patients with incoBoNT/A injected into the hand and forearm muscles revealed a statistically significant improvement in clinical rating scores of rest tremor and tremor severity, with no relevant difference in grip strength .Samotus and coworkers  injectedImproved efficacy was demonstrated for essential tremors ,48,49, bIn addition to tremors of the extremities, PD patients frequently have a tremor affecting chin, lips, jaw, and tongue. Jaw tremor was beneficially treated with injections of BoNT into the masseter muscles in three PD-patients .Clinical consequence: At present, the injection of BoNT cannot be recommended for treatment of tremors in PD. We have to await the results of studies that are presently being conducted, but in individual cases, injection may well be worth taking into consideration The possibility of a functional paresis is a limiting factor , thus maAnterocollis see , camptocThe pathogenesis of camptocormia is still a matter of controversy and the exact pathophysiology is not fully understand . CamptocSeveral studies on injections into the iliopsoas muscle proved negative ,54,55, lData on success in using BoNT in Pisa syndrome, as a form of lateral trunk flexion, are even less satisfactory. In such cases, an overlapping of the two symptoms occurs frequently in the patient populations because many patients with Pisa syndrome present with camptocormia and vice versa.In a study by Bonanni et al., nine patients with lateroflexion (Pisa syndrome) were injected with BoNT and placebo, in a blinded cross-over (after three months) study design. Under EMG control, the patients received 4 × 125 (1 mL each) units aboBoNT/A into the paraspinosus muscle. All patients were videotaped and evaluated with the Trunk Dystonia Disability Scale (TDDS), a Visual Analogue Scale (VAS) and a goniometric measurement of the lateral displacement. In the placebo group no benefit was registered, but in the BoNT-group, treatment was effective in six patients. Four patients have had ongoing BoNT treatment for the two years since the study .n = 13) or placebo (n = 13), while both groups received intensive physical therapy. The precise sites of injection were determined for all patients according to their EMG report and individual injections were permitted. The iIliopsoas muscle alone was injected in all the patients. The total dose ranged between 50 and 175 U incoBoNT/A. The verum group benefited in particular in measures of their pain but also showed a more prolonged efficacy on several clinical and kinematic variables. It is interesting to note that both groups improved significantly in terms of static postural alignement and in range of motion [In the subsequent study, an RCT performed by Tassorelli and coworkers , 26 patif motion .In a case report, good success was reported after injection of 50 U incoBoNTA into the quadratus lumborum .In a small prospective study, six patients with PD and camptocormia were treated with 75 or 90 U onaBoNT/A, with injections into each external oblique muscle bilaterally under sonographic guidance. The mean camptocormia angle showed significant attenuation (38° vs. 18°) , whereasAnother pilot study with 15 patients evaluated the efficacy of BoNT injection in paraspinal and non-paraspinal axial muscles after magnetic resonance imaging and sonographic-guided electromyography evaluation . A benefClinical consequence: In recent years, BoNT has been applied in different patients for treating camptocormia and/or a Pisa syndrome. EMG and/or sonography has been performed in all patients beforehand, with injections into the psoas, paraspinal musculature and that of the abdominal wall, depending on the clinical findings. Unfortunately, up to the present, only temporary and slight, and non-lasting success has been achieved. But in individual cases, a therapeutic trial can well be indicated .Dystonia is common in PD patients, especially in younger patients, occasionally as a primary symptom, more frequently as a motor complication of levodopa therapy ,65. DescSpasmodic dysphonia can occur in all Parkinsonian patients, in both the abductor and the adductor subtype . BoNT isThe same holds true for oromandibular dystonia . There iFocal dystonia of the upper limbs is often task-specific. For example, writer’s cramp is frequent, and striatal hand as well ,66. WhilA small study on treatment for “dystonic clenched fist” in three CBD , and seven PD patients, examined the effect of BoNT. All patients had some degree of flexion at the proximal metacarpophalangeal joints and required injections into the lumbricals. The effect depends on the severity of the deformity and the degree of contracture. All patients had significant benefit to pain, with accompanying muscle relaxation, and palmar infection, when present, was eradicated. Four PD patients obtained functional benefit .(1)Involuntary extension of the big toe:The other toes remain in the resting position or move only slightly, over-flexing takes place in the big toes . Therapy(2)Flexion of the toes:This second form usually causes more discomfort to the patients, as it induces involuntary movements in the toes, in particular the small ones, but also the big toes. It occurs frequently as exercise-induced dystonia. Here, a distinction has to be made whether only one of the two or both toe flexing muscles are involved. The short flexor is found in the sole of the foot, the long flexor in the lower calf. Here too the injection into the muscle is performed under ultrasonic guidance see .