There has been a highly active area in the pain management of osteoarthritis (OA) over the past 2 decades. The study aims to unmask the global status and trends in this field.Publications on pain management of OA from 2000 to 2019 were retrieved from the Web of Science (WOS) database. The data were analyzed using bibliometric statistical methodology. The software VOS viewer was used for bibliographic coupling, co-authorship, co-citation, co-occurrence analysis and to investigate the publication trends in pain management of OA.and Cartilage published the most relative articles. Researches could be grouped into 5 clusters based on co-occurrence network map: Health and Epidemiology; Sport Medicine; Clinical Study; Mechanism Research and Medical Technology and Science. Medical Technology and Science was predicted as the next research topic in this field.A total of 8207 researches in amount were included. The relative research interests and number of publications indicated a rising trend. The USA made the greatest contribution to this field, with the most publications, total citations and the highest H-index, while Sweden had the highest average citation per publication. The most contributive organization was Boston University. The journal OA The number of publications about pain management of OA would be increasing based on current global trends. The USA made the largest contribution to this field. The development of Medical Technology and Science may be the next popular topics in the pain management of OA research. Knee OA is the most common joint disorder in elderly individuals, and overall prevalence of symptomatic knee OA is 8.1% based on China Health and Retirement Longitudinal Study (CHARLS) among Chinese adults.,3 Pain is a distressing experience association with actual or potential tissue damage with sensory, emotional, cognitive and social components, which is the first and predominant symptom of OA that causes patients to seeking medical care and broadly contributes to the global burden of musculoskeletal conditions.,6 Pain in OA comes from several sources, both peripheral and central. Pain can affect the quality of life of patients seriously, which indirectly increases the occurrence rate of cardiovascular event and all-cause mortality.–10Osteoarthritis (OA) is an abnormal remodeling of joint tissue within the affected joint including pathologic changes such as degradation of the articular cartilage, thickening of the subchondral bone, formation of osteophytes, variable degrees of inflammation of the synovium, degradation of ligaments and hypertrophy of the joint capsule. Knee OA pain relief often involves a mix of surgical treatment ; pharmacological treatment ; and nonpharmacological treatment . However, the global development trend regarding pain management for OA has not been well studied yet. Thus, it is needed to summarize the current status of pain management in OA and to predict promising keywords and trends.The main purpose of knee OA pain management is to alleviate joint pain, improve daily function and quality of life by increasing muscle strength, physical activity and emotional functioning. bio-receptor, microbiome-gut-brain axis and stem cell. Therefore, we conduct a brief discussion of pain management research in knee OA, unmasking trends that could be helpful for gaining a wide knowledge of global developments in the field and future directions.Bibliometric analysis can provide information based on literature database and literature metrology characteristics, which is used to qualitatively and quantitatively estimate trends in recent years research activity. It provides a way to seize development in a certain field and to compare the contributions of scholars, journals, institutions, and countries. In recent years, bibliometric analysis has been successfully applied in several research areas to assist the development of clinical policies and guidelines, and also been used in evaluating research trends in electronic health,22.1 All publications were searched in the WOS from 2000 to 2019, including the researches in this field in recent 20 years. In this study, the retrieval types were as follows: (TS = knee OA OR KOA) and (TS = pain OR pain treatment OR pain management OR pain assessment) and (Language = English) and (Document types = Article) and (publishing year = 2000–2019). Country-specific information was also retrieved through the WOS index.Bibliometric analysis was conducted using the Web of Science (WOS) Core Collection, which is considered as the optimal database for bibliometric analysis.2.2The data mining of all included publications was downloaded from the WOS database such as title, author, year of publication, nationalities, affiliation, journal, keywords and abstract. Graph Pad Prism 5 and Origin Pro 2018 were used to analyze the data after manually cleaned. Ethical approval was not required as no human and animal subjects were enrolled.2.3,27 Relative research interests was calculated as the number of publications in a certain field divided by all-field publications per year. Use Microsoft Excel (Office2019) to build a forecasting trend model and plot the time curve of the publication: Y = 55.789X − 93.611, R2 = 0.9996. In this formula, the independent variable X represents the year and Y represents the number of publications per year.The basic features of publications were described by using the intrinsic function of WOS. The H-index reflects both the number and citation impact of publications.2.4 In this research, VOS viewer was used for co-citation, co-authorship, bibliographic coupling and co-occurrence analysis.VOS viewer software 1.6.15  was used for bibliometric visualization and analysis of the literature.33.13.1.1Sixty-seven countries and regions in amount published articles in this field. Among these countries, the USA published the largest number of articles , followed by England 901, 10.98%), Australia , China , and Canada   to 978 (2019). Moreover, the relative research interests of this field were increasing during last few years , while England ranked second , followed by Canada , Sweden , and Australia   had the most top average number of citations. France (40.1) ranked second, followed by the USA 38.15), England (37.98), and Canada (35.01)  had the most top number of H-index, followed by England (84), Canada (65), Australia (62), and Germany (60) ; University Sydney (523023 times); Monash University (509989 times); University Calf San Francisco (492158 times); University Melbourne (404647 times) ; BMC Musculoskeletal Disorders ; Arthritis Care and Research ; Knee Surgery Sports Traumatology Arthroscopy ; American Journal of Sports Medicine . . Fig. b3.3.7Total link strength was shown for 64 countries, with each selected country owing at least 5 papers in this field. The top 5 countries with large total link strength were the following: the USA (1817853 times); Australia (777616 times); England (682022 times); Canada (525319 times); China (500276 times) ; Felson DT (355 times); Guermazi A (339 times); Nevitt MC (310 times); Hunter DJ (270 times) ; University Calf San Francisco (631 times); University Sydney (596 times); Monash University (438 times); University Iowa (383 times) ; England (762 times); Australia (692 times); Germany (539 times); Canada (463 times) ; Altman R, 1986, arthritis rheum, v29, p1039, (779times); Bellamy N, 1988, J rheumatol, v15, p1833, (734 times); Zhang W, 2008, osteoarthr cartilage, v16, p137, (298 times); Felson DT, 2001, ann intern med, v134, p541, (259 times) ; Annals of The Rheumatic Diseases ; Arthritis Rheum-Us ; Journal of Rheumatology ; Pain  (Fig. Total link strength was shown for 1165 journals, with each selected journal owing at least 20 co-citations in this field. The top 5 journals with large total link strength were following: OA 3.4,37 Keywords were analyzed using Vos viewer, which were set as minimum occurrences number was 5 in total publications. As shown in Figure Co-occurrence analysis shows that the relationship of items based on the number of publications in which they occur together.Keywords in total included publications were marked specific colors based on average appearing time Fig. B. The bl44.1Bibliometric and visualized analysis can unmask the current status and predict hot topics in research field. With population aging, studies in OA pain may bring clinical guidelines. Thus, our study was conducted to evaluate pain management studies in OA about contributing countries, institutions, authors, journals, and research focus. As shown in our study, a significantly increasing number of publications per year is presented. In addition, the relative research interests was increasing dramatically recent years, especially in 2004 to 2018. A total of 64 countries had published relative studies in this field. Based on the current data, more studies with in-depth pain management knowledge in OA will be published in the coming year. The present optimistic results in turn will also allow investigators to conduct further high-quality research.4.2The total number of citations, average citations per paper, and H-index of a country represent its academic impact and quality of publications. The USA made the greatest contributions to the global research in terms of total number of publications as well as total citation frequency and H-index. Well, Sweden has the highest average number of citations. Thus, the USA can be regarded as the leading country in this field, and Sweden also played a significant role owning to high average citation frequencies. China ranked fourth in total number of publications. However, the total citation, h-index, and average number of citations ranked twelfth, twelfth, and twentieth, respectively. The discrepancy between the quantity and quality of publications may be due to an important reason. The academic evaluation system in China has focused on publish quantity of publications instead of quality.The OA and Cartilage, Annals of The Rheumatic Disease, Knee Surgery Sports Traumatology Arthroscopy, American Journal of Sports Medicine, and BMC Musculoskeletal Disorders published more studies on pain management of OA. The number of papers in OA and Cartilage is as many as the sum number of another four journals. The journals in Figure Almost all the top 20 institutions including 18 universities and 2 medical centers were from the USA, England, and Australia, except Lund University in Sweden, which implying that establishing top class research institutions is essential to improving a country's academic level. Guermazi A, Felson DT, and Hunter DJ are the top 3 authors who published the most articles in this field. The top 20 authors could be regarded as the pioneers in pain management of OA. Their future studies may have a substantial impact on the development in this field and should be closely monitored to grasp the latest advancement.and Cartilage published most relevant articles, and the USA was in the leading position in this field. Co-authorship analysis was used to assess collaboration among countries, institutions, and authors. The one with greater total link strength suggested that the country/institution/author would be more likely to cooperate with others. Co-citation analysis was conducted to evaluate the academic influence of studies. The top studies with large co-citation frequency could be regarded as the landmark studies about pain management of OA. OA and Cartilage was the journal with the highest citation frequency in this domain.In the present study, the relatedness between papers with regards to country, institution, and journal was established by bibliographic coupling analysis. Bibliographic coupling analysis constructed on the shared references among publications, providing deeper insights on how authors use and build links among the existing literature. The analysis showed that OA 4.3Based on the co-occurrence analysis, we discovered directions and hot topics in this field. The keywords in title and abstract in all included studies were analyzed to create a map of a co-occurrence network. As the co-occurrence map shown, 5 research directions were observed, including “Health and Epidemiology”; “Sport Medicine”; “Clinical Study”; “Mechanism Research,” and “Medical Technology and Science”. The present results could help clarity the trend of future research. In the center of the co-occurrence map, the keywords, including knee OA, pain, arthritis, double-blind, and cartilage, were shown more prominently with higher weight. Thus, further high-quality studies evaluating pain management for OA in these 5 directions are still required.