The objective of this study was to examine the association of 14 variables with TB in respiratory patients. The variables included: urban/rural, persons in 1200 sqft area, TB in family, crowding, smoking (family member), gender, age, education, smoking, workplace, kitchen location, cooking fuel, ventilation, and kerosene uses. Eight hundred respiratory patients were tested for sputum positive pulmonary TB; 500 had TB and 300 did not. An analysis of the unadjusted odds ratio (UOR) and adjusted OR (AOR) was undertaken using logistic regression to link the probability of TB incidences with the variables. There was an inconsistency in the significance of variables using UOR and AOR. A subset model of 4 variables  based on significant AOR was adjudged acceptable for estimating the probability of TB incidences. Uses of kerosene ) consistently related to incidences of TB. It was estimated that 50% reduction in kerosene uses could reduce the probability of TB by 13.29% in respiratory patients. The major recommendation was to replace kerosene uses from households with a supply of clean fuel like liquid petroleum or natural gas and rural electrification. Mycobacterium tuberculosis (MTB) bacteria , is one of the important contagious diseases and regarded as one of the major causes of global mortality and morbidity1. In the year 2018, a total of 1.5 million peoples worldwide died from TB and it is in the top 10 death-causing diseases2. The prevalence of TB is related to several variable, including low socio-economic status, immune-compromised conditions, smoking habits, the spread of multi-drug resistant TB (MDR-TB) and environmental factors9. The current research focuses on environmental and other variables to help develop policies and actions for effective control of TB.Tuberculosis (TB), caused by 14. Worldwide, South Asia accounts for 44% of TB cases, followed by Africa (24%) and Western Pacific (18%)2.The environmental variables such as uses of solid fuels coupled with poor indoor air quality are the common cause of compromised immunity and a large number of incidences of TB21 have shown that exposure to fine particulate matter  from burning biomass, smoking, kerosene fuel, vehicular pollution, etc. trigger the risk of TB infection and full-blown disease. The use of kerosene, especially in the lamps for lighting purposes, have been identified to have a significant association with TB25. Combustion fumes also impair alveolar macrophages function, which trigger the MTB infection and damages the defence mechanism against the bacteria28.Several studies29. In India, until recently, approximately 800 million individuals 30 living in 160 million households depend on solid fuel as a primary fuel for cooking. Further, a survey from 13 states31 has reported that the major preferred fuel for 69% of the household was kerosene. More than 65% of rural households in the states of Uttar Pradesh and Bihar are dependent on kerosene lamps as their primary source of lighting32. The household air pollution is increasing due to uses of solid fuels and kerosene, making a large population vulnerable to TB infection34.About 41% of the global population depends on solid fuels, comprising animal dung, wood, crop residues, and coal for cookingUjjwala scheme: https://www.india.gov.in/spotlight/pradhan-mantri-ujjwala-yojana#tab=tab-1) to rural areas and Saubghagya scheme (https://saubhagya.gov.in/) to provide 22 million electricity connections to below poverty line households. Once data on the effectiveness of the schemes become available, the future studies could establish the improvements in air quality and reduction in TB incidences.There have been recent government schemes for liquid petroleum gas connections . The UOR depicts the odds that an outcome occurs for a particular variable, compared to the odds of the outcome occurring in the absence of that variable44. Generally, in real life, a clear relationship between a single variable and an outcome does not exist. In the case of incidences of TB, many other variables might have a role. One can adjust the UOR by controlling other variables, resulting in an adjusted odds ratio (AOR) for each variable45. It is important that for TB incidences, many variables coexist and the focus should be on AOR rather than UOR applied in many studies48. It is important to understand the degree of association of each coexisting variables and translate the understanding to generate a net probability of getting TB. Such analyses can also earmark the variables that should be addressed to prevent TB from progressing.Most of the studies noted above49. For example, cigarette smoking impairs antimycobacterial immune responses in mice50.The most variables in this research relate to air pollution exposure and respiratory infection. Respiratory infection increases the risk of TB development51 in India. Therefore, the subjects for this study were drawn from Kanpur city and nearby areas, in the state of Uttar Pradesh (UP), who visited CCC. It is clarified that all subjects had pre-existing respiratory ailments and analysis and results in the research refer to such subjects. The subjects participated in the questionnaire-based survey , Kanpur. This research's objective was to study the association of 14 independent variables  was undertaken using a logistic model to show the association when variables coexist. This study has employed a data set of 800 respiratory patients. Finally, the study has applied the logistic model to identify the independent variables that significantly influence the incidences of TB in respiratory patients.A strategy to regulate the significant variables can reduce the potential spread of TB. Most of the subjects (more than 75%) were from Kanpur and nearby districts .http://www.iitk.ac.in/dord/institutional-ethics-committee-iec).The first step was to obtain the approval for the questionnaire and protocol for conducting the survey from the ‘Institutional Ethics Committee (IEC) for Research Involving Human Subjects’ at the Indian Institute of Technology Kanpur (IITK). The subjects were informed about the purpose of the study, maintaining the confidentiality of data/identity, expected benefits of participation, and duration of study to ensure that participation in the study was entirely voluntary. The questionnaire was developed both in English and Hindi languages. Before conducting the survey, duly handwritten and self-attested consent was taken from all the subjects. There is no data/information in this article which reveals identity of subjects. The authors confirm that all experiments were performed in accordance with relevant guidelines and regulations of IEC (All subjects were examined for sputum positive pulmonary tuberculosis by the two authors (Dr. Subodh Katiyar and Dr. Sandeep Katiyar), Chest and TB physicians. Then we had two streams of subjects, one who had the TB (referred to as Cases) and those who did not have the TB (referred to as Controls). The subjects from the two streams were surveyed face to face from November 2016 to March 2017. Of 800 total subjects, 500 (Cases) had TB and 300 (Control) did not have TB.38. In the family category, there were five independent variables, namely, residence location , family members in 1200 sq. ft. of area (FMW) (https://www.commonfloor.com/dda-mig-flats-delhi/povp-50k1kg), TB in the family (TBF), crowding per room (CPR), and smoking by a family member (SFM). In the personal category, there were four independent variables, gender (GEN), age (AGE), education (EDU) and smoking (SMO).A questionnaire ).We defined the independent variable workplace (WPL) in the occupation category depending on where a person spent at least 8 h in a day. The question on WPL had multiple responses; schools, office, home, farms, construction and factory . The multiple responses were clubbed into two groups: clean environment workplace 18. Both kitchen ventilation and household combustions associate with TB, especially in women53. In this context, data were compiled under the category kitchen, which had three independent variables, namely, (i) kitchen location (KLO) (partitioned inside the house (PIH) or non-partitioned inside the house (NPIH)), (ii) cooking fuel uses (CFU) (LPG or solid fuels) and (iii) ventilation in the kitchen (VEN) (at least one window of size 2ft by 2ft or no window). The last independent variable was kerosene in cooking and/or lighting (KCL) , which measures if the odd ratio is statistically significant to show that exposure has indeed caused the outcome .The significance of UOR was examined based on z-test at the confidence interval (CI) of 95% i.e. significance level (P) of 0.05 45 to consider all independent variables as coexisting for their association with TB.UORs reported in many studies55 and independent variables can take on continuous and/categorical realizations56. The dependent variable Y has two possible values y = 1 (person having TB) and y = 0 (person not having TB). The transformed varaiable TB (x) is the natural log of the odds ratio of yi = 1 versus yi = 0 that is the log of odds of TB occuring relative to not occuring in the respiratory patients. There were 14 independent variables  . The logistic regression uses the maximum likelihood technique to estimate the coefficients of independent variables. The rest of the analysis, significance and model acceptance tests are similar to the general linear regression.The logistic model was used to understand the relationship between the dependent variable and one or more independent variables by estimating probabilities using logistic regression to predict the likelihood of occurrence of an event  consider all 14 independent variables, (ii) develop a smaller model using step-wise regression (enter and remove the variable at 0.15 level of significance), and (iii) examine the model from (ii) to rebuild the model only for significant variables. The suitability of the model and significance of the variables were examined from changes in the natural log-likelihood (log (L)) levels. For the logistic regression, we have used SYSTAT (version 11) software.The above modelling exercise will identify significant variables that will determine the probability of getting TB. Specifically, regulation or elimination of significant variables has been evaluated in the districts (most subjects came to CCC) in terms of reducing TB cases.The subjects in this study consist of 500 TB cases  and females 230 (46%)) and 300 controlled cases  and females 107 (36%)). Among all TB patients, the TB stage was: 58% primary, 26% secondary and 16% tertiary.Supplementary Table An analysis of UORs with 95% confidence interval (CI) for independent variables and inferences of previous studies are given in Table The variation in RUR and SFM did not show any statistically significant difference in UORs. The significant variables those showed association with TB include: TBF (UOR 1.73 (1.27–2.35), FMW (UOR 1.55 (1.14–2.09)) and CPR (UOR 1.34 (1.00–1.78)). TBF appears to be an important variable as TB is a contagious disease and spreads through the air medium. The literature suggests that all eight studies show the TBF as a significant variable : RUR , FMW , TBF , CPR  and SFM  ), EDU , SMO  and AGE ) were significant : GEN , AGE , EDU  and SMO  , 1.66  and 1.62  respectively. It may be noted that all these variables relate to indoor air pollution, most significant being ventilation, impacting the women (housewives) who have shown a greater likelihood of getting TB. It is seen from the previous studies ; this association is well–established in the literature.95, 3.54p-value and AOR (with 95% CI) is given in Supplementary Table As a first step, we have considered all 14 independent variables (Table The maximum log (L) was − 486.54 Fig.  for the It may be noted that the independent variables  showed significant UOR Table . HoweverAs the second step, we performed step-wise logistic regression to make the model smaller by dropping insignificant variables (as determined by stepwise regression). At the same time, we did not compromise the model predictively (i.e. Reduction in log (L)). The following model (Eq. ) was obtIt is to be noted that for the smaller model (Eq. ), the lop-value = 0.026), we should drop it. This unusual situation may have occurred as the subjects may not have told the truth because of the stigma it carries about smoking or at the time of the survey they might have left smoking.In the next level of analysis, we see that SMO has a negative coefficient (Eq. ). It impIn light of the above, we have further dropped two variables, SMO, and TBF which had negative coefficients. However, in the process, the log (L) marginally decreased to − 494.83 (a decrease of 1.16%) Fig. ) that isIn the above model, all the independent variables are significant and positively relate to the incidences of TB. To further examine if any of the significant independent variables can be further dropped and how would the log (L) will decrease, the variable KCL was dropped on purpose.It is to be noted that by dropping KCL, the log (L) sharply decreased to − 510.98 (3.16%) Fig. .yi = 1) was estimated. For a better comparison, the estimated probabilities are plotted in descending order for both the models  from kerosene burning64 Out of 901 Gg/year BC emission in India, about 110 Gg/year is from kerosene burning65.If kerosene uses can be controlled it is likely to have a significant impact on reducing incidences of TB. It also makes sense from the point of administrative control and management as kerosene supply is well-structured and households using kerosene are well-documented. In India, kerosene is widely used for cooking (4.57 million tons/year) and in lamps for lighting (1.45 million tons/year)67. According to the WHO68, exposure to BC can lead to cardiopulmonary morbidity and mortality. WHO also suggests that BC may act as a universal carrier of chemicals of varying toxicity to the lungs68. Fullerton et al. have shown a larger loading of particulates in alveolar macrophages in the persons using kerosene lamps than those using candles or electric lamps69. Other emissions from kerosene combustion include carbon monoxide, nitrogen dioxide, carbon dioxide, sulfur dioxide, formaldehyde, and various VOCs (volatile organic carbons)64. Out of all sources , the emission factor for BC from kerosene lamps is nearly two orders of magnitude higher at 84 gm/kg of kerosene65. Literature70 also suggests that kerosene has other air pollution issues and requires replacement, especially in developing countries.Several studies suggest that emissions from kerosene lamps are the precursor for TB infection and diseaseIt was decided to examine the strategy for replacing 50% kerosene from the districts of Kannoj, Kanpur, Kanpur Dehat, Lucknow and Unnao in the State of Uttar Pradesh Fig. , which hAs a strategy to prevent the incidences of TB, we have developed a scenario that 50% of kerosene uses is reduced for cooking and lighting purposes. As a first step, we randomized data set off 800 subjects to avoid any biases of selecting the 50% cases of kerosene uses, which would be replaced with other clean fuel. Using the subset model (i.e. Eq.  ), the meUjjwala scheme of LPG supply and Saubghagya scheme of rural electrification must be strengthened and expanded.The study has estimated the reduction in probability of TB incidences in respiratory patients if 50% kerosene uses is stopped. Arguably the findings can convince the policy makers to accelerate replacing kerosene from households with the clean fuel like liquid petroleum gas (LPG) or petroleum natural gas (PNG) and rural electrification. In the Indian context, the While this study evidenced the potential prevention of TB incidences, the other benefits include better indoor and outdoor air quality and increased immunity for other diseases and reduction in mortality. Findings of this study could possibly apply to other south Asian countries which are similar in culture, urban-poor divide, economic conditions and high prevalence of TB. The policymakers can take science-based decisions for major interventions for control of TB. Therefore, we focused the study on helping policymakers understand the causal linkage responsible for TB and encourage them for long-term planning and investment.The current research has looked at the association between TB incidences and 14 independent variables by analyzing the unadjusted odds ratio (UOR) and adjusted odds ratio (AOR) in 800 respiratory patients. The variables include: urban/rural, persons in 1200 sqft area, TB in family, crowding, smoking (family member), gender, age, education, smoking, workplace, kitchen location, cooking fuel, ventilation, and kerosene uses. It was concluded that inferences from UORs were not consistent among the studies and thus, actions taken may not be effective in all situations. It was concluded that variables must be dealt with as a group and their significance should be based on the adjusted odds ratio (AOR). For example, independent variables TB in family, kitchen location, and occupation showed significant UORs but lost their significance when examined through AOR, derived from the logistic model. In the logistic model, only four variables kerosene uses, kitchen ventilation, gender and workplace, were found significant and adequate compared to a full model of 14 variables.It was concluded that uses of kerosene ) and emissions thereof consistently related to the incidences of TB. The linkage between incidences of TB and kerosene uses was quantified and it was concluded that a 50% reduction in kerosene uses could prevent 13.29% of existing TB cases.In this study, most subjects (more than 75%) were from Kanpur and nearby districts  in Uttar Pradesh, India. The findings of this study, in a strict sense, may not hold true for the rest of the districts in Uttar Pradesh or other states in India.The conclusion of kerosene and TB linkage can be useful to other south Asian countries similar in culture, urban-poor divide, economic conditions and high prevalence of TB. The science-based findings can prompt the policymakers to control variables responsible for TB and inspire them for long-term planning and investment.Supplementary Information.


Branchiommaluctuosum , originally described from the Red Sea, is first reported here from the Albanian coasts, based on records held in Vlora Bay, a locality near to Valona harbour and Narta Lagoon. Possible pathways of arrival in the area are uncertain. However, species’ larval ecology and life-history traits suggest a secondary spreading through shipping. Social media data mining allowed the confirmation of its establishment in the area, with specimens showing high densities in shallow waters on artificial hard substrates and to backdate its arrival in the area since at least November 2016. Citizen science continues supporting marine biology in the Mediterranean area, especially in countries where proper field studies and research projects are still limited.The invasive fan worm  The Mediterranean Sea is considered a hotspot of biodiversity, with around 17,000 accepted species, of which around one fourth is endemic . This diDespite Descriptor 2 of the EU Marine Strategy Framework Directive  suggestiAnnelida ranks high  on the outer surface of the radiolar axes of the crown , originally described from Bermuda, Branchiommaboholense , native to the Indo-Pacific, and Branchiommaluctuosum , originally described from the Red Sea  in the late 1970s (B.luctuosum in Albania (Adriatic Sea).Amongst NIS species invading the Mediterranean Sea, the phylum nks high . Within munities  and, withe crown . Branchi Red Sea . Despite Red Sea . On the te 1970s , recordste 1970s  and, beyte 1970s , Turkey te 1970s , Cyprus te 1970s  and Spaite 1970s . Indeed,40°45’72’’N, 19°39’80’’E) were posted by one of the authors (A.G.) in October 2019 on the Facebook group Regjistri Elektronik i Specieve Shqiptare (Electronic register of Albanian species: https://www.facebook.com/groups/220793668293252). Soon after its identification, additional photos uploaded on Facebook by the author of the present finding and dealing with the marine biota of the Vlora Bay were screened in the two Facebook profiles maintained by him  to search for a possible presence of the species in the area prior to the post noted in the origin. Finally, a careful bibliographic research was done to evaluate the distribution of this species in the Mediterranean Sea.The present record falls within the framework of an ongoing project that aims at monitoring the marine biodiversity in Albania. In particular, a folder of photos and videos of an unknown annelid species living in the shallow waters of Vlora Bay, Albania  based on their large sizes, external appearance/general colour pattern with a brownish/greenish body and a dark velvet crown and absence of macrostylodes. These characters altogether make this species easier to identify with respect to the other alien and native Branchiomma species living in the Mediterranean Sea, even from underwater photographs and videos. This is confirmed by the fact that the species has already been widely recorded in the Mediterranean Sea based on ROV observations and visual census , that occupies the same niche , Actiniaequina  and Balanusperforatus Bruguière, 1789, or as an epibiont of the ascidian Styelaplicata  and the crustacean Majasquinado   .Finally, worth a mention, the number of alien species detected in recent years in the Mediterranean Sea is also increasing thanks to citizen science projects and related field surveys e.g. . However31017BA7-FAF5-58EE-97BC-5AE0E94A2EB010.3897/BDJ.8.e54790.suppl1Supplementary material 1B.luctuosum in AlbaniaSupplementary-Citizen-science detects the arrival and establishment of Data typeRecord of Branchiomma luctuosum in the Mediterranean SeaFile: oo_413312.xlsxhttps://binary.pensoft.net/file/413312Valentina Tanduo, Aleksander Golemaj, Fabio Crocetta


Because the relationship between Crohn’s Disease (CD) activity and CD-related fatigue remains poorly understood, this study investigated the role of underlying psychological processes . It was expected that the relationship between CD activity and CD-related fatigue would be mediated by depression and anxiety and also by a deficit in emotional processing. This prediction was tested in 110 CD patients who completed self-reported questionnaires assessing fatigue (FSS), clinical activity of Crohn’s Disease (HBAI), psychological suffering (HADS), and emotional processing (EPS-25). A path analysis showed both direct and indirect effects in the relationship between CD activity and CD-related fatigue, accounting for 33% of the variance. One indirect effect on the experience of fatigue was depression, but there was no effect of anxiety. These preliminary results confirmed that disease activity induces an increase in depressive symptoms, which in turn leads to an increase in the level of fatigue. The most novel result of the present study is that emotional processing had an indirect effect on the relationship between CD and CD-related fatigue: when the disease was more active, patients exhibited greater disruption of emotional processing, which in turn led to greater fatigue. These results did not reveal any association between depression and emotional processing. In conclusion, this work highlights the role of emotional processing in CD-related fatigue and the importance of taking this factor into account in order to manage this condition better. Crohn’s Disease (CD), like all types of Inflammatory Bowel Disease (IBD), is characterized by chronic, recurrent inflammation of the gastrointestinal tract that causes the most common symptoms: diarrhea, blood and mucus in the stool, and abdominal cramping. It can also cause systemic symptoms outside the gastro-intestinal tract, such as redness or pain in the eyes, mouth sores, painful joints, skin complications, and fatigue.Fatigue is defined as a persistent and overwhelming sense of tiredness, weakness, or exhaustion, which can be mental, physical or both . It is nPast research addressing the issue of fatigue in CD has established a link between depression and anxiety symptoms and CD-related fatigue . More spStudies of Multiple Sclerosis (MS), another inflammatory autoimmune disease, have shown that emotional processing