(3)Inversion and/or supination of the foot:This form of dystonia is frequently more complex and difficult to treat, as it causes occasional functional paralysis with an increased risk of falls resulting. A therapeutic trial with low dosage may be indicated in individual cases.Parkinson patients frequently have dystonia in the feet: kinesigenic and exercise induced foot dystonia, considered a hallmark of early-onset PD . Most frp = 0.039), with no difference of efficacy between the two injection sites [In an open-label study with BoNT, Pachetti and coworkers  reportedon sites . In a fuon sites . The samon sites .The use of BoNT has also been discussed for dyskinesia. Positive reports, however, are only found in single case studies ,74. In oClinical consequence: Although no approvals are yet available, the use of BoNT for focal dystonia in PD is a viable option. In fact, treatment of foot dystonia is the therapy with the best evidence. At present, there is only insufficient evidence for therapy of dyskinesias with BoNT. Focal dystonias are also common in CBD unfortunately there are no studies on this.Freezing of gait (FOG) is quite frequent in PS, especially in the advanced stage and unfortunately responds but poorly to medication . For a nIn 1997, Giladi et al. described positive effects, which they then confirmed in a second study in 2001 ,76. BoNTIn a further study from the same study group, 150 U onaBoNT/A (n = 6) or normal saline (n = 5) was injected into each leg’s calf muscles. No improvement was observed in either group, but leg weakness and falls led to early termination .Vastik and coworkers investigated 20 PD-patients with FOG. 10 patients with FOG were treated with BoNT injection into both tensor fasciae latae muscles. The FOG questionnaire showed a decline of scores after BoNT therapy .Another group was not able to demonstrate any beneficial effect on FOG with 5000 U rimaBoNT/B injected into four areas of the soleus-gastrocnemius complex of the predominantly affected leg, and no significant improvement in nine (BoNT) vs. five (placebo) patients .A good number of patients with PS complain of a restless leg syndrome (RLS). Specific studies in PS, however, are not available. Several small-sized studies were published on the use of BoNT for RLS ,81,82, iClinical consequence: At present, the injection of BoNT in the therapy of FOG and RLS in PS cannot be recommended. Further studies are required.Pain is a common complaint in PD, with their causes being quite diverse ,84,85. TA positive effect can be assumed particularly in cases of dystonia . In an uIn a study at the Toronto Western Hospital, the indication for therapy with BoNT was examined retrospectively. In the 117 PD patients pain was the main indication for BoNT treatment (50.6%), with dystonic pain in 77.6% and musculoskeletal pain in 22.4% of the cases. Considering pain as indication, 81% of all patients with PD reported benefits after the first BoNT injections, with 53.4% of the cases describing their response as very much improved .In a controlled study, the same group studied the effect of BoNT on limb pain in 12 advanced PD patients . TreatmeClinical consequence: In many indications for BoNT, pain is improved. At present the effect on approval is limited, there is thus no primary indication for BoNT in the treatment of pain in PS.Disturbance in perspiration is frequent in PS ,88, occuClinical consequence: BoNT is only indicated in the therapy for pronounced, focal hyperhidrosis. There is no indication for generalized profuse perspiration.In PD patients, the entire motility of the gastrointestinal tract is disturbed . This leThe most frequent use of BoNT for the GIT entails sialorrhea see . A furthAlfonsi et al.  treated An additional gastrointestinal option might involve injection of BoNT into the pyloric sphincter in PD patients with gastroparesis. Up to the present, information on two patients has been published, detailing the injection of 100 U onaBoNT/A, whereby an improved gastric emptying was obtained .There have long been descriptions for the therapeutic effects of BoNT on an anism which caused constipation . Two stuClinical consequence: In cases of sialorrhea resulting from swallowing disturbance, the injection of BoNT into the salivary glands is the therapy of choice. In individual cases, an injection with BoNT can be considered for dysfunction of the esophageal and anal sphincters.Parkinson’s syndrome (PS) is a multisystem degeneration with a number of motor and non-motor symptoms that have but an insufficient response to dopaminergic medication. In particular, the therapeutic possibilities for the non-motor disturbances are limited and frequently have strong side effects. In some indications, BoNT has demonstrated the capability for closing the gap in treating Parkinson symptoms and to provide symptomatic relief. Thus, BoNT has been approved in the meantime for the treatment of sialorrhea and an overactive bladder. But there are also motor symptoms for which approval has been granted and which occur frequently in PD, for example cervical dystonia and blepharospasm, which are frequently overlooked in PS and are thus not subject to treatment trials. A number of other indications are possible or should be studied further, e.g., tremor, and focal dystonia. The therapeutic possibilities of BoNT for treating symptoms in PS have not yet been exhausted. The same symptoms are to be discussed in the case of APD. In PSP, neck rigidity and blepharospasm/lid opening inhibition, in MSA Anterocollis, blepharospasm/lid opening inhibition and sialorrhea and in CBS focal dystonia should be mentioned in particular.