–41 In addition, technology-based on regenerative medicine and transforming medicine such as biomimetic tissue engineering is required. “Mechanism Research” plays a key role in pain management of knee OA. Primary studies investigating the pain mechanism and relation between mechanism and symptoms remain the focus of this research filed.,42–45The overlay visualization map was identical to the co-occurrence map except that items were colored differently. This method was important for monitoring the progress of research. In this overlay visualization shown in Figure Based on the finding of our study, the increasing number of publications indicated that the pain management serves as a key position in knee OA research. The positive finding in turn encourages investigators to perform further studies. The bibliometric and visualized analyses could provide the researchers with the knowledge of leading countries, famous authors, and top institutions in the field. With this knowledge, novice researchers can have a visual picture and gain insight more quickly. In addition, the co-occurrence analysis and overlay visualization map identify the prevalent trend and future research direction, which is helpful for the funding sources to make reasonable investment plan and provide support for formulation of pain management policy.4.4Although the present study evaluated the status and trends of studies about pain management in OA via bibliometric and visualized analyses, the following items about limitations have to be mentioned. English language studies were included based on the database of WOS. Non-English language literature could have been omitted, leading to language bias. Additionally, differences may exist between the real world and the present results. Therefore, we still need to focus on the latest primary studies and other non-English studies in our daily research work.5and Cartilage had the largest number of publications related to this topic. We can believe that more studies about pain management for OA will be published in the coming years. Particularly, the “Medical Technology and Science” studies, involving pain management for OA is the next popular hot spot.The present study unmasked the global trends in pain management for OA. The USA was the largest contributor to studies and had the leading position in global research in this field. The journal OA Conceptualization: Taoyu Chen, Jiaying Zhu.Data curation: Jiaying Zhu, Jianjun Fan.Formal analysis: Taoyu Chen.Funding acquisition: Pengcui Li.Investigation: Yu Zhao.Methodology: Taoyu Chen.Project administration: Pengcui Li, Xiaochun Wei, Jianjun Fan.Resources: Yu Zhao.Software: Haoqian Li.Supervision: Pengcui Li, Xiaochun Wei.Validation: Haoqian Li, Xiaochun Wei.Visualization: Taoyu Chen, Haoqian Li.Writing – original draft: Taoyu Chen, Jiaying Zhu, Xiaochun Wei.


Deficits in gestures act as early signs of impairment in social interaction (SI) and communication in children with autism spectrum disorder (ASD). However, the pieces of literature on atypical gesture patterns in ASD children are contradictory. This investigation aimed to explore the atypical gesture pattern of ASD children from the dimensions of quantity, communicative function, and integration ability; and its relationship with social ability and adaptive behavior. We used a semi-structured interactive play to evaluate gestures of 33 ASD children (24–48 months old) and 24 typically developing (TD) children (12–36 months old). And we evaluated the social ability, adaptive behavior, and productive language of ASD and TD children by using the Adaptive Behavior Assessment System version II (ABAS-II) and Chinese Communication Development Inventory (CCDI). No matter the total score of CCDI was corrected or not, the relative frequency of total gestures, behavior regulation (BR) gestures, SI gestures, and joint attention (JA) gestures of ASD children were lower than that of TD children, as well as the proportion of JA gestures. However, there was no significant group difference in the proportion of BR and SI gestures. Before adjusting for the total score of CCDI, the relative frequency of gestures without vocalization/verbalization integration and vocalization/verbalization-integrated gestures in ASD children was lower than that in TD children. However, after matching the total score of CCDI, only the relative frequency of gestures without vocalization/verbalization integration was lower. Regardless of the fact that the total score of CCDI was corrected or not, the relative frequency and the proportion of eye-gaze-integrated gestures in ASD children were lower than that in TD children. And the proportion of gestures without eye-gaze integration in ASD children was higher than that in TD children. For ASD children, the social skills score in ABAS-II was positively correlated with the relative frequency of SI gesture and eye-gaze-integrated gestures; the total score of ABAS-II was positively correlated with the relative frequency of total gestures and eye-gaze-integrated gestures. In conclusion, ASD children produce fewer gestures and have deficits in JA gestures. The deficiency of integrating eye gaze and gesture is the core deficit of ASD children’s gesture communication. Relatively, ASD children might be capable of integrating vocalization/verbalization into gestures. SI gestures and the ability to integrate gesture and eye gaze are related to social ability. The quantity of gestures and the ability to integrate gesture with eye gaze are related to adaptive behavior.Clinical Trial Registration:www.ClinicalTrials.gov, identifier ChiCTR1800019679. Autism spectrum disorder (ASD) is a neurodevelopmental disorder with heterogeneous manifestations mainly characterized by impairments in social interaction (SI) and communication, as well as the presence of restrictive and repetitive behaviors  or ANCOVA , we found that the relative frequency of total gestures in ASD group was lower than that in TD group  = 33.346, p1 < 0.001; F2 = 20.136, p2 < 0.001], the relative frequency of SI gestures , the relative frequency , and the proportion  of JA gestures in the ASD group were significantly lower than those in the TD group, while there was no significant difference in the proportion of BR gestures and SI gestures among groups (p > 0.05)  .F1 = 31.710, p1 < 0.001] and the relative frequency of vocalization/verbalization-integrated gestures  in ASD group were significantly lower than that in TD group when we used ANOVA. While we utilized ANCOVA to adjust for the total score of CCDI, we found that only the relative frequency of gestures without vocalization/verbalization integration was significantly lower . Moreover, when we used ANOVA or ANCOVA, we found no significant difference among ASD and TD groups in the proportion of vocalization/verbalization-integrated gestures and gestures without vocalization/verbalization (p > 0.05).We found that the relative frequency of gestures without vocalization/verbalization integration  and the proportion of eye-gaze-integrated gesture  in the ASD group were significantly lower than that in TD group. And ASD group showed a higher proportion in gestures without eye-gaze integration than the TD group . Besides, we found no significant difference among ASD and TD groups in the relative frequency of gestures without eye-gaze integration (p > 0.05)  .We found some statistically different gestural indexes between ASD and TD groups by utilizing ANCOVA. Those indexes might reflect the deficiency of ASD children’s gestural communications most. Therefore, for reducing the number of calculated correlations, we only analyzed the correlation between ABAS-II and those gestural indexes. Besides, considering that the “proportion” indexes  are merely complementary to each other, we only choose the proportion of eye-gaze-integrated gestures.r = 0.368, p = 0.035) and eye-gaze-integrated gestures ; the total score of ABAS-II was positively correlated with the relative frequency of total gestures  and eye-gaze-integrated gestures . In TD group, the scores of ABAS-II were not significantly correlated with gestures   .p > 0.05 for all). In TD group, the social skills score in ABAS-II was positively correlated with the relative frequency of JA gestures  when controlling the total score of CCDI . In TD children, dyadic interaction with another person forms in the first 3 months of life, and dyadic interaction with object forms in the first 6 months of life. At 9–12 months, TD children begin to coordinate the two types of dyadic interactions to form triadic interactions . These cBefore adjusting for the total score of CCDI, we found that ASD children were less likely to integrate gesture and vocalization/verbalization than TD children. However, after correcting for the total score of CCDI, we found that the ability of ASD children to integrate gesture and vocalization/verbalization was no different from TD children. Recently, Conversely, no matter that we corrected for the total score of CCDI or not, ASD children were worse at integrating gesture and eye gaze than TD children. Likewise, For ASD children, the better social ability, the more SI gestures, and the better ability to integrate gesture and eye gaze. SI gestures are used to attract or maintain another person’s attention to oneself to initiate or maintain interaction . Thus, wPrevious studies have shown that ASD children had deficits in adaptive behavior . The impHowever, when controlling the productive language, the correlations between gesture, adaptive behavior, and social ability disappeared in ASD children. It may indicate that the relationships between gesture, adaptive behavior, and social ability are influenced by productive language. Future studies should explore the role productive language plays on relationships between gesture, social ability, and adaptive behavior.In the TD group, we found no significant relationship between gestures, social ability, and adaptive behavior. However, when we controlled productive language, the social ability was positively correlated with JA gestures. That is probably because the development of gestures in TD children is more closely related to language development .P < 0.05, which might be a consequence of the Type 1 error chance. In future studies, we should increase the number of participants and set up the significance level of p < 0.01.By reviewing research, we can find that TD children’s gestures and language develop rapidly in the second and third years after birth. Consequently, we enrolled 12–36 months TD children. And gestures and early language development are closely linked. It is necessary to consider the impact of language when exploring the difference in gesture patterns between ASD children and TD children. In some previous research on gestures of ASD children, the chronological age of TD children ranged from 12 to 36 months. After matching, they enrolled ASD children who are 1–2 years older than TD children , 2017. AWe discovered the atypical gesture patterns of ASD children: (1) ASD children produce fewer gestures and have deficits in triadic interaction gestures . (2) The deficiency of integrating eye gaze and gesture is the core deficit of ASD children’s gesture communication. Relatively, children with ASD might be capable of integrating vocalization/verbalization into gestures. Furthermore, we found that SI gestures and the ability to integrate gestures and eye gaze are related to the social ability. The quantity of gestures and the ability to integrate gestures with eye gaze are related to adaptive behavior.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 the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.QY, XZ, and HD contributed to conception and design of the study. QY and SC organized the database. QY, LL, and HZ performed the statistical analysis. QY wrote the first draft of the manuscript. QY, SL, YX, and HD wrote the sections of the manuscript. All authors contributed to manuscript revision, and read and approved the submitted version.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.