in people with MS is more dysfunctional compared to healthy controls . They shIn line with past findings, e expected that the link between clinical activity of the disease and fatigue would be mediated by the severity of depression and anxiety symptoms. More importantly, we also expected to observe that emotional processing would be more dysfunctional when the disease is clinically active, leading to greater CD-related fatigue. In other words, we expected that the link between clinical activity of the disease and CD-related fatigue would be mediated by the severity of emotional dysregulation Finally, we expected these mediators to be intercorrelated and the main objective of the study was to examine their respective relative weight in the association between clinical activity of the disease and CD-related fatigue. cf. .The 110 volunteer CD patients were recruited between June 2016 and June 2017 in two hospitals: (1) a referral center for the medical management of IBD, and (2) the gastroenterology department of a teaching hospital in a medium-sized provincial city in France. They were aged 18 years or older and had a medical diagnosis of CD; 50% of the sample had an active disease see . ParticiIn accordance with French legislation and the Declaration of Helsinki, participants were fully informed about the purpose of the study, which was approved by the Ile-de-France Ethical Research Committee (no. 2015-09-05). Once all their questions about the study had been answered and they had given their written consent, they completed (in 25 min) a paper-and-pencil questionnaire containing the measures outlined below.Demographic and disease-related information included age, gender, marital status, years of education, employment status, and medical treatment.Clinical activity of CD was assessed with the modified Harvey-Bradshaw activity index . Items are rated on a 7-point scale ranging from (1) “disagree” to (7) “agree”; the fatigue threshold score is set at 36. The mean of the scores for the nine items represents a continuous variable with values ranging from 1 (no fatigue interference) to 7 (maximum fatigue interference). This scale has good psychometric properties , which is a 14-item scale used as a brief instrument for detecting the intensity of depression and anxiety in patient populations (r = 0.46), representing 22% of the common variance , which is a 25-item self-report questionnaire designed to identify and measure emotional processing styles and potential deficits in healthy individuals and those with psychological or physical disorders. It comprises five subscales, each with five items that are rated on a 10-point (0–9) attitudinal scale: suppression , signs of unprocessed emotion , unregulated emotion (inability to control one’s emotions), avoidance , impoverished emotional experience . Total score can range from 0 to 225, higher scores indicating poorer emotional processing. In the original English version of the EPS developed in the United Kingdom, these five factors explained 59.4% of the total variance, and overall internal reliability was high (α = 0.92), ranging from 0.70 to 0.80 for the five factors. A French version has been developed . To gain a better understanding of the characteristics of the sample, the differences in the mean scores of participants with active and inactive disease were calculated using Student’s t-test. Next, to explore the bivariate relationships between the variables under study, zero-order correlations were calculated. Our research hypotheses were tested through a multiple mediation model using Amos 22 software. We evaluated model fit using the following indices: Carmines-McIver Index (χ2/df)  , the Non (χ2/df) , the Com (χ2/df) , and the (χ2/df) . If the SD = 12.06), with a slight predominance of women (55.45%); the majority were married or living with a partner (54.55%), and 65.46% had a professional activity. 50% had a clinically active disease, and for 60% of those, the clinical activity was light.Participants had a mean age of 38.04 years , and 69.09% reported anxiety. While patients reported moderate levels of anxiety, the prevalence in the sample was 69.09%. Overall level of anxiety was low . Mean depression scores were low , although 45.45% of patients reported symptoms of depression.In our sample, 60% reported a moderate fatigue  compared to the general population , with the mean of the clinical sample nearing two standard deviations below the mean of healthy controls. All subscale scores were significantly different from those obtained by healthy controls , avoidance , unprocessed emotions , unregulated emotions , and impoverishment . The average scores obtained on the unprocessed emotions dimension were particularly high, indicating intrusive and persistent emotional experiences, which may be an indicator of a traumatic experience. Suppression of emotions also reflects the cost of trying to deal with emotions for these patients.Regarding emotional processing see , the EPScontrols , whetherResults showed that there was no significant difference between anxiety scores of patients with an active disease and those with no disease activity: both groups reported clinical-level anxiety, with no decrease when the disease was no longer active. There were significant differences in fatigue and depression in relation to disease activity. Patients with an active disease reported significantly more fatigue and depression see .Regarding emotional processing, patients with an active disease had significantly more difficulty on all dimensions of emotional processing. Compared to patients with a clinically inactive disease, they showed greater avoidance of emotional triggers, had a more detached experience of emotions, exerted more control of emotional experience and expression, and showed a higher tendency to express anger.Finally, it is important to note that scores for avoidance, emotional suppression and unprocessed emotion were particularly high in the active disease group. In other words, these patients had impoverished emotions, avoided negative stimuli, perceived events as significantly more external to them, and experienced more anger than patients with an inactive disease.r = 0.25, p < 0.01), women having higher scores than men. The younger participants had higher scores for anxiety  and emotional suppression . Furthermore, Disease activity was positively correlated with depression , emotional processing , and fatigue , but not with anxiety . In fact, the only variable that correlated significantly with anxiety was fatigue. Finally, emotional processing was positively correlated with fatigue .We analyzed the bivariate relationships between age, sex, Disease Activity, depression, anxiety, the total score of the emotional processing variable and its five dimensions  and fatigue. The results are shown in 2 = 24.16, df = 22, X2/df = 1.10, NNFI = 0.98, CFI = 0.99, and RMSEA = 0.03 . Disease activity was positively associated with fatigue , depression , and Emotional regulation . Moreover, emotional regulation  and Depression  were associated with fatigue. The model explained 40% of fatigue variance.The main objective of this research was to examine the role of specific psychological factors  underlying CD-related fatigue.These preliminary results confirmed all the predictions, except the expected positive link between disease activity and anxiety. This could be explained by the prevalence of CD patients with anxiety symptoms in our sample . The patients/participants provided their written informed consent to participate in this study.IB and MC-G: substantial contributions to the conception or design of the work, analysis or interpretation of data for the work. LM and MD-B: the acquisition of data for the work and they organized the database. FS: analysis or interpretation of data for the work, he performed the statistical analysis. LB and GS: substantial contributions to the acquisition of data for the work. IB, FS, MC-G, GS, and LB wrote sections of the manuscript. All authors contributed to manuscript revision, 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.