The key to the management of chronic obstructive (CB) and chronic obstructive pulmonary disease (COPD) is to control symptoms of the disease and to prevent deterioration in the health of affected patients. Myrtol has been proved to be effective in treating the symptoms of patients with CB and COPD and preventing the deterioration in their health. However, there has been no systematic review of the efficacy and safety of myrtol in the treatment of CB or COPD. The purpose of this study is going to evaluate the effects of myrtol on the management of CB or COPD based on randomized controlled trials.Electronic literature and other ongoing studies will be searched before November 31, 2019. Randomized controlled trials that report the use of myrtol in the treatment of CB or COPD (in the absence and presence of concurrent treatments) will be selected for inclusion regardless of language. Primary outcomes will include cumulative numbers of exacerbation events and the number of days of disability including days in bed, days off work due to breathing complications, and days on which the participant was unable to undertake normal activities due to breathing complications. Study selection, data extraction, and deviation the derivation risk assessment will be carried out by 2 independent investigators. Meta-analysis will be carried out by the RevMan5.3 software.The study will provide summary results for estimating the efficacy and safety of myrtol for future treatments of CB or COPD.This systematic review will determine if myrtol is an effective and a safe intervention on the symptoms and the prevention of exacerbation of CB or COPD.Ethical approval will not be required for this study because no identifying patient data will be used. The review will be published as an article or a conference presentation in a peer-reviewed journal.OSF registration number: DOI 10.17605/OSF.IO/PXRBV There are world-wide concerns about the high morbidity of COPD and its serious economic and social burdens.,4 COPD results from an abnormal inflammatory response to exposure to harmful gases, as well as to particulate matter. Fatalities from COPD are high: an estimated 2 million people die from the disease each year in Asia, accounting for 2/3 of global COPD deaths. In China, more than 100 million people suffer from COPD.Chronic obstructive pulmonary disease (COPD) is a clinically preventable and treatable disease characterized by persistent respiratory symptoms and airflow constraints. It is currently the fourth leading cause of death in the world,,7 Then these treatments have inevitable side effects,,9 which have prompted some COPD patients to seek more alternative treatments. Therefore, it is extremely important to find alternative COPD treatments that lack undesirable side effects.Although the National Institute for Health and Clinical Excellence (NICE) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have recommended developing evidence-based treatments for COPD, including treatments using short- and long-acting bronchodilators, inhaled corticosteroids, and low-dose and sustained-release theophylline.–13 In recent years, an increasing number of evidences revealed that mrytol has positive effect in chronic obstructive (CB) and COPD management, and has been widely used to treat CB and COPD.–18 However, there is little evidence concerning its efficacy and safety for CB or COPD patients. Therefore, the aim of this study is to conduct a systematic review to explore the efficacy and safety of mrytol for CB or COPD.Myrtol is extracted from the leaves of plants of Myrtaceae and has been shown to have secretolytic, mucolytic, secretomotoric, and anti-inflammatory properties.1.1Our objective is to provide a comprehensive systematic review and meta-analysis of the safety and efficacy of myrtol for patients with CB or COPD. The results of the research will provide evidence for clinicians in guiding the treatment of CB and COPD.22.1,20This study was registered on OSF. Registration number: DOI 10.17605/OSF.IO/PXRBV. Our meta-analysis will be based on the Preferred Reporting Items for System Review and Meta-analysis Protocols (PRISMA-P).2.2The study will be submitted to a peer-reviewed journal for eventual distribution in electronic and printed form. This study is a retrospective study of published literature and does not require ethical approval.2.32.3.1Electronic literature searches will be conducted separately by 2 investigators (WYC and LLY) according to the syntax of each database and the principles of Population, Intervention, Comparison, Outcomes, and Study design (PICOS) in evidence-based medicine. We will search the following electronic database for studies on the treatment of CB or COPD uploaded since the establishment until November 31, 2019: PubMed/MEDLINE, EMBASE, the Cochrane Library, the Web of Science, Ovid, Scopus, the CNKI Database, the CBM database, the Wan Fang Database, and the VIP database.Search terms to be considered for searches will include: “Gelomyrtol,” “Myrtol,” “myrtol standard,” “ELOM-080,” “COPD,” “chronic bronchitis,” “chronic obstructive pulmonary disease,” “Pulmonary Disease,” “bronchitis,” and “clinical trial.” The example of specific search for PubMed is shown in Table 2.3.2https://www.clinicaltrials.gov/), the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), the Australian New Zealand Clinical Trials Registry (https://www.anzctr.org.au/), and the Chinese Clinical Registry (http://www.chictr.org.cn/index.aspx). Other publications, such as relevant systematic reviews and meta-analyses, will be reviewed to identify additional trials.We will also retrieve unpublished data from ongoing studies in the NIH clinical registry Clinical Trials.Gov , the European Respiratory Society, or the World Health Organization(WHO).2.3.5Randomized controlled trials with myrtol as the only treatment will be included. If the same intervention is performed in both the treatment group and the control group, a study will also be considered to evaluate the comprehensive effect of myrtol plus other interventions. For the control group, we will consider placebo or sham treatment, nonintervention and other interventions.2.42.4.11.Cumulative numbers of exacerbations. Exacerbation was defined as an increase in cough and by volume and/or purulence of sputum. The primary outcome is the effect of myrtol on cumulative numbers of exacerbations during the treatment period.2.Number of days of disability such as days in bed, days off work, and days on which the participant was unable to undertake normal activities.2.4.21.Measures of lung function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEFR).2.Adverse effects of treatment: Total number of adverse events.3.Hospitalization and mortality.4.Quality of life as measured by a tool validated in patients with COPD.2.5We will import the search results into Endnote X (V.9.0). Two investigators (PXC and HDM) will evaluate