To evaluate and to correlate levels of physical activity with the pulmonaryfunction of children with and without a diagnosis of asthma. This study was conducted in two phases with schoolchildren aged betweeneight and 16 years old in Porto Alegre/RS. In the first phase , the sample was classified as asthmatic if a physician had everdiagnosed them with asthma and if they reported symptoms and treatment forthe disease in the past 12 months. In the second phase (control-case), thefollowing were measured: anthropometry, physical activity levels, time spentin front of screens, and lung function (spirometry). Data are presented inmean and standard deviation or median and interquartile interval and byabsolute and relative values. Chi-square, Student’s t-test or Mann-Whitneytest and Spearman correlation were applied, with p<0.05 beingsignificant. 605 students participated in the study, 290 children with a clinicaldiagnosis of asthma and 315 classified as a control. 280 (47.3%) were malechildren, with an average age of 11.0±2.3 years old. The spirometric valuesshowed differences in the classifications of airway obstruction levelsbetween the asthma and control groups (p=0.005), as well as in the responseto bronchodilator use for FEV1/FVC (p=0.023). In the correlation assessment,there was no correlation between physical activity with anthropometricvalues, nor with pulmonary function, pre-and post-bronchodilator. The study demonstrates that there is no relationship between eitheranthropometric values or physical activity levels with pulmonary function ofasthmatic children. As such,it is considered a worldwide public health problem. It has several severityclassifications, and only the correct diagnosis can indicate the best therapeuticmethod to be applied.,Physical exercise can exacerbate the symptoms. However, induced bronchoconstrictionmust be understood as separate from uncontrolled symptoms during a crisis, and assuch there different treatments.,,The recommendations of the American College of Sports Medicine (ACSM) suggest thatchildren and young people practice at least 60 minutes of physical activitydaily.,Asthmatic and obese children have their symptoms exacerbated, as they have adecreased response rate to inhaled corticosteroids.A study was carried out in two phases with students from public schools in PortoAlegre (RS) aged 8 to 16 years old:Phase I : a characterization of the sample, with anabbreviated questionnaire applied to the guardians of the students,following the standards of the International Study of Asthma andAllergies in Childhood (ISAAC) study.Phase II (control case): after characterization and identification of theasthma and control  groups, the outcomes of the anthropometry,levels of physical activity and lung function (spirometry) wereevaluated.Prior to inclusion in the study, both guardians and patients consented to participatewith a free and informed consent form (guardians) and an agreement form(children/adolescents).In addition, the study was approved by the Research Ethics Committees (CEP) of thePontifícia Universidade Católica do Rio Grande do Sul, as well as by the MunicipalHealth Secretariat of Porto Alegre, under Substantiated Report No. 73,585/12 and No.7,793/2012, respectively.In the anthropometric evaluation, the following were evaluated:The body mass index (BMI),For the fat percentage (%F), following the methodology proposed bySlaughter et al.,Waist to stature ratio (WSR),All of the anthropometric assessments were collected by a single, previously trainedresearcher. For the skin folds, a scientific adipometer of the brand/model Lange wasused. Body mass was obtained with individuals in an orthostatic position, withminimal clothing, no shoes, and weighed using a digital scale  previously calibrated with a precision of100 grams. Stature was measured with the participants barefoot, feet in a parallelposition, ankles together, arms extended along the body and the head positioned sothat the lower part of the eye socket was on the same plane as the external earhole. Stature measurements were taken using a portable stadiometer  with an accuracy of 1 mm.To assess lung function, spirometry tests were applied before and after theapplication of 400 µg of salbutamol (bronchodilator), following internationalcriteria and guidelines (American Thoracic Society and European RespiratorySociety).For the purpose of assessing physical activity levels, a questionnaire designed andvalidated for the study population was applied. It was proposed by Hallal et al.,For the design and sample calculation, both the selection of schools and that ofstudents occurred in a randomized way (simple random). In total, seven publicschools in Porto Alegre were selected, based on the sample calculation the ISAACstudies,For the statistical analysis, descriptive and categorical variables were presented byabsolute and relative frequencies, and descriptions of continuous variables, werepresented by means and standard deviation (M±SD) or median and interquartile(MD-IQ). To make comparisons between the groups (asthma and control), normality wasassessed by the Z test (Kolmogorov-Smirnov), and the values were analyzed using theχ2 test and the t independent Student test for homogeneous variables and theMann-Whitney test for non-homogeneous variables. In addition, for the purpose ofcorrelating levels of physical activity, anthropometry and lung function, Spearman’scorrelation was applied, with a significance value of p<0.05.In phase I, 2,899 questionnaires were distributed in seven public schools in the cityin order to identify and characterize the sample. Of these, 2,500 were considered tobe eligible for the study (86.2%), reporting an asthma prevalence rate of 20.4%(n=511). Of the 2,500 schoolchildren, 1,211 (48.4%) were male, and had an averageage of 11.4±2.3 years.In phase II, 605 students were randomly selected and evaluated, 280 (47.3%) of whomwere male, and had a mean age of 11.0±2.3 years. In addition, students were dividedinto two groups:Asthma group: 290 students classified as asthmatic.Control group: 315 students classified as healthy.In In In In The objectives of this study were to evaluate and correlate the levels of physicalactivity with the pulmonary function of children with and without a clinicaldiagnosis of asthma. The results pointed to a non-existent correlation for both thegroup of asthmatics and the group of healthy children. In addition, both groupsshowed very similar values in terms of physical activity levels and anthropometricmeasurements, with differences only for pulmonary function (FEV1 and FEV1/FVC).These results indicate that students in this age group have very similar physicaland anthropometric patterns, regardless of whether or not they have a chronicrespiratory disease.,Regarding the spirometric indices presented, the results showed differentialnormality between the groups, since asthma, a chronic obstructive disease, leads toreduced values of FEV1 and FEV 1/FVC. The relationship between FEV1/ FVC corroborated the results found in FEV1, indicatingobstructive disorders at rest (p≤0.001). Pulmonary function tests are importantmarkers for the management of chronic respiratory diseases in adults and children,especially those with asthma. The analysis of changes in lung volumes and flowsduring forced expiration helps in the treatment and prognosis of the disease.Regular pulmonary function assessments are essential for monitoring children withasthma. There may be bronchial obstruction in an asthmatic child, even if he or sheis asymptomatic. This represents a greater risk of exacerbating a severe crisisassociated with reduced lung function.,After the use of bronchodilators, there was an improvement in FEV1/ FVC in the groupof students with asthma and in the control group (p≤0.003). The results werepositive when there were differences in the spirometry results with the use ofbronchodilators. Bronchodilators are the most widely used drugs for the treatment oflung diseases, especially in cases of asthma. They are usually applied by inhaling,as they act quickly.,With regard to anthropometric measurements, the continuous variables of the BMI data,fat mass index and waist/stature ratio are described. There was no significantdifference in fat mass index for either group (p≤0.757). For the WSR, there was adiscrepancy between the two groups (p≤0.048). The group of asthmatic children hadWSR rates above those without asthma. However, previous studies do not confirm thesefindings,Physical exercise is considered one of the main palliative factors in the treatmentof asthma. Asthmatic children may have their daily and physical activities reduceddue to the exacerbation of symptoms.One previous study that assessed functional capacity in children with asthma pointedout that 88% of asthmatics and 56% of healthy children performed less than two hoursa week of physical activity. These numbers worsen when parents report inquestionnaires that they believe physical activity is dangerous for their children,thinking that exercise triggers crises. ,The parents’ reluctance to encourage exercise may be due to exercise-inducedbronchospasm, which can often be as intense as an asthma attack. In families whoseparents believe that exercise can improve asthma control and quality of life,children are more active.Data show that children aged 8-12 years spend an average of 6 hours a day involvedwith electronic devices. Our study presented several limitations. The population included urban school-agechildren and youth, most of whom were not asthmatic and only a small number who hadmoderate to severe asthma. In addition, the overweight/obesity group was small,limiting the sampling power of the associations. A longer study is suggested, inwhich assessments can be made in all seasons of the year.Sociedade Brasileira de Pneumologia e Tisiologia - SBPT),Although the international guideline Global Initiative for Asthma (GINA),