A framework for understanding the interrelationship of individual and environmental factors that influence adolescent health and well-being, as well as opportunities for policy-level interventions, is known as Positive Youth Development (PYD). The current study represents one of the largest studies of Croatian adolescents to date, and aimed to examine associations between school and family factors linked to PYD, and mental health outcomes experienced by Croatian youth.N = 9,655) residing in the five most populous cities in Croatia, with the aim of examining cross-sectional associations of family and school factors with adolescent mental health. The mean age of participants was 16.3 years (SD = 1.2), and 52.5% of participants were female. School and family factors included school attachment, school commitment, family communication, and family satisfaction. Depression, anxiety, and stress were assessed as outcomes. Multigroup structural equation modeling (SEM) was used to examine relations of interest among female and male adolescents.A multi-site survey study was conducted among adolescents (Among school factors, increased school attachment was found to be significantly associated with reduced depression, anxiety, and stress for female adolescents, and with decreased depression and stress for male adolescents. Increased school commitment was significantly associated with decreased depression and anxiety for female adolescents; conversely, an increase in school commitment was associated with an increase in anxiety and stress for male adolescents. Increases in family communication were significantly associated with reduced depression, anxiety, and stress only for male adolescents, while increased family satisfaction was significantly associated with reduced depression, anxiety, and stress for female adolescents and with decreased depression and stress for male adolescents.Findings suggest that interventions for mental health promotion and prevention of internalizing problems should address both school and family contexts, and may be more effective when accounting for differing developmental experiences of female and male adolescents. Worldwide, the global burden of mental health conditions among adolescents is increasing. Studies have shown that around half of mental health problems start by middle adolescence while 75% of adult mental health issues start before the age of 24 . It is ePhysiological and psychological maturation during adolescence alters cognitive, emotional, and motivational processes, and these developmental changes interact with other processes that influence adolescents’ mental and behavioral health, including individual traits, family and social environments, and the broader social and economic climate . A frameWithin the Five Cs Model, competence reflects a positive appraisal of personal academic, social, and career abilities that enables success in social tasks, problem-solving, and decision-making , 2013. CIn the present study, the Five Cs Model is augmented by Benson’s Theory of Developmental Assets , 2011, w1 Based on previous research, we hypothesized that: (1) there would be significant associations between school and family external assets and youth mental health, (2) mental health symptoms would be more severe in adolescent females, and (3) associations between school and family factors and youth mental health indicators would be stronger for adolescent females.As we will describe, degree of connection to school and family environments, the presence of supportive adults, acceptance, and effective communication, are all factors that relate to adolescent mental health and well-being. The current study sought to improve understanding of the relation between these school and family factors and the mental health of Croatian youth. We examined the association between school external assets (school attachment and school commitment) and family external assets (family communication and family satisfaction) and indicators of adolescent depression, anxiety, and stress. In addition, we examined how these relationships differed by adolescents’ gender.School connectedness has been researched under many different terms , but desAs a potential protective factor, strong correlations between school connectedness and PYD have been identified . A recenMany studies have found that a low level of school connectedness is associated with depression and anxiety in youth . In addiFindings on gender differences in school connectedness are mixed. Some authors report no differences in emotional connection  while soThe family systems perspective states that the family is the most critical system to which an individual belongs . As a reFamily satisfaction is a construct that reflects several family assets, and is defined as the degree to which one feels pleased and gratified within one’s family . Low famResearch on adolescents at risk of mental health or conduct problems has identified effective parent–child communication as a protective factor and problematic communication between parents and children as a risk factor for poor adolescent psychosocial adjustment . The quaAdditionally, there may be important differences in the role of communication based on the gender of adolescents. 2), and over 20% of youth aged 15–17 are at risk of poverty  were recruited to complete a survey questionnaire for this study. In all cities except Zagreb, all schools were included with the intent to reach a quota of 25% of all high-school students in each locality. Given the large population size of Zagreb, the capital of Croatia, the sample was stratified according to three Croatian high school education programs: general preparatory grammar education, 3-year educational schools, and 4-year educational schools. Three- and 4-year programs prepare students for employment in specific professions after graduation, while preparatory grammar school is intended for students planning to attend university. Zagreb’s local education authority provided the total number of students enrolled in all three types of education programs and 15% of the total student number was calculated and then stratified by the three education programs. The number of schools per stratum was calculated and each school was chosen according to the school size, average school performance, school location, and gender composition of students in order to achieve the maximum representation of the Zagreb high school student population. The number of included students from each school was equal to the school size proportion in the total sample. A total of 77 schools were included in the sample.M = 16.3, SD = 1.2). 52.5% of participants were female, and 26.5% were enrolled in a professional 3-year education program, 49.9% in a professional 4-year education program, and 23.6% in a general education (university preparation) program. The program distribution closely represented the national distribution of students enrolled in each program. Participants were also approximately equally distributed across first, second, and third years of programs, with a lower number of fourth-year students due to the presence of 3-year school programs in the sample. Socio-demographic characteristics of participants are presented in Participants were aged between 14–19 years  within city or region level. The study team organized meetings with school headmasters and school counselors in each of five sites to obtaining their approval and partnership. Letters were sent in order to inform parents that the study was taking place. According to the Ethical Codex for Research with Children , adolescAll measures were either constructed in Croatian  or transattachment to teachers and school (α = 0.89) and commitment to schooling (α = 0.89). Examples of the attachment items include, “I am satisfied with my teachers” and “Teachers treat us with care and respect.” Commitment items include, “I study regularly” and “I strive to be a better student.” All items were endorsed using a four-point rating scale, with response options ranging from “never” to “very often.”School connectedness was assessed with the 17-item School Bonding Scale , which hThe Family Satisfaction Scale  questionThe Family Communication Scale  questionThe Depression, Anxiety, and Stress Scale–21 Items (DASS-21) is a self-reported assessment with three scales designed to measure the emotional states of depression, anxiety, and stress . Each ofStructural equation modeling  of the measurement model, and to use all available data. Using information from all