the retrieved studies based on inclusion criteria. They will conduct a preliminary screening of the title and abstract to exclude articles that do not meet requirements. Unmatched studies will be moved to the trash box in Endnote X (V.9.0). The reasons for the exclusion of selected studies will be recorded in an Excel table. The next step will be to read the full text and to evaluate the reason for inclusion based on the full text. Two investigators will examine the reference list to confirm possible missing studies. The results of the selection process will be cross-checked by 2 investigators. Any differences will be resolved through discussion and a consensus. A third investigator (LSQ) will arbitrate unresolved arguments. Each eligible study will be assigned a research ID using the following format: first author's last name + space + year of publication . The selection of studies will be summarized in a PRISMA flow diagram  will review the eligibility of each included study and extract data by using a standardized template. This standardized template will include the following information: article information , participant information , intervention details , and outcome details (measuring methods and adverse events). Any differences identified during data cross-checking will be resolved through discussion and the recommendation of a third investigator (LSQ).2.6 Two investigators (LLY and WYC) will input the relevant information of each study into RevMan software. The quality of the methodology of each included study will be evaluated from 7 perspectives, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential sources of bias. The investigators will assess the risk of the 7 biased projects one by one, and grade the risk of each item into 1 of 3 levels as follows: high, low or unclear. Differences will be settled through discussion. A third investigator (LSQ) will be consulted, if necessary, to reach a consensus. If the essential information is lost or unreported, the authors of the original study will be contacted for the risk of deviation assessment. The assessment results will be displayed in the bias risk summary chart.The bias risk of each included study will be assessed by using Cochrane Collaboration's tools in randomized trials.2.7Q test and I2 statistics. If I2 ≤ 50%, then the heterogeneity between multiple studies will be acceptable. When I2 > 50%, meta-analysis will not be carried out. We will try to find out the root causes of heterogeneity from various aspects and provide a narrative and qualitative summary.The differences of the intervention and control groups will be evaluated. The data of clinical studies will be input into Revman software (V.5.3) for data synthesis. The data will be synthesized and analyzed according to the level of statistical heterogeneity. If the study is homogeneous enough in terms of design and comparison, we will use a random effect model for meta-analysis. The heterogeneity will be tested by Cochrane Risk ratios with 95% CIs will be used to evaluate dichotomous outcomes. Continuous outcomes will be calculated by using the mean difference or standardized mean difference with 95% CIs. The mean difference will be applied if the same scale is used to estimate an outcome in different studies. The standardized mean difference will be applied for different measurement tools. Before statistical analysis, the units of the outcomes from the different studies will be transformed into the International System of Units.Data may be missing from studies whether intentionally or unintentionally. We will contact the corresponding author of such studies for this reason. After the investigators confirm that the data was missing, the available data will be analyzed. The missing data will not be used in the preliminary analysis. However, the impact of the missing data will be assessed in the sensitivity analysis. The potential impact of the missing data on the final result of the review will be analyzed in the discussion.2.7.1If there is significant heterogeneity in the included trials, then we will conduct subgroup analysis according to the region of the studies, age, stage of the subjects, types of treatments, and different outcomes.2.7.2Sensitivity analysis will be used to identify the robustness of the review conclusions, such as methodological weaknesses, missing data, and heterogeneity qualities. According to the situation of each clinical trial included in the integration, which factors can be considered to affect the integration results, so that it can be carried out according to the actual situation by excluding trials with high risk of bias or canceling each study on a case-by-case basis. And after performing the meta-analysis again, compare it with the previous meta-analysis.2.7.3Funnel plots will be used to assess publication bias. If there is significant publication bias, then asymmetric funnel plots will be generated. More obvious asymmetries will indicate higher degrees of bias.2.8,25 The evidence level will be classified into four possible ratings as follows: very low, low, moderate, or high.Online Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to independently assess the quality of evidence for each outcome by the reviewers.3At present, there are many treatment methods and drugs for COPD, including glucocorticoids, bronchodilators, antibiotics and so on, however these methods still cannot meet the needs of CB or COPD patients. The studies on myrtol in the treatment of CB or COPD increases at present, so it is necessary to evaluate the effect of myrtol on CB or COPD.Myrtol has been proved to have the effects of anti-inflammation, dilution of mucus and so on. However, the efficacy and safety of myrtol in the treatment of chronic bronchitis or chronic obstructive pulmonary disease is not clear. Therefore, we believe that the results of this meta-analysis will provide some reference for clinicians and researchers.3.1If there are any amendments in this protocol, we will give the date of each amendment, describe the situation of the change, and give the reason.www.topeditsci.com) for its linguistic assistance during the preparation of this manuscript.We thank TopEdit (Conceptualization: Liyun Liu, Yongcan Wu, Zhenxing Wang, Shuiqin Li, Fei Wang.Data curation: Liyun Liu, Xiaomin Wang, Caixia Pei.Formal analysis: Liyun Liu, Yongcan Wu, Caixia Pei, Xiaomin Wang.Funding acquisition: Zhenxing Wang.Investigation: Liyun Liu, Yongcan Wu, Xiaomin Wang, Fang Yang, Demei Huang.Methodology: Liyun Liu, Yongcan Wu, Xiaomin Wang.Project administration: Liyun Liu, Yongcan Wu, Zhenxing Wang, Shuiqin Li, Fei Wang.Resources: Zhenxing Wang, Shuiqin Li.Software: Caixia Pei, Demei Huang.Supervision: Xuhong Yan, Liang Dong, Yinghong Liu, Degui Chang, Xujun Yu.Validation: Liyun Liu, Yongcan Wu, Xiaomin Wang.Writing – original draft: Liyun Liu, Shuiqin Li.Writing – review & editing: Zhenxing Wang, Shuiqin Li, Fei Wang.