Cancer stem cells (CSCs) play an important role in drug resistance, recurrence, and metastasis of tumors. Considering the heterogeneity of tumors, this study aimed to explore the key genes regulating stem cells in intestinal-type and diffuse-type gastric cancer.RNA-seq data and related clinical information were downloaded from The Cancer Genome Atlas (TCGA). WGCNA was used to clustered differentially expressed genes with similar expression profiles to form modules. Furtherly, based on the mRNA expression-based stemness index (mRNAsi), significant modules and key genes were identified. Next, the expression of key genes was further verified by the Oncomine database.MRNAsi scores of GC were significantly higher than that of normal tissue. Additionally, mRNAsi scores of intestinal-type GC (IGC) were significantly higher than that of diffuse-type GC (DGC). WGCNA showed that the blue module of IGC and the brown module of DGC were both the most significantly associated with mRNAsi. We screened out 16 and 43 key genes for IGC and DGC and found that these genes were closely related, respectively. Functional analysis showed the relationship between the key genes confirmed in the Oncomine database and the fate of cells.In this study, 16 and 43 genes related to the characteristics of CSCs were identified in IGC and DGC, respectively. These genes were both associated with cell cycle, which could serve as therapeutic targets for the inhibition of stem cells from both types of GC. As a common neoplasm worldwide, gastric cancer (GC) is the main cause of cancer-related deaths . Accordi+ cells possess properties of radio- and chemo- resistance [+ GC cells have strong tumorigenic and self-renewal ability. However, ALDH1 mRNA expression cannot be detected in IGC [Recently, cancer stem cells (CSCs) have attracted more and more attention. And they are characterized as cells in the tumor which have the capacity of self-renewing and causing the heterogeneous cancer cell lineages. Many studies have shown that CSCs play a crucial role in the metastasis, differentiation, and drug-resistance of cancer –7. At prsistance –14. The sistance . Howeversistance . ALDH1, d in IGC . Some scMalta et al. compared the genetic maps of tumor cells and embryonic stem cells and proposed a new index, stem cell index. They analyzed a dataset of 99 stem/progenitor cells from the Progenitor Cell Biology Consortium (https://www.synapse.org/pcbc) and used a one-class logistic regression machine learning algorithm (OCLR) to train on different types of stem cells and progenitor cells, and thus got the stemness index. Furthermore, they applied the stemness index analyze the transcriptome of TCGA and obtained the mRNA expression-based stem index (mRNAsi) of different types of tumors including GC, with the value between -1 and 1, and the higher the value of mRNAsi, the stronger properties of cancer stem cells. The mRNAsi is considered as a quantitative indicator of CSCs to show how many tumor cells will be with the same properties as stem cells. Previous researches have also revealed that mRNAsi was associated with biological processes and tumor heterogeneity, which provided novel insights for further cancer research [To better describe the characteristics of CSCs, research . Based oresearch , 20. ThiGiven the close relationship between tumor stem cells and tumors, in this study, we explored the characteristics of GC histological subtype by the stemness index, and the WGCNA model was used to determine the most relevant module of mRNAsi index, with the key genes identified. Our study intends to explore markers associated with the stem cell characteristics of IGC and DGC, which would help clarify the biological characteristics and progression of GC subtypes and inform the future diagnosis and therapy of GC.https://portal.gdc.cancer.gov) in March 2020. The mRNAsi of normal and GAC specimens in TCGA were downloaded from previous studies [https://www.perl.org), and gene names were converted into the corresponding gene symbols through the Ensemble database (https://asia.ensembol.org/index.html).The RNA-seq data of 30 normal and 343 human gastric adenocarcinomas (GAC) specimens were downloaded from the TCGA database  < 0.05, WGCNA  is a multiplex analysis method to cluster genes with similar expression patterns. The WGCNA package in R was utilized to build a co-expression network of DEGs . First, Further, we chose significant modules related to mRNAsi, and genes in these modules were considered to be co-expression of genes related to CSC. First, gene significance (GS) was calculated, which reflected a linear regression between the gene expression and mRNAsi in each module. A cutoff value (< 0.5) was applied in the merge of highly similar modules. And then the modules that had the largest average GS were considered the most mRNAsi-related modules. After finding the most significant module, we used module membership (MM) to determine which gene in each module was highly related to mRNAsi, that is, to screen out key genes. The threshold values for the selection in the module of IGC or DGC were set: cor. GS > 0.5, cor. MM > 0.8; cor. GS > 0.8, cor. MM > 0.8, respectively.P-value < 0.05 and FDR < 0.05 were chosen as the criteria in this section.Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to study the biological functions of the key DEGs. And these analyses were conducted by the cluster profiler package in R . P-valuehttps://www.string-db.org) was chosen to investigate and generate the PPI network among key genes.R package corrplot was selected to estimate the Pearson correlation to illuminate the co-expression relationship of key genes at the transcriptional level . The 11.https://www.oncomine.org) was investigated the mRNA expression of key genes between histological subtypes of GC and normal samples. The threshold was set as: gene rank = top10%; fold change = 2; P-value = 1E−4.Oncomine  and SPSS (Version 21). The difference of mRNAsi scores between the normal and the tumor group was calculated using the Wilcox test and multivariate logistic regression analysis adjusted by age and sex. The Kruskal test analysis and multivariate logistic regression were selected to clarify the interrelationships between the scores of mRNAsi and clinical characteristics. The survival package was performed to evaluate the prognostic value of mRNAsi, a two-sided log-rank test, and multivariate Cox proportional hazards models adjusted for age, sex, stage, grade were employed to determine statistical significance. A P < 0.001. Further, in terms of clinical features, 323 GAC patients were classified by age, gender, TNM stage, tumor stage, histopathological types, respectively; for which, mRNAsi was not associated with age (P = 0.133), gender (P = 0.780), T (P = 0.140), N (P = 0.579), M (P = 0.598) stage, but only had a declining trend with the improved tumor stage  or β = 8  to ensure a scale-free network, and 27 and 10 gene modules with similar expression profiles in IGC and DGC were obtained for subsequent analysis (Fig. Furthermore, WGCNA was used to construct a co-expression network of DEGs with the soft threshold β = 5 (scale-free Rsis Fig. b, c. Thesis Fig. a, b. HowNext, the mRNAsi-related key genes were verified in the Oncomine database. As shown in Fig. In IGC, the GO analysis results indicated that key genes participated in the biological process of nuclear division. The main cellular component manifested enrichment mainly at the spindle. The main molecular function enriched these genes in DNA replication origin binding, and the KEGG analysis demonstrated that the major pathway was cell cycle Fig. a, c. In We explored the interactive relation of the above key genes using Pearson correlation and found that the key genes in the blue module of IGC or the brown module of DGC had relatively strong correlation, with the minimum correlation coefficient of 0.41 and 0.58, and the correlation among genes was shown in Figs. GAC, as the main type of GC, can be classified into the diffuse and intestinal type. IGC occupies the majority with a better prognosis, while DGC is more malignant with a worse prognosis. Although numerous researches have spotted the diagnosis and treatment of these two types of GC, the molecular characteristics of them are still not clear. In this study, using mRNAsi, we screened out 16 genes related to stem cell characteristics of IGC and 43 genes of DGC. Further analysis showed that these key genes had strong interaction and had high co-expression relationship at the transcription and protein levels. These results suggested that key genes selected based on mRNAsi may indicate different molecular characteristics of IGC and DGC. Our study extended the knowledge of GC molecular characteristics and would provide new insight into the clinical treatment of GC histological subtypes.We initially analyzed the relationship between clinical characteristics and mRNAsi scores in GAC, and the results showed that tumor samples had a higher stemness index when compared with normal samples, which was consistent with former studies . MeanwhiFurthermore, we used WGCNA to distinguish significant modules related to mRNAsi and identify stemness-related key genes. In IGC and DGC, the blue module and the brown module showed significant positive correlations with mRNAsi respectively, indicating that the key genes in these modules had higher stem cell characteristics. Based on GS and MM, 16 and 43 stemness-associated genes were obtained from IGC and DGC, respectively, and in two types of GC, these key genes were highly expressed. Further functional analysis revealed that the key genes in IGC and DGC were both primarily concentrated in the cell cycle pathway. The cell cycle pathway plays a critical role in the development of GC, which is not only associated with the proliferation of GC cells but also related to the prognosis of the tumor. For example, cyclin D1 was one of the biomarkers of poor prognosis in GC patients . And theMoreover, among the key genes obtained above, BUB1 was highly expressed in both IGC and DGC and has higher connectivity in PPI network, but it was with highly expression in IGC. As a common candidate key gene, BUB1 had a mitotic serine/threonine kinase checkpoint that was up-regulated in numerous cancers and associated with tumorigenesis, proliferation, and metastasis –31. In tThe Oncomine validation indicated that all key genes were highly expressed in IGC, among which PLK4 is a serine/threonine-protein kinase that regulates centriole duplication. It has been reported that its deregulation could cause centrosome number abnormalities, mitotic defects, chromosomal instability, and, consequently, tumorigenesis. And PLK4 has emerged as a therapeutic target for the treatment of multiple cancers . This deThere are some limitations to this article: First of all, although we used the under-sampling method to balance the sample, the actual sample equilibrium will make the results more reliable. Next, this study was a retrospective study based on TCGA network database, and the PPI network among key genes was explored with the STRING database, since the data contained in the database was generally not examined by a human curator, the conclusion and the relationship among genes need further biological verification. Finally, due to the limitation of sample size, the correlation between stem cell index and some clinical characteristics, such as survival, may not be well explored and needs to be further tested in a larger sample population.In conclusion, we identified genes that maintained the characteristics of IGC and DGC. These genes could become therapeutic targets to inhibit the properties of both stem cells. However, our conclusions were based on retrospective data, so further biological studies are in need to verify these findings.Taken together, 16 and 43 genes correlated to the characteristics of CSCs were identified in IGC and DGC, respectively. These genes were related to cell cycle, which may serve as therapeutic targets for the inhibition of the stem cells from both types of GC. However, our conclusions derived from bioinformatic analysis still need further basic studies to validate.Additional file 1: Table S1. The DEGs between the IGC and normal tissues. Table S2. The DEGs between the DGC and normal tissues.Additional file 2: Figure S1. Expression validation of 36 stemness-related key genes expression in DGC.