measures avoids the need to create scale summary scores, which can have problematic or poorly understood measurement and analytic properties, and allows missing data to be addressed during model estimation (when missing data are missing completely at random or missing at random). SEM also provides informative model fit and precision indices, and estimation approaches can be used that are robust to non-normality . Figure 2). Finally, comparative and parsimonious fit was assessed using change in model Bayesian information criterion (BIC) value. Because the chi-square test of overall model fit is known to be overpowered in large samples , their measurement properties in the present sample were examined using confirmatory factor analysis. Once a satisfactory measurement model for each construct was established, a structural model was specified representing the hypothesized relations among latent variables. Absolute fit of confirmatory factor and full models was assessed using model root-mean-square error of approximation (RMSEA) and standardized root mean square residual (SRMR), as well as a test of close fit (the probability that RMSEA is below 0.05). Comparative fit was evaluated using the comparative fit index (CFI), Tucker–Lewis index (TLI), and a test of the difference in chi-square statistics between alternate models  did not provide information on gender or provided no responses to questionnaire items, and were not included in the analytic sample . Any remaining missing response data (2.4%) were addressed using a full information maximum likelihood approach during model estimation. Standardization of observed and latent variables was employed, and statistical significance of associations was evaluated at a significance level of α = 0.05. Prior to confirmatory factor and full latent variable model fitting, an unconditional multilevel model was fitted to assess whether variation in outcomes occurred at city or school levels. No substantial variation was identified at either level , and consequently single level models were fitted for all subsequent stages of modeling.All models were fitted with Msion 8.4  using man = 5,074) and female (n = 4566) adolescents are presented in Descriptive statistics of observed predictor and outcome scale scores for male (2) p-value < 0.001; reduction in BIC value = 11032.20).The initial confirmatory factor model was adequately fitting; substantially improved fit was achieved by permitting covariances and residual covariances among several scale variables to be freely estimated  and comparative fit indices . As a final step in model fitting, a sensitivity analysis was carried out to assess whether freely estimating some covariances and residual covariances altered final model interpretation. Final model results and interpretation did not substantively differ from a full latent variable model without the modifications, and as a result they were retained.SD) increase in school attachment was associated with a 0.09 SD decrease in depression, 95% CI ; with a 0.06 SD reduction in anxiety, 95% CI ; and with a 0.11 SD decrease in stress, 95% CI . For male adolescents, each SD increase in attachment was associated with a 0.06 SD decrease in depression, 95% CI , and with a 0.09 SD decrease in stress, 95% CI .Results of the final model assessing the relation of school and family factors with student depression, anxiety, and stress are presented in SD increase in commitment was associated with a 0.11 SD decrease in depression, 95% CI , and with a 0.05 SD decrease in anxiety, 95% CI . For male adolescents, school commitment was associated only with anxiety and stress; conversely to females, a one SD increase in commitment was associated with a 0.06 SD increase in anxiety, 95% CI , and with a 0.06 SD increase in stress, 95% CI .The second school factor, school commitment, was significantly associated with depression and anxiety for female adolescents. Each SD increase in family communication was associated with a 0.22 SD decrease in depression, 95% CI ; with a 0.26 SD reduction in anxiety, 95% CI ; and with a 0.24 SD decrease in stress, 95% CI . The second family factor, family satisfaction, was significantly associated with all latent outcome variables for female adolescents. Each SD increase in satisfaction was associated with a 0.33 SD decrease in depression, 95% CI ; with a 0.28 SD reduction in anxiety, 95% CI ; and with a 0.34 SD decrease in stress, 95% CI . For male adolescents, family satisfaction was significantly associated with depression and stress, with each SD increase in family satisfaction associated with a 0.16 SD decrease in depression, 95% CI , and with a 0.10 SD decrease in stress, 95% CI .The family communication factor was significantly associated with depression, anxiety, and stress only for male adolescents. Each p-values < 0.001). School attachment and commitment were moderately correlated for both female and male adolescents , while family satisfaction and communication were highly correlated for both female and male adolescents . Family satisfaction and communication were not highly correlated with school attachment and commitment for female nor male adolescents . Finally, correlations among latent variables were examined. Depression, anxiety, and stress were highly correlated for both female and male adolescents . Exploring these dynamics could help to clarify the existing mixed research findings. For example, some studies have found that adolescent internalizing disorders negatively impact family functioning . In contFindings indicate family satisfaction is associated with depression and stress for both male and female adolescents, with a larger association for female adolescents. These results align with those of To approach youth mental health comprehensively, preventive interventions should focus on improving the relational context of schools and families, investing in capacities of teachers to relate with students more meaningfully and providing tools for better family functioning. Schools represent one of the most important community settings where the mental health of young people can be promoted. For example, The family has a vital and unique role in providing a supportive environment for PYD, buffering the negative impacts of various stressors on youth mental health . Yet, paThis study has several limitations. First, as a cross-sectional design, the causal relations among school and family factors and depression, anxiety, and stress could not be examined. Future longitudinal studies are needed to examine the directionality of these relations. Future studies should also include measures of parental mental health, parent–child relationship quality, family socioeconomic status, and context . Regarding school factors, some important constructs were not incorporated into this study, including academic motivation, school climate, or parents’ involvement in school. Additionally, only self-reported measures were used, and there may have also been underreporting of mental health outcomes by male adolescents due to concerns about adherence to gender norms .Despite the above limitations, findings of this study emphasize the importance of school and family contexts to adolescent mental health, including levels of depression, anxiety, and stress. Observed differences in multi-group models also suggest that strategies for mental health promotion and prevention planning may need to be tailored to female and male adolescents. More generally, evidence-based knowledge translation strategies should be developed to ensure that all stakeholders recognize the importance of preventing mental health disorders among adolescents and young adults, with appropriate resources directed to this objective . To thisThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical approval for the study was obtained from the Ministry of Science and Education, National Agency for Education, and Ethical Committee at the Faculty for Education and Rehabilitation Sciences, University of Zagreb. Written informed consent for participation was not provided by the participants’ legal guardians/next of kin because: According to the Ethical Codex for Research with Children , adolescMN, MF, JM, and VK designed the study and participated in data collection in the city of Zagreb. MN coordinated the data collection on other sites and supervised the project. NP analyzed the data and prepared analysis and result sections. All authors contributed to drafting and revising the 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.