Oryza, will play a significant role in helping to solve this 10 billion people question due to its place as a staple food for billions. The genus Oryza is composed of 27 species that span 15 million years of evolutionary diversification and have been shown to contain a plethora of untapped adaptive traits, e.g., biotic and abiotic resistances, which can be used to improve cultivated rice. Such traits can be introduced into cultivated rice, in some cases by conventional crossing, and others via genetic transformation and gene editing methods. In cases where traits are too complex to easily transfer to cultivated rice , an alternative strategy is to domesticate the wild relative that already contains the desired adaptive traits – i.e., “neodomestication”. To utilize the Oryza genus for crop improvement and neodomestication, we first need a set of genomic resources that can be used to efficiently identify, capture, and guide molecular crop improvement. Here, we introduce the concept of platinum standard reference genome sequences (PSRefSeq) – a new standard by which contiguous near-gap free reference genomes can now be produced. By having a set of PSRefSeqs for every Oryza species we set a new bar for how crop wild relatives can be integrated into crop improvement programs.As the world’s population expands from 7.6 billion to 10 billion over the next 30 years, scientists and farmers across the globe must explore every angle necessary to provide a safe, stable and sustainable food supply for generations to come. Rice, and its wild relatives in the genus  As the world population grows and climate change dictates new conditions for agriculture worldwide, finding new solutions to ensure a sustainable food supply is crucial. Rice is the staple food in the regions of the world with the largest projected population growth. Moreover, these regions and their available arable land are expected to be most negatively affected by climate change in the future . CultivaOryza, first via conventional crossing and now more recently using plant transformation and gene editing tools, to produce new, more resilient varieties of cultivated rice . There are four species complexes within the Oryza genus: (1) O. sativa, (2) O. officinalis, (3) O. ridleyi, and (4) O. meyeriana  during the cooler morning hours in O. officinalis, as well as genes involved in low temperature adaptation have been identified in O. rufipogon are also strong candidates for introgression into cultivated rice . This adaptivity has resulted in a range of beneficial traits that have been selected to “fine-tune” existing accessions of cultivated rice, which are crucial for adapting to changes in environmental conditions Table 1Ataminata . This gealiensis . Both ofnd Korea . Abioticted rice .O. rufipogon, the closest WR of Asian cultivated rice, was found to contain yield-enhancing QTL (yld1 and yld2). These QTL were found to be associated with increased yield (18% and 17%) relative to the high-yielding Chinese hybrid rice V64 , and increased grain weight   . Besidesngladesh . OverallO. sativa (produced by colchicine-treatment to cause genome doubling) was less affected under severe drought stress, with less effect on net photosynthetic rates and peroxidation levels of its cell membranes demonstrated higher activity of the enzymes  implicated in decreasing the amount of reactive oxygen species, which limited membrane lipid peroxidation , established in 2003, set out to create a genus-level comparative genomics platform for the interrogation of the genus Oryza and provide information on rice-related genome evolution and organization, comparative genomics, physiology, biochemistry, and crop improvement. I-OMAP began with the generation of a set of publicly available deep-coverage BAC libraries and manually edited physical maps for cultivated rice and WRs used in active breeding programs  dataset, to be used as a reference guide to characterize all standing natural variation within Asian cultivated rice , centromere/telomere and gene annotations.For ZS97 and MH63, genome completeness was estimated at ~92.7% (ZS97), ~94.8% (MH63) using the CEGMA pipeline with a core set of 248 eukaryotic genes . BUSCO e dataset . When coO. sativa 15 PSRefSeq dataset, combined with the original IRGSP RefSeq  and the presence/absence of variants (PAVs). O. sativa are comprised of transposable elements (TEs). The Oryza PGG will allow us to better annotate and understand TEs in the WRs of rice and shed light on the contribution of TEs to genome size variation and genome plasticity of adaptive traits. For instance, the TE content of O. coarctata was estimated to be the lowest among Oryza species, despite a predicted genome size of 665 Mb  to study the formation of de novo protein-coding genes. They identified 175 candidate de novo genes and estimated the rate of de novo gene origination as 51.5 de novo genes per MYA. De novo originated genes can provide novel biological functions and have previously been shown to play a key role in pathogen resistance in plants  and interspecific hybrids, with O. sativa as the recurrent parent, have been successfully produced to carry the following biotic stress-resistance traits: brown planthopper resistance, whitebacked planthopper, and bacterial blight resistances from O. officinalis, O. minuta, and O. latifolia, respectively  were found to be introgressed from O. granulata , which resulted in the generation of two non-shattering mutant plants in the orthologs of qSH1 and sh4. Now, with gene editing technology such as CRISPR-Cas9 . For example, homologues of genes involved in the domestication of rice in the WRs could be targeted for neodomestication to produce a domesticated ideotype in a WR. SPR-Cas9 , it is pSPR-Cas9 . Besidesbarriers .S. pimpinellifolium . Four of the six genes  were successfully targeted and contained indel mutations, which resulted in a WR with a domesticated “phenotype”, i.e., an altered morphology, a three-fold increase in fruit size, a ten-fold increase in fruit number compared to the WR, and a 500% increase in lycopene accumulation in the fruit, relative to the cultivated Solanum lycopersicum  along the coastal regions from Pakistan to Myanmar  as the contiguity and fidelity of the PSRefSeq allows for better precision for single guide RNA (sgRNA) selection . Given the paucity of available genome assembly resources, a PSRefSeq for O. coarctata would play a vital role in the precise identification of the orthologues of domestication genes that could be targeted for neodomestication.Similarly to wild tomato, neodomestication of the WRs of rice is theoretically possible, albeit non-trivial.  