Although mindfulness-based interventions (MBIs) have garnered empirical support for a wide range of psychological conditions, the psychological processes that mediate the relationship between MBIs and subsequent symptomatic improvement are less well-understood. In the present study we sought to examine, for the first time, the relationship between mindfulness, negative interpretation bias as measured by the homophone task, and anxiety among adults with Generalized Anxiety Disorder (GAD). Forty-two individuals with GAD completed measures of mindfulness, interpretation bias, and anxiety before and after treatment with Mindfulness-based Stress Reduction (MBSR). Contrary to prior research, we did not find evidence of an indirect relationship between baseline levels of mindfulness and anxiety via negative interpretation bias. MBSR did result in significant reductions in negative interpretation bias from baseline to post-treatment; however, we did not find evidence of an indirect relationship between changes in mindfulness and changes in anxiety via changes in interpretation bias. Taken together, these results provide minimal support for the hypothesized relationship between mindfulness, negative interpretation bias, and anxiety among adults with GAD. Limitations and specific suggestions for further inquiry are discussed. A growiVarious researchers have examined the use of MBIs to treat GAD. For example, The literature examining the psychological processes through which MBI may improve anxiety and worry among adults with GAD is small and nascent. Cognitive-behavioral models of anxiety disorders  propose are rather than interpreting them through their cognitive filters.Although much of the teaching in MBSR is centered around training one’s attention to present moment experiences, there is also a very strong emphasis on the way or attitude in which one pays attention. Indeed, Kabat-Zinn identified seven attitudinal foundations of mindfulness  which are embedded within the meditative practices and embodied by the teacher. Several of these attitudinal foundations of mindfulness could contribute to the development of a less biased view of the world, such as, non-judging (observing without judging) and “beginner’s mind,” which is conceptualized as a way of seeing the world that is new and uninfluenced by past experiences . These cThe relationship between mindfulness and interpretation bias has only recently been examined. In the present study, we sought to replicate and extend these findings in a sample of adults with GAD who received treatment with MBSR. MBSR is a standardized, protocolized course that was developed to teach participants how to cultivate mindfulness through a range of meditative practices. This course is now available in most major cities in the United States and has now been used in hundreds of research trials to address a variety of psychological and medical symptoms.Our first aim was to replicate n = 42) to an active control condition, Stress Management Education , for the treatment of GAD in Boston, Massachusetts  were used to cultivate awareness of internal present-moment experiences with an attitude of acceptance and non-judgment. For example, the movement practices contain gentle stretching and slow movements, focusing on present experience and being kind to the body. Participants were also instructed in “informal” home mindfulness practice .The following questionnaires and tasks were administered at baseline (week 0) and endpoint (week 8).The Five-Facet Mindfulness Questionnaire (FFMQ) is a widely used 39-item self-report measure of mindfulness that was empirically derived from a factor analysis of various mindfulness questionnaires. The five facets of mindfulness that emerged from the factor analysis are: describing, observing, acting with awareness, non-judgment, and non-reactivity (activity . The FFMactivity . Items aThe homophone task was developed by The Beck Anxiety Inventory (BAI) is a widely used 21-item self-report measure of anxiety . It has Participants without data for a particular measure were not included in analyses pertaining to that measure. Missing item-level data was imputed to the measure mean. Analyses were conducted using SPSS version 25.Forty-two people with GAD participated. Seventeen (40%) were female, seven (19%) were non-white  and the average age was 41.9 (SD = 14.5) years. Summary data for all measures at each time point can be found in Aim 1: Investigating the indirect relationship between level of mindfulness and level of anxiety via level of negative interpretation bias at baseline.To test for the hypothesized indirect relationship, we conducted a simple mediation analysis using ordinary least squares path analysis using the PROCESS macro in SPSS . This anab = 0.023) based on 10,000 bootstrap samples contained zero (-0.025 to 0.083). Indeed, the only significant relationship we observed was the direct effect of mindfulness on anxiety when holding interpretation bias constant  = −3.629, p = 0.001, d = −0.54, decrease in negative interpretation bias, t(41) = 2.778, p = 0.008, d = 0.43 and decrease in anxiety, t(35) = 4.055, p < 0.001, d = 0.68 from baseline to endpoint.We first conducted three separate two-tailed paired ab = 0.029) based on 10,000 bootstrap samples included zero .The datasets generated for this study will not be made publicly available as permission was not granted in the consent. Permission to access the data can be made by contacting the corresponding author EH (The studies involving human participants were reviewed and approved by the Partners Human Research Committee/IRB at MGH. The patients/participants provided their written informed consent to participate in this study.EH and HR conceived and carried out the experiment and wrote the manuscript. IO and CG assisted in the preparation of the manuscript and edited the parts of the revisions. BG, MD, EB, and NS helped to shape the analysis and discussion, provided critical feedback, and provided important contributions to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drug-drug interaction is an emerging threat to public health. Currently, there is an increase in comorbid disease, polypharmacy, and hospitalization in Ethiopia. Thus, the possibility of drug-drug interaction occurrence is high in hospitals. This study aims to summarize the prevalence of potential drug-drug interactions and associated factors in Ethiopian hospitals.2 statistics, and Logit event rate were also performed.A literature search was performed by accessing legitimate databases in PubMed/MEDLINE, Google Scholar, and Research Gate for English-language publications. To fetch further related topics advanced search was also applied in Science Direct and HINARI databases. The search was conducted on August 3 to 25, 2019. All published articles available online until the day of data collection were considered. Outcome measures were analyzed with Open Meta Analyst and CMA version statistical software. Der Simonian and Laird’s random effect model, IA total of 14 studies remained eligible for inclusion in systematic review and meta-analysis. From the included studies, around 8717 potential drug-drug interactions were found in 3259 peoples out of 5761 patients. The prevalence of patients with potential drug-drug interactions in Ethiopian hospitals was found to be 72.2% . Based on severity, the prevalence of major, moderate, and minor potential drug-drug interaction was 25.1, 52.8, 16.9%, respectively, also 1.27% for contraindications. The factors associated with potential drug-drug interactions were related to patient characteristics such as polypharmacy, age, comorbid disease, and hospital stay.There is a high prevalence of potential drug-drug interactions in Ethiopian hospitals. Polypharmacy, age, comorbid disease, and hospital stay were the risk factors associated with potential drug-drug interactions. Drug-drug interactions (DDIs) are types of adverse drug events (ADEs) that can occur when the effect of a drug is altered by another drug that is taken. Commonly it ends up with a qualitative and/or quantitative change in drug action . They maIt can be categorized based on the severity and mechanisms by which drugs interact with each other , 4. BaseThere are different factors for the occurrence of potential DDIs. The age of the patient, common disease state and polypharmacy; pharmacokinetic and pharmacodynamic nature of drugs; the influence of disease on drug metabolism; prescriber issues such as multiple drug prescription by multiple prescribers, inadequate knowledge of prescribers’ on DDIs or poor recognition of the relevance of DDIs by prescribers are among the risk factors significantly associated with the occurrence of potential DDIs –10.DDIs are common in cardiovascular, Human Immunodeficiency Virus-infected, psychiatric patients, and renal and hepatic insufficiency  patients. Because this type of patient requires multiple types of drugs, their kidney and liver may decrease the excretion and metabolize the ability of medications. Therefore, the occurrence of DDIs in this type of patient may be significant , 11, 12.DDIs are also more frequent in hospitalized patients, patients who stay in the hospital for a longer time, and/or receive more drugs per day –16. HospPhysicians and pharmacists alert fatigue is a common reason for the occurrence of drug-drug interactions for patients receiving interacting drugs. Even though computerized DDI alert systems could decrease the occurrence of DDIs, numerous alerts produced by such system lead physician and pharmacist alert fatigue. This alert fatigue results in a considerable override of DDI alerts. A study done in Japan showed physicians overrode DDI alerts at a high rate in computerized drug interaction alert system .DDIs may have undesirable or harmful effects in addition to their desirable effects . ClinicaDDI is being an evolving public health problem currently . In EthiAs a result, potential DDIs causing serious risk to patient health. Therefore, this study attempted to review and quantitatively estimate the prevalence of potential DDIs and associated risk factors in hospitals, both among inpatients and outpatients in Ethiopia.https://www.crd.york.ac.uk/prospero/display_recored.php?ID=CDR42020149416.The review protocol was created based on Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). The checklist was strictly followed while reporting this systematic review and meta-analysis √ All male and female patients in any age  and admitted to hospital wards or visited outpatients√ All published articles without time limit√ Patients who had any disease and admitted to hospital wards or visited outpatients√ Studies which were published by English language and provided sufficient data for the review√ Articles with missing or insufficient outcomes√ Studies that were conducted in primary health care settings√ Articles not published in peer reviewed journal.We had searched literatures from a legitimate database such as HINARI, Science direct, PubMed/MEDLINE, Google Scholar, and Research Gate for English-language publications. The literature search was performed to retrieve relevant findings closely related to the prevalence of potential DDIs and associated factors with DDIs among outpatients and inpatients in Ethiopian hospitals.The search was conducted with the aid of carefully selected search-words without specification in time. “Prevalence”, “occurrence”, “potential DDIs”, “associated factors” and “Ethiopia” were the search words used in this review and meta-analysis. AND/OR words were used for the identification of the articles. The search was conducted from August 3–25, 2019 and all published articles available online until the day of data collection were considered.A standardized data extraction form was prepared in Microsoft Excel by the investigators. Important information which was related to study characteristics such as: Region, Study area, Author, Year of publication, study design, Pathology, Target population, Study setting, Interaction database, Number of patients, Number of patients with DDIs, and lists of medications that caused the interactions were extracted. Moreover, the outcome of interest , Potential DDIs  and associated factors of DDIs) were also extracted.Fourteen studies were selected based on their abstract, inclusion, and exclusion criteria. Studies were searched, identified, and screened from different search engines that are published in the English language.The quality of the selected studies was performed. All selected studies were reviewed according to twelve criteria adapted from a previous study . these cThe outcome measure in this review and meta-analysis is the prevalence of potential DDIs. It primarily aimed to assess the pooled estimates of potential DDIs in the hospitals of Ethiopia. This study has also two secondary outcome measures: Associated risk factors for potential DDIs and number of potential DDIs  in Ethiopian hospitals.P value of less than 0.05 (one-tailed) was considered significant 97.5% of adult patients with heart diseases treated in inpatient ward  were susIn this review and meta-analysis, age, polypharmacy, comorbid disease, and hospital stay were significantly associated with the occurrence of potential DDIs in the hospitals. Similarly, the finding from a review in a developed country highlighted these risk factors. Many studies had emphasized that the high occurrence of potential DDIs in old age is due to physiological changes related to age, comorbid diseases, and a high rate of medication use . In addiDifferent studies were also supported as polypharmacy and comorbid disease increases the likelihood of the occurrence of potential DDIs , 42, 43.Comorbid disease increases the occurrence of potential DDIs. Because the reason might be, the drugs prescribed for the comorbid disease are often used in combination that leads to the possibility of the occurrence of potential DDIs. Furthermore, increased hospital stay leads to the occurrence of potential DDIs. Since, hospitalized patients are more likely exposed to multiple illnesses, comorbid conditions, chronic therapeutic regimens, poly-pharmacy, and frequent modification during their stay of therapy .The first limitation of this review and meta-analysis was the drug-drug interactions found were the only potential and doesn’t address the actual DDIs due to a lack of studies. Some of the studies included in the review and meta-analysis had small sample sizes. These might have led to bias. The other limitation of this review was Egger’s test funnel plots revealed as there is no publication bias but this estimation may not be accurate as small studies are included for the review and there are studies that had small size. The fourth limitation of this study was clinical heterogeneity among included studies, so it should be considered with caution. The classification of severity may be defined differently between studies, so this may be another limitation of this study.The prevalence of patients with potential DDIs in Ethiopian Hospitals was found to be high i.e. 72.2% . As of these, the most prevalent DDIs were moderate severity, 52.8%. In this review polypharmacy, age, comorbid disease, and hospital stay were the risk factors associated with potential DDIs. This review and meta-analysis had considerable clinical heterogeneity among included studies, so it should be considered with caution.Additional file 1: Table 1.Additional file 2: Table 2. Excluded studies after review of full text articles with justification.Additional file 3: Table 3. Quality of included studies.


We analyzed quality of life, cognitive function, depressive symptoms, and motor symptoms. Significant improvements were found in the overall, physical, psychological, social participation, and intimacy domains of quality of life, as well as in cognitive function and depressive symptoms for both groups. Only the NW group showed improvement in the autonomy domain. Individuals with PD had a similar enhancement of non-motor symptoms after walking training, with or without poles. However, the NW group showed a more significant improvement in the autonomy domain, strengthening the applied and clinical potential of NW in people with PD. Future studies are needed to determine the efficacy of walking training without poles in subjects with PD.Nordic walking’s (NW) degree of effectiveness regarding health-related parameters in people with Parkinson’s Disease (PD) is a subject of debate. While NW seems to improve functionality, a clear non-motor benefit has not been demonstrated. The aim of this randomized controlled trial was to compare the effects of 9-week NW and free walking (FW) training programs on quality of life, cognitive function, and depressive symptoms in individuals with PD. Thirty-three people with PD, (Hoehn and Yahr 1–4) were randomized into two groups: NW ( Changes in the central nervous system resulting from Parkinson’s disease (PD) lead to the manifestation of non-motor symptoms, such as cognitive deficits and increased depressive symptoms ,2. The sIn addition to drug therapy, exercise has been considered as a therapeutic tool for treating depression and improving QoL in people with PD ,6. In PDFree walking is the standard physical activity recommended for this population. However, Nordic walking  has been indicated, mostly because of its greater motor complexity requiring the activation of other cortical regions such as the premotor cortex ,11. It iFrom a mechanistic standpoint, enhanced cognitive function implies mitigating not just movement disorders but also non-motor symptoms including autonomic dysfunction, sleep disorders, and pain ,5,14. AlThese training programs might induce adaptations that might influence health-related QoL, because non-motor symptoms have, collectively, a greater impact on QoL than motor symptoms . We hypoClinicalTrials.gov . The study was performed in accordance with the 1964 Helsinki declaration and its later amendments. All participants read and signed an informed consent form before starting their participation in the study. All participants were recruited from the Neurology ambulatory of HCPA, in Porto Alegre, Rio Grande do Sul, Brazil. After the initial contact by telephone, patients were invited to participate in the study according to eligibility criteria. Assessments and training sessions were performed at the Escola de Educação Física, Fisioterapia e Dança (ESEFID) da Universidade Federal do Rio Grande do Sul (UFRGS) , conducted according to the Consolidated Standards of Reporting Trials (CONSORT) recommendations. No changes in methods after trial commencement were made. The study was approved by the ethics committee of Hospital de Clínicas de Porto Alegre (HCPA)  (ref no. 24595713.4.0000.5327) and was registered at n = 34). Patients who agreed to participate in the protocol were assigned a number and randomly allocated into one of the two groups using an online method to randomize using software (www.randomization.com). Allocation was concealed using sequentially numbered and sealed opaque envelopes that were opened only when each participant was admitted to the study. An independent assessor controlled the implementation and the sequence of randomization, with allocation index of 1:1.We aimed to perform a clinical trial testing the superiority of a relatively new endurance modality  against a well-known endurance activity  that has already shown positive results in the literature. We chose to compare the superiority effects of two interventions, i.e., Nordic walking and free walking, for ethical reasons. Physical exercise is extremely important in maintaining quality of life and improving symptoms in people with PD. The sample size calculation showed that 30 patients would be sufficient (15 in each group) for a power of 90% at an α = 0.05 and a correlation coefficient of 0.9 for the variables, based on standard deviations and the differences between the means of a study with QoL outcomes . ConsideEligibility criteria were: (1) having a clinical diagnosis of idiopathic PD, according to Parkinson’s Disease Society Brain Bank criteria, by a neurologist; (2) PD severity ranging from 1 to 4 on the Hoehn and Yahr Scale (H&Y); (3) currently using of pharmacological treatment for PD; (4) aged 50 years or more; (5) being sedentary or not engaging in any type of physical activity for at least six months ; (6) notFollowing baseline testing, participants were randomly allocated into two training groups: Nordic walking and free walking. Interventions were conducted for both groups with two sessions per week, 35 min per session, progressing to up to 60 min total in the last training cycle, totaling nine weeks, always during the ON period of the dopaminergic medication cycle. Interventions were supervised by physical education professionals and physiotherapists, who provided immediate physical assistance when necessary during the training session.The primary outcome of the present study was QoL. QoL has been extensively utilized for purposes of assessing the level of satisfaction with activities and subjective feelings about life conditions and has demonstrated good levels of reproducibility and validity . SecondaQuality of life outcomes and non-motor parameters (cognitive function and depressive symptoms) were compared between Nordic walking and free walking, in terms of time (pre- and post-intervention), and group × time interaction. QoL was assessed with the following instruments: the World Health Organization Instrument for Quality of Life Assessment questionnaire  . Non-motMotor symptoms and severity of PD were evaluated using the Unified Parkinson’s disease rating Scale-III (UPDRS-III) and H&Y, respectively ,20. Anth®–Decathlon, Nordic Walker, China), and learning of NW technique was based on the Four Support System of Nordic Walking: Brazil Locomotion Method  joint mobilization + warm-up with a three-minute free walk at a self-selected walking speed (SSWS); (2) main part—specific training of the group; (3) cool-down. The Nordic walking group used poles recommended for the correct practice , and body relaxation techniques. The training protocol consisted of three parts: (1) joint mobilization and warm-up with a three-minute free walk at a SSWS (eight min); (2) main part–specific training (35 to 50 min): continuous or interval walking on different terrains , with two to five minutes of rest in predetermined times. The training protocol was standardized among all subjects. The difference between the workout sessions in this part of the session was the use or not of poles during walking; (3) cool-down with stretching, and core and breathing exercises (five minutes).Training was individually prescribed according to the maximum distance performed in 6-min walking test for determining the volume of training. Heart rate was used for determining the intensity of training based on the mathematical model of Tanaka . We usedTo facilitate the learning process of the Nordic walking movement technique, we used the rhythmic verbal command, “1,2,3,4”. Patients were instructed to count at this rate and to imagine the time by step frequency. To be fair, it was proposed to the participants in the free walking group that they could experience NW after the nine-week free walking intervention. Two videos showing training examples are given in p < 0.001 and by sex with p > 0.05. Data were analyzed using the statistical software Statistical Package for Social Science .Data are presented as mean and standard deviations or 95% confidence interval (CI 95%) for continuous measures. Baseline characteristics were compared by using one-way analysis of variance (ANOVA). Intent-to-treat analyses were carried out for all outcomes using the Generalized Estimation Equation (GEE), to compare the outcomes between the groups  and time (Pre and Post). The Bonferroni post-hoc was used to identify differences between the means for all variables. Variables with significant interactions were included in the model as covariates. We recognize that many possible factors could affect QoL, such as sex  and cognitive function , and these factors were controlled as covariates in all GEE models. QoL domains were corrected by MoCA with The flowchart detailing the steps of participant selection is shown in Adherence was defined as the percentage of intervention sessions fully accomplished without protocol deviations given the total number of scheduled sessions. The program adherence was high . All patients who completed the intervention had 100% class attendance, demonstrating adherence to training.p < 0.001, for all. Only the autonomy, past activities/present/future and death and dying domains had statistically significant difference in the interaction between group × time (p = 0.05). The Bonferroni post hoc was applied, for which the means of each group were observed at each time point to identify where the difference occurred.The detailed results for QoL WHOQOL OLD and WHOQOL BREF can be seen in p < 0.001). The same pattern occurred for the intimacy domain, adjusted by gender (p = 0.013). The Nordic walking group significantly increased values of intimacy after the training program (p = 0.001), while the free walking group reduced these values.The Bonferroni post-hoc test for interaction time*group shows that Nordic walking was more efficient than free walking, in the field of autonomy. After the training protocol, the participants in the Nordic walking group improved and increased values of autonomy (p = 0.025). Interestingly, regarding the Death and dying domain, the groups exhibited different behaviors: the free walking group showed an increase , while the Nordic walking group showed a decrease after nine weeks .Regarding the Past activities/present/future domain, the Bonferroni post-hoc test for interaction time*group showed that Nordic walking and free walking groups were significantly different, with higher values for the Nordic walking group (p = 0.007), and higher values were found in the Nordic walking group compared with the free walking group.In addition, social participation revealed a statistically significant difference in relation to the group*time interaction (p < 0.05). Regarding the Environmental and Social relationship domains, higher values were found in the Nordic walking group. However, these parameters remained unchanged post-intervention in the Nordic and free walking groups, and no significant time*group interactions were found.The detailed results for QoL by WHOQOL BREF can be seen in p = 0.046) and depressive symptoms (p < 0.001) post-intervention for both groups. The Nordic walking group showed higher values for cognitive function assessed by the MoCA and lower scores for depressive symptoms assessed by the GDS-15 compared with the free walking group. However, no statistically significant time*group interactions were found for these outcomes. Detailed results of cognitive assessments and depressive symptoms can be seen in In relation to non-motor symptoms, a significant time effect was found for cognitive function (p < 0.001), although not statistically significant between the groups (p = 0.128). The Nordic walking group showed a decrease in motor symptoms 15.10 ± 3.2 to 11.64 ± 2.1, and the free walking group decreased from 23.19 ± 3.9 to 17.43 ± 3.8 in the UPDRS, without group*time interaction.Regarding motor symptoms of PD , there wThe aim of this study was to examine the effects of nine-week Nordic walking and free walking training programs on QoL, non-motor symptoms , and motor symptoms in people with PD. The present study showed that Nordic walking seems to be more efficient than free walking in the autonomy, social participation, and intimacy domains of QoL. In addition, in the Past activities/present/future domain, the Nordic walking group had higher values compared with the free walking group post the nine-week intervention. In relation to the Death and dying domain, the free walking group showed increasing scores, while the Nordic walking scores decreased after nine weeks of training. The QoL general, physical, and psychological domains of the WHOQOL-BREF, and non-motor symptoms improved after both interventions.Our hypothesis was that Nordic walking can be more effective than free walking in improving the QoL and non-motor symptoms in PD because of the stimulation of mechanoreceptors provoked by excitatory stimuli from using poles, leading to an increased improvement in these outcomes. Thus, the hypothesis of the study was partially accepted.Many possible factors can affect QoL, cognitive function, and depressive symptoms in individuals with PD . SignifiOur findings corroborate those of previous studies showing the beneficial effects of endurance training for different purposes in people with PD ,11,21. QThe improvement in QoL (including autonomy), cognitive symptoms, and depressive symptoms in endurance/walking studies is recognized in individuals with PD, but the question in this study was whether walking with walking sticks could offer greater advantages in these outcomes compared with free walking in this population. Although the improvement in autonomy after a walking program seems obvious, the comparison of the use or not of poles during walking, until now, has not been tested in people with mild to severe Parkinson’s disease. Our results have demonstrated that Nordic walking seems to promote more significant benefits in the autonomy domain compared with free walking. This finding could be potentially explained by the adjustments necessary for the control of gait related to the central pattern generator. According to this model, other cortical adjustments are needed due to the greater complexity of the technical task related to Nordic walking, in order to sustain and support poles on the ground ,25,26,27The importance of exercise programs with progressively increasing intensity was also evidenced by the present findings, for both walking protocols. Furthermore, our findings are in line with previous results in other disorders such as fibromyalgia. Exercise at high intensity  in people with PD seems to promote an endogenous increase of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), insulin-like growth factor-3 (IGF3) and neurotransmitters such as dopamine and serotonin. These markers are some of the potential mechanisms for improvement of the autonomy domain in PD. To the best of our knowledge, the present study is the first to provide information related to the effects of Nordic walking in comparison to free walking on depressive symptoms and QoL in patients with PD. However, the present study has limitations. First, the sample size was relatively small, and we were unable to stratify randomization by gender, age, time, and stage of PD. Although there were no statistically significant differences between the Nordic walking and free walking groups for these variables, they may have affected the results of cognitive function and QoL as the patients had different values between the groups at baseline. These differences, however, were mitigated by adjusting the GEE models for age and sex. Second, there was no control group, so, we cannot calculate the effects on exercise associated with environmental factors related to social attention and care, in terms of social participation, e.g., Hawthorne Effect. On the other hand, using the present design, we managed to explore the differences between a widely used training method (FW) and a new method (NW). We aimed to perform a clinical trial testing the superiority of a relatively new endurance modality (NW) against a well-known endurance activity (FW) that has already shown positive results in the literature ,29,30. TThe strengths of this clinical trial are the originality of the topic addressed and the promising results obtained with the two interventions, i.e., walking with and without poles, for subjects with PD with scores between 1–4 on the H&Y scale (subjects with mild to severe PD), especially regarding QoL and non-motor symptoms. Because the progression of PD symptoms leads to reduced autonomy and greater functional dependence, applying these findings in a clinical setting would be of considerable benefit to this population.In conclusion, the present study reveals that nine weeks of Nordic walking training was able to improve QoL in people with PD. Our findings have demonstrated that Nordic walking promoted more significant benefits in the autonomy, intimacy, and social participation domains of QoL than free walking. Results indicated that nine-week periodized programs with moderate intensity of Nordic and free walking was sufficient to produce, similarly, improvements in non-motor symptoms in people with mild to moderate PD. In addition, Nordic walking and free walking reduced depressive symptoms in people with PD. Cognitive function was enhanced similarly in the Nordic walking and free walking groups. These results strengthen the applied and clinical potential of Nordic walking in patients with PD.


Borrelia afzelii.Lyme disease is the most common tick-borne illness in the USA, Canada, and Europe. Clinical manifestations vary greatly, with localized skin findings functioning as early signs of the disease, followed by disseminated disease. The rarest dermatologic presentation of Lyme is a borrelial lymphocytoma, occurring distinctly in Europe and caused typically by Borrelia burgdorferi demonstrated mixed positivity. He was treated with a 21-day course of amoxicillin, with complete resolution of symptoms and no sign of secondary Lyme disease.We report a case of a Caucasian 5-year-old European-American boy with slowly progressing, painless edema and erythema of his right pinna. Travel history revealed significant exposure to ticks during a recent trip to Eastern Europe. Laboratory testing for Borrelial lymphocytoma is a rare manifestation of Lyme disease in North America, although not uncommon in Europe. Diagnosis is made by the presence of a painless erythematous swelling typically found on the ear lobe, nipples, or testes. Laboratory tests are available but with low sensitivity, therefore, a high index of suspicion is necessary for a clinical diagnosis to be made. Treatment for isolated borrelial lymphocytoma is doxycycline 4 mg/kg up to 100 mg twice daily, whereas for children less than 8 years of age amoxicillin 50 mg/kg divided three times daily, for 3–4 weeks, is preferred. Ixodes species. Typical species include Ixodes scapularis (black-legged tick or deer tick) on the East coast of North America and Ixodes pacificus (western black-legged tick) on the West coast in North America, whereas Ixodes ricinus (sheep tick) is most common in Europe. Infections are caused by species of the bacterial spirochete family, Borreliaceae. In North America, the most predominant culprit of disease is Borrelia burgdorferi; in Europe, the most predominant culprits of disease are Borrelia afzelii and Borrelia garinii [Lyme disease is endemic in North America, and is the most common cause of tick-borne illness in the USA, Canada, and Europe . Zoonoti garinii .Clinical manifestations of disease typically involve the skin and cardiovascular, musculoskeletal, and nervous systems. Hematogenous dissemination of bacteria occurs within days to weeks following a tick bite; host-driven immune responses often lead to specific symptoms . BorreliA 5-year-old Caucasian European-American boy was referred to Hematology due to concern for a possible autoimmune disorder because of slowly progressing, painless edema and erythema of his right pinna. He was seen recently by Otolaryngology and a primary ear disease was ruled out. Since he had history of immune thrombocytopenia (ITP) at 3 years of age, a concern for an underlying autoimmune disorder was raised. He was in his normal state of health until 4 months prior (in September), when he was noted to have patchy red swelling of his right external ear with no associated pruritus or pain. Initially the erythema waxed and waned; it only lasted hours at a time. However, for the preceding 2 months it had become unremitting. Associated signs included an evanescent circular red rash on his left cheek, also for the last 4 months. He did not experience any constitutional or musculoskeletal symptoms.On examination, his vital signs were normal for age: temperature 36.9 °C, pulse 124 beats per minute, blood pressure 106/65, weight 11.9 kg, and height 85.2 cm. He appeared well with the examination most notable for an erythematous, edematous right auricle . We also considered autoimmune and/or rheumatologic conditions. However, a complete blood count with differential , lymphocyte subpopulations , serum immunoglobulins , and complement C3 109 mg/dL and C4 17.1 mg/dL levels were normal, and anti-nuclear antibodies (ANAs) and an anti-extractable nuclear antigen (ENA) panel  were negative.Of interest, his travel history revealed that he had spent 2 months in the Czech Republic over the summer, in a heavily wooded area, and was bit by a significant number of ticks before he returned to the USA just a few weeks prior to the initiation of symptoms.B. burgdorferi was positive, although Western blotting for IgM antibodies had 0 of 10 bands and for IgG antibodies 3 of 10 bands, with 5 bands indicating a positive result.Collectively, the presence of the auricular lesion, cervical lymphadenopathy, an associated lesion suspicious for erythema migrans (EM), and history of tick exposure led to the possibility of BL. An enzyme-linked immunosorbent assay (ELISA) test for antibodies against Due to sufficient clinical suspicion, he was placed on amoxicillin 50 mg/kg per day for a 21-day course. Within days of starting the antibiotic, both erythema and edema of the affected area were improved and eventually resolved. The Infectious Disease service was consulted, and on 3-month follow-up his symptoms resolved, and he showed no signs of secondary Lyme disease. A skin biopsy with polymerase chain reaction (PCR) was considered; however, due to clinical improvement this was deemed unnecessary given low yield to identify the organism after successful antibiotic treatment. Nine months following initial diagnosis he remained asymptomatic without return of auricular swelling or new skin, muscle, joint, or neurological findings.We report here the case of a 5-year-old pediatric patient with slowly progressing, painless edema and erythema of the right pinna diagnosed with BL. He had subsequent resolution of auricular inflammation with antibiotic treatment for Lyme disease without sequelae of secondary Lyme disease.Ixodes ricinus tick is endemic. To the best of the authors’ knowledge there are no recent case reports in North America, indicating the paucity of patients with this clinical manifestation and lack of clinical recognition. The present case report highlights that the recognition of a rather common infection, such as Lyme disease, may be obscured when the underlying species is not endemic to the area.BL is a rare manifestation of Lyme disease in North America , but notB. burgdorferi is the typical causative species for Lyme disease in North America, B. afzelii is the most predominant species associated with BL in Europe, probably explaining the negative Western blot for IgM and IgG against B. burgdorferi. There is currently no available laboratory test for B. afzelii in the USA and testing of cases with BL in Europe report sensitivity as low as 40% [Although w as 40% . In genew as 40% , 7. In tw as 40% –10.BL is a subtype of a heterogenous group of benign lymphoproliferative conditions called cutaneous pseudolymphomas. This set of conditions refers to a predominantly lymphocyte-derived inflammatory infiltrate, which may encompass additional inflammatory cells. BL is caused by B cell lymphocytic infiltration of the dermis and subcutis, producing discoloration and edema of the affected site, often at the location of the tick bite. It characteristically presents as a 1–5 cm purple or red-colored plaque or nodule, most commonly at the ear lobe, nipples, or testes as the organism prefers tissues with somewhat cooler temperature , 12. ConTypically, symptoms appear within days to 6 months following a tick bite, and most frequently within the months of August or September . The preBL is a rare dermatological manifestation of Lyme disease. It is rarely, if ever, seen in North America due to its association with borrelial species more commonly found in Europe. Diagnosis is made by the presence of a painless erythematous swelling typically found on the ear lobe, nipples, or testes. Laboratory testing is available, however, it is limited by low sensitivity. Prompt diagnosis and treatment initiation is essential to avoid ramifications of late disseminated Lyme disease. This case highlights the importance of recognition of rare manifestations of a common disease, in particular, in those with significant travel history.