In recent years, the research and development of genome editing technology have been progressing rapidly, and the commercial use of genome-edited soybean started in the United States in 2019. A preceding study’s results found that there is public concern with regard to the safety of high-tech foods, such as genetically modified foods and genome-edited foods. Twitter, one of the most popular social networks, allows users to post their opinions instantaneously, making it an extremely useful tool to collect what people are actually saying online in a timely manner. Therefore, it was used for collecting data on the users’ concerns with and expectations of high-tech foods. This study collected and analyzed Twitter data on genome-edited foods and their labeling from May 25 to October 15 in 2019. Of 14,066 unique user IDs, 94.9% posted 5 or less tweets, whereas 64.8% tweeted only once, indicating that the majority of users who tweeted on this issue are not as intense, as they posted tweets consistently. After a process of refining, there were 28,722 tweets, of which 2,536 tweets (8.8%) were original, 326 (1.1%) were replies, and 25,860 (90%) were retweets. The numbers of tweets increased in response to government announcements and news content in the media. A total of six prominent peaks were detected during the investigation period, proving that Twitter could serve as a tool for monitoring degree of users’ interests in real time. The co-occurrence network of original and reply tweets provided different words from various tweets that appeared with a certain frequency. However, the network derived from all tweets seemed to concentrate on words from specific tweets with negative overtones. As a result of sentiment analysis, 54.5% to 62.8% tweets were negative about genome-edited food and the labeling policy of the Consumer Affairs Agency, respectively, indicating a strong demand for mandatory labeling. These findings are expected to contribute to the communication strategy of genome-edited foods toward social implementation by government officers and science communicators. TM high-oleic soybean1, which has been cultivated in the United States since 2019. In Japan, the Cross-ministerial Strategic Innovation Promotion Program (SIP) of the Cabinet Office, which started in 2014, and other projects financed by the government have been the main supporters of the development of agricultural and animal products through genome editing technology. Examples include tomatoes rich in gamma-aminobutyric acid (GABA)  , potatoed (GABA) , wheat wd (GABA) , red sead (GABA)  and Japad (GABA) , which hThe social implementation of genome-edited products requires three main conditions: (i) the government’s handling policy, (ii) intellectual property rights, and (iii) public acceptance . Japan hGenerally, questionnaire surveys have been carried out to identify consumer interests and concerns. This method has the great advantage of garnering more information through answers to detailed questions, along with the information about the respondent’s background. On the contrary, this method comes with some shortfalls. First, it is difficult to collect the ideal quantity of opinions in a timely manner and therefore analyze it in response to changing social situations. Second, it has been suggested that surveys do not capture the conversational or hierarchical nature of public opinion formation and that the operationalization of survey questions leads to a narrow definition of public opinion . Recentl2019 was a milestone year for the regulation of genome-edited products in Japan. The Ministry of Environment and five other ministries released policies for handling genome-edited organisms . As for ® , from May 25 to October 15, 2019, with the search string “genome editing (which included ‘genome-edited’ in Japanese) AND labeling” in Japanese. We performed Mieruka Engine® searches using API provided by the NTT DATA Corporation , which has the resale rights of Twitter data in Japan. The use of materials for data analysis is permitted by the Copyright Act of Japan.To explore public concern regarding genome-edited foods and their labeling, Twitter data were collected from a cloud software, Mieruka EngineThere are three types of tweets: original tweets, reply tweets, and retweets. In our study, retweets were regarded as partially or fully agreeing with the opinions of the original tweeters. Although tweet redundancy increases the chance of opinions influencing many people, we excluded duplicates for an accurate analysis. The collected tweet data were refined according to the following rules: (i) if a Twitter user tweets or retweets the same text multiple times, whether intentional or not, only one of them is analyzed; (ii) if the duplicate tweets were from different people, those texts are all subject to analysis – this happens frequently in retweets; and (iii) if a tag or link is different but the text is the same, it is considered the same tweet.® predicted their profiles when possible. Unique user IDs posted from May 25 to October 15 were collected and counted. Because of system rules, user profiles of tweets from June 15 to October 15 were available in Mieruka Engine®. To verify whether the same users tweeted repeatedly on this issue, unique user IDs were categorized based on tweet counts  posted during this period.Twitter users registered their profiles when creating their accounts; some left them blank. For users without profiles, Mieruka EngineDuring data collection, the tweet count  increased sharply on several occasions. Prominent peaks were detected with Python (version 3.7.6), using SciPy 1.4.1. The prominence of a peak allows measurements of the degree to which a peak is protruding, depending on its position in relation to other peaks. A prominence cut-off of 300 was set to detect important peaks evenly over the entire period of the study. When peaks were detected, influential events were determined from the content of each tweet.On September 19, the MHLW announced that the notification of genome-edited foods would start on October 1, and the CAA declared that labeling of genome-edited foods should not be mandated. To examine the overall picture of how users discussed genome-edited foods and their labeling in response to government’s announcements, we created co-occurrence networks based on tweets posted from September 19 to 22. At first, we analyzed 530 original and reply tweets excluding retweets using the free text-mining software KH Coder . Then we® software.To infer users’ opinions on these policies, original and reply tweets posted during the same period in the former section were selected for classification according to sentiment on genome-edited food and its labeling. Oftentimes, the sentiments expressed for “genome-edited food” and “labeling” in tweets differed; therefore, they were counted independently, and text and information provided by the URL link were used to determine the sentiments. Three researchers differentiated Twitter sentiment into three groups: positive, negative, and neutral. Tweet classification was performed using the criteria in From the 29,299 tweets that were extracted with the search string “genome editing (which included ‘genome-edited’ in Japanese) AND labeling” in Japanese, 577 were excluded in accordance with the policies laid out in the “Materials and Methods” section. Thus, the dataset consisted of 28,722 tweets of which 2,536 tweets (8.8%) were original tweets, 326 tweets (1.1%) were replies, and 25,860 tweets (90%) were retweets.To learn about the kind of people who were interested in the labeling of genome-edited foods, we categorized the age and gender of unique user IDs . Of 14,0To verify that the same users tweeted repeatedly in each peak, unique user IDs were categorized based on tweet counts . The stuWe investigated the time course of daily tweet numbers to reveal the responses to information related to the labeling of genome-edited foods. When it was expressed in a subcommittee meeting of the Cabinet Office’s Consumer Committee that mandatory labeling for genome-edited foods would be difficult, many users posted tweets in response to news regarding it. This is a key reason for the significant increase in tweet count compared to the period before June 21 and thus formed the peak in The third peak, The fourth peak, The fifth peak, The cause of the sharp increase in tweet count on October 7, the peak in Using co-occurrence networks, we analyzed the appearance and relevance of words in original and reply tweets, and all tweets including retweets posted from September 19 to 22 and compared patterns of the two networks.genome-edited, food, mandatory labeling, and