Myanmar . In Indiar tides . For dec success . Thus, Ooarctata Table 1Belection . MoreoveSM and NA-B contributed equally to this work and share co-first authorship. SM and NA-B wrote the manuscript. AZ contributed to writing the manuscript, editing and organizing the structure of the manuscript. RW reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by KAUST to RW.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.


Other significant risks emerged for some coping strategies and some defenses regarding both depression and trauma in patients and caregivers. Conclusions: This research suggests that for both patients and caregivers unconscious adaptive processes have a central role in dealing with overwhelming feelings related to the disease.Background: Patients of malignant mesothelioma (MM) and their caregivers face significant physical and psychological challenges. The purpose of the present study is to examine the emotional impact after the diagnosis of MM in a group of patients and familial caregivers in a National Priority Contaminated Site (NPCS). Methods: A sample of 108 patients and 94 caregivers received a sociodemographic/clinical questionnaire, the Beck Depression Inventory II, the Davidson Trauma Scale, the Coping Orientation to the Problems Experienced—New Italian Version, and the Defense style questionnaire. The risk of depressive and post-traumatic stress disorder (PTSD) symptoms in relation to the strategies of coping and defense mechanisms was estimated in patients and caregivers separately by logistic regression models. Results: For patients, a high risk of depression was associated with high usage of Defense Style Questionnaire (DSQ) Isolation (OR: 53.33; 95% CI: 3.22–882.30;  The impact of asbestos is currently a serious concern for public health. Recently, Furuya et al.  summarizDue to the large use of asbestos before the national ban in 1992 .Mesothelioma incidence has been investigated at several National Priority Contaminated Sites (NPCSs) in Italy in order to obtain estimates on the impact of asbestos on residents. Statistically significant excesses of mesothelioma incidence were recorded at 20 of these sites, including Casale Monferrato, where a large fiber cement factory  is headquartered. The factory has had an impact on the health not only of workers employed at the plant (mostly men), but also that of their relatives (mostly wives) and other residents, with no other sources of asbestos exposure besides environmental pollution .The standardized incidence ratios (SIR) of MM in Casale Monferrato are 910.7 (95% CI: 816.5–1012.8) in men and 1338.1 (95% CI: 1176.7–1515.4) in women [The consequences of MM on mental health are particularly relevant in National Priority Contaminated Sites (NPCSs). Our previous studies in the NPCS of Casale Monferrato have remarked negative mental health outcomes in the whole residing population ,7.MM patients and their familial caregivers face significant physical and psychological challenges, such as a limited life expectancy, and poor and fatal prognosis . The lacHumans cope with adversity and negative emotions in adaptive and non-adaptive ways. Coping strategies and defense mechanisms are psychological processes that allow an individual to manage painful emotions arising from stressful and traumatic experiences. However, they differ in several fundamental aspects. Coping is a conscious and intentional process for managing specific internal and external demands that are believed to exceed the resources of a person. In contrast, defense mechanisms are mainly unconscious and unintentional, and aim to protect the ego from the intensity of disruptive internal/external conflicts and dangers . MoreovePrevious studies have shown that in order to face the traumatic emotions linked to MM diagnosis and its symptoms, MM patients commonly activate avoidant strategies which involve cognitive and behavioral efforts to minimize the real health danger of asbestos exposure ,15,21,24The purpose of the present study was to examine the emotional impact (depression and trauma) of a diagnosis of MM in a group of patients and familial caregivers in the NPCS of Casale Monferrato with a special focus on the coping strategies and defense mechanisms that are used by these two groups.The present study was part of the Assessing Psychological Variables in Mesothelioma (AVPM) Project, conducted at the Mesothelioma Unit of Casale Monferrato-Alessandria, Italy. The protocol was approved by the local Institutional Review Board of the University of Turin and the Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo Ethical Committee . The study was carried out in accordance with the Declaration of Helsinki. All subjects provided written informed consent and their anonymity was ensured.The present study followed a cross-sectional design, having continuous recruitment between September 2014 and December 2018. Cases were selected from the medical database of the Mesothelioma Unit based on the following inclusion criteria: diagnosed with MM or being a primary familial caregiver of an MM patient, the ability to speak Italian, living in in the NPCS of Casale Monferrato and providing written informed consent. Exclusion criteria were as follows: diagnosis of a psychiatric illness or central nervous system disease, and having a caregiver with a disease related to asbestos exposure.Potential participants were recruited through an invitation from medical staff  at the site, who introduced the study and gave the participants an information sheet. The response rate for both patients and caregivers was 80%. In the recruitment phase, the two groups were unrelated and independent. Patients were recruited within 6 months of diagnosis. Researchers were not involved in patient care, but trained medical staff in recruitment and test administration, which was carried out by hospital psychologists in an individual setting. Data were anonymously and independently analyzed by researchers.An ad hoc questionnaire was used to collect sociodemographic and clinical variables including: gender, age, educational level, job, marital status, psychotherapy history, psychological examination, drugs use, type of MM, and localization. Asbestos exposure  determined through a ReNaM questionnaire (for patients only).The Beck Depression Inventory, Second Edition (BDI-II)  is a 21-The items refer to sadness, pessimism, a sense of failure, self-dissatisfaction, guilt, self-punishment, self-deprecation, self-accusation, suicidal ideas, crying, irritability, social withdrawal, indecisiveness, body image distortion, difficulties at work, sleep disturbance, fatigue, loss of appetite, weight loss, preoccupation, and decreased libido. All but two items have four possible responses of increasing intensity. For example, under sadness the responses range from “I do not feel sad” to “I am so sad or unhappy I can’t stand it”. The range of possible scores is 0–63. The degree of a symptom was measured with a four-item Likert-type scale reflecting the presence or frequency of the symptom.The BDI-II has been translated into several languages and adapted to different cultures, and its utility has been demonstrated in many studies . The ItaThe Davidson Trauma Scale (DTS)  is a 17-Items were rated on five-point frequency  and severity scales . Respondents were asked to identify the trauma that is most disturbing to them and to rate, in the past week, how much trouble they have had with each symptom . The DTS yields a frequency score (ranging from 0 to 68), severity score (ranging from 0 to 68), and total score (ranging from 0 to 136).Items can be categorized into three clusters corresponding to the DSM-IV diagnostic criteria for PTSD diagnosis: Criteria B “re-experimentation” ; Criteria C “avoidance and numbing” ; Criteria D “hyper-activation” . Further research has shown that DTS could be used to differentiate patients with PTSD and partial PTSD from those with no PTSD in the general population, and to detect differences between treatments of differing efficacy . DTS hasThe Coping Orientation to Problems Experienced—New Italian Version is a 60-item self-report questionnaire assessing the frequency of strategies usually activated to cope with stressful events on a four-point scale (1–4) . ResponsIn the present study, we asked participants to answer the questions by considering the MM diagnosis as the stressful event. In contrast to the original version, the new Italian version has a five-factor structure  . The dimThe Defense Style Questionnaire DSQ-40)  is a 40-  is a 40χ2) and analysis of variance (ANOVA) were used to evaluate differences between patients and caregivers, and gender. The homogeneity of variance was verified with the Levene test. The Brown–Forsythe and Welch tests were used when the homogeneity of variance assumption did not hold for the data. The mean ages were compared with the Student’s t-test for independent samples. Descriptive statistics were used to characterize the sample in terms of sociodemographic and clinical variables. The chi-squared test (2 statistic). As measures of association, odds ratios (OR) and their 95% confidence intervals (CI) were reported. ORs greater than 1 indicated higher risks for depression and post-traumatic stress of being patient/caregiver or male/female or a strategy of coping and defense mechanisms activated, according to the model. The results were considered significant at a p-value less than 0.05. All analyses were performed using SPSS v25.0 for Windows .The risk of depressive and PTSD symptoms in relation to coping strategies and defense mechanisms was separately estimated in patients and caregivers. Logistic regression models were used to explore significant factors associated with the two outcomes: depression (BDI) and PTSD symptoms (DTS). This was achieved by treating the effective response as the dependent variable and other factors as independent variables, which were introduced into the model as dichotomous ordinal variables and scored according to each respective cut-off, or to the mean for the five-factor “coping” structure. According to the original cut-offs proposed by Beck et al. , “13” waχ2 = 30.6; p < 0.001) and age  between patients and caregivers. Approximately 46% of patients had a lower secondary diploma, while 48% of caregivers had an upper secondary diploma . Most patients were retired or housewives (36%) or blue collar workers  (35%), whereas 33% of caregivers were employees  . Most subjects in the total population were married, with no previous experience of psychological counseling and no psychiatric drug use . Individual psychotherapy had not been recommended to the majority of participants, whereas group psychotherapy had been recommended to about half. Among the patients, 61% of men had occupational exposure and 56% of women had environmental exposure to asbestos. There were also gender significant differences in average age , educational level  and job . The average age was 65.0 years (SD = 11.2) for men and 59.2 years for women (SD = 12.5). Most men (46%) had a lower secondary diploma, while 42% of women had an upper secondary diploma. Moreover, 38% of men were blue collar workers (38%), whereas 38% of the women were retired or housewives (The sample  compriseusewives .p = 0.010). However, the latter were more severely traumatized . The results of ANOVA analysis  showed tp < 0.001) and traumatized  than men and used more coping strategies, particularly social support , avoidance , positive attitude , problem solving  and turning to religion . For defense mechanisms, women achieved higher scores than men for sublimation , anticipation , withdrawal , reaction formation , passive aggressive behavior , acting out , displacement  and somatization . On the other hand, men reported a higher level of dissociation than women .Various statistically significant differences were observed between men and women in terms of behavior as well as coping strategies and defense mechanisms . Women wp = 0.042). Independent variables associated with BDI-II and DTS were examined by logistic regression analysis separately for patients and caregivers. There were 25 patients and 31 caregivers above the cutoff point for depression (BDI-II), and 12 patients and 30 caregivers above that for post-traumatic symptoms (DTS). The intergroup difference was significant only for post-traumatic symptoms (p = 0.01) and DSQ Somatization . Conversely, high use of Coping–Turning to religion  and DSQ Humor  was found to have a protective effect against depression . In terms of effect estimates on post-traumatic symptoms, statistically significant risks were observed for DSQ Passive–aggressive behavior  and Coping–Avoidance strategies , while DSQ Autistic fantasy  and Coping–Positive attitude  had a potentially protective effect .In patients, a high risk of depression was associated with high use of DSQ Isolation , especially those with a high use of Coping–Avoidance , DSQ Acting out , DSQ Devaluation , and DSQ Displacement . Meanwhile, a protective effect was observed in caregivers aged 61–69 years  and those with a high use DSQ Sublimation  . With regard to effect estimates on post-traumatic symptoms, a statistically significant risk was observed for DSQ Acting out  .Among caregivers, women had an elevated risk of depression  is defined as the cognitive and behavioral attempts to distance oneself both from a problem and the related emotions ,56. ThesThe protective effects of religious devotion may be attributable to its role as filter for aggression and anger . RelyingData suggest that defense mechanisms are important both for prevention and development of successive depressive or post-traumatic conditions. Psychoanalytic theories conceptualize defenses as a continuum, differing in degree of maturity, where primitive and/or immature mechanisms imply a severe alteration of reality testing, while more mature defenses allow for management of threatening feelings without distorting reality . Our datIn line with this notion, we observed that immature defenses  significantly increased the risk of developing post-traumatic conditions, although, surprisingly, autistic fantasy had a protective effect in patients. Autistic fantasy allows individuals to withdraw into a different state of consciousness so that they can temporarily distance themselves from external/internal stressful stimuli and their overwhelming impact . In the The findings of this study add to previous knowledge on psychological distress following an MM diagnosis by demonstrating that unconscious adaptive processes play a major role in the way patients and caregivers respond to overwhelming feelings related to the disease. Such evidence strongly suggests the need for psychological interventions addressed to both patients and caregivers, and that take into account not merely coping strategies, but also unconscious somatopsychic processes. In particular, from our clinical point of view, we believe that group interventions addressed to patients and caregivers together could constitute the better setting for the elaboration of unconscious processes connected to death anxieties aroused from MM, considering that the diagnosis has a traumatic impact on all the family members and on the relationship between them. Such interventions would be better time-limited, given the short life-expectancy for MM. Moreover, we suggest a somatopsychic focus for those interventions. Indeed, as suggested by our results, often both patients and caregivers rely on unconscious defense mechanisms to protect themselves from overwhelming emotions connected to the diagnosis, thus lacking a full and conscious comprehension of practical and affective consequences of the disease. Thus, a psychotherapeutic work with a somatopsychic focus can help restore the connection between the impact of physical symptoms and emotions, feelings, and fantasies related to the disease .There were some limitations to our study. Firstly, we used only self-report measures that may have been influenced by social desirability biases. Secondly, since we did not collect any clinical data, we were unable to analyze our results based on disease stage or localization. Thirdly, since we considered MM patients and caregivers of the NPCS as specific subgroups, no generalization can be made regarding the whole MM population. Nevertheless, our study had a large sample size and used a variety of tests along with appropriate statistical models to identify relevant risk factors for, and protective factors against, psychological distress after a diagnosis of MM. Further research is needed to determine whether our findings are applicable to populations at other NPCSs.