consumer, which were discussed in the context of the obligatory labeling of genome-edited foods. Furthermore, the word the Nikkei (referring to the Nikkei newspaper) was strongly related to the words food labeling, obligation, and distribution system; it was speculated that the content published in the Nikkei uses the above words. Subgraph 2 contained two words: technology and use. Subgraph 3 consisted of three words – breeding, producer, and obligate – which points toward people asking producers for mandatory labeling. Subgraph 4 consisted of two words: voluntary and provision of information. It shows that many tweeters were concerned about the provision of information (in the notification to the MHLW) being non-mandatory. Subgraph 5 consisted of tweets regarding news of government policies and the commercialization of genome-edited foods, and an article from Asahi Shimbun (Asahi newspaper) influenced this subgraph. Subgraph 6 was influenced by tweets regarding studies on potatoes without harmful substances and fast-growing red sea breams, as well as tweets about the resulting public anxiety. Subgraph 7 contained two words: Japan and United States and FTA. Tweeters were concerned that the United States–Japan FTA might result in the import of undesirable genome-edited foods because of pressure from the United States.In the co-occurrence network of original and reply tweets without retweets, seven clusters were observed  opposed genome-edited food, and 37 (7.0%) were in favor of it. With regard to the CAA policy, 333 (62.8%) tweets were negative and 27 (5.1%) were positive . Among t® software, which did not consider the respective sentiments for genome-edited food and labeling policy in a tweet. Of the same 530 tweets mentioned above, 79 tweets (14.9%) were determined to be positive, while 97 (18.3%) were determined to be negative.For comparison, the sentiment for each tweet was determined using the Mieruka EngineGenome editing technology is expected to rise in fields such as medicine and agriculture. However, science and technology are not autonomous entities, and research trajectories are largely influenced by public opinion; even if crops produced using new breeding techniques do not fall under GMOs, commercializing them is by no means easy . The pub2. The reason for the deviation in our study was not clear, but users with these profiles were most interested in genome-edited foods and their labeling. A total of 94.9% of user IDs posted five or less tweets, in particular 64.8% tweeted only once. The majority of the users who tweeted about this issue do not seem as intense as they posted tweets consistently.In this survey, among user IDs whose profiles were available, 71.5% were male, and male users in their 50s and older outnumbered male users in other age groups . Females® from June 29 to July 29, 2020. The maximum tweet count per day reached 1,343,045 tweets on the election day: June 5. In terms of the Fukushima Daiichi Nuclear Power Plant accident, which was directly related to life-threatening and energy problems, approximately 25 million tweets were posted within a span of 195 days, and the maximum tweet count per day was more than 640,000  using the search string “genome editing (which included ‘genome-edited’ in Japanese) AND labeling” in Japanese with a maximum tweet number per day of 3,426. To compare the number of tweets on this issue and another much-discussed political issue, tweets on a political issue  were retrieved using the Mieruka Engine 640,000 . CompariTo ascertain users’ opinions with regard to the labeling of genome-edited foods, Twitter data were collected from May 25 to October 15 using the search string “genome editing (which included ‘genome-edited’ in Japanese) AND labeling.” Throughout this period, the tweet count changed significantly in response to government announcements and news published by the media and other information sources. A spike in the tweet count may be an indication of growing concern among Twitter users . An anal® software tended to be positive more than those determined by researchers in this study. Sentiment analysis of the software was conducted by determining the presence of words in positive and negative categories, and not by the context. This might be a reason for the difference between the two methods. For high-volume and automated processing, the deep learning of text data could potentially allow for the identification of complex sentence structures, taking into account multiple word combinations, and lead to improvement in the accuracy of sentiment analysis.Sometimes, the Twitter character limit (140 characters) and the chatty, colloquial style of tweets complicated sentiment judgment, resulting in approximately one-quarter to one third inconsistent tweets among the three researchers. Sentiments determined by the Mieruka EngineRetweets accounted for 90% of total tweets in our study; co-occurrence networks were significantly different with or without retweets because of an increase of the proportion of specific words in retweets . There a2 emissions , colloquial style, and bias among Twitter users. To achieve a more detailed and accurate analysis, using a combination of a Twitter analysis and other methods, such as questionnaire surveys, would help cover for the deficits of the Twitter analysis. Furthermore, it will be meaningful to analyze consumers’ opinions and attitudes at the first commercialization of genome-edited food employing data mining by deep learning, considering many complex factors, such as social situation surrounding genome-edited foods, news content, online discourse or questionnaire survey, and individual profile, among others, in the future.All dataset except raw Twitter data generated for this study are included in the article/YT provided the initial research design, discussed the results, and wrote, reviewed, and edited the manuscript. SS wrote the manuscript, performed research design and data analysis, and discussed the results. YK also wrote the manuscript and worked on research design, data collection and analysis, and the discussion. SI discussed the results as well. NF worked on data analysis and discussed the results as well as reviewed and edited the manuscript. All authors contributed to the article 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.


Urban residents can benefit from spending time in outdoor spaces and engaging with nature-related activities. Such engagement can improve health and well-being, support community cohesion, and improve environmentally-friendly behaviours. However, engagement with nature may not be equal amongst different members of society. We investigated individual variation in engagement with nature in Singapore, a high-density city in tropical Southeast Asia. Through a survey of 1000 residents, we analysed relationships between demographic factors such as age, income, and sex, and the frequency of visitation to different ecosystem types, and the frequency of engagement with different nature-related activities. Parks and neighbourhood open spaces were among the most commonly-visited outdoor spaces, with nature reserves and other natural areas being visited less frequently. Common activities included sitting outdoors, art and photography, and running, while hiking and nature recreation were less frequent. In contrast with previous studies, we found relatively small differences among different groups of the population in their preferred types of outdoor activities. Older people, those with lower incomes, and without degrees were less likely to visit most types of outdoor space and engage with most types of nature-related activities. In the case of nature reserves, the distance from the visitor’s home had a significantly negative influence on the frequency of visitation. These findings demonstrate that the benefits of engagement with nature are not equally enjoyed by all demographic groups, and that some groups lack engagement across the board. Strategies to increase nature engagement in tropical cities could include increasing the local availability and accessibility of different types of outdoor space, and education and public outreach programmes to encourage participation. Many urban residents have few opportunities to interact with ecosystems and organisms, leading them to have little or no experience with nature . IncreasUrban residents spend most of their time within built-up areas, which are mainly dominated by built infrastructure. Outdoor natural and semi-natural spaces in cities–including parks, gardens, and remnant patches of forest or other natural ecosystems–are therefore important in providing spaces for human-nature interactions ,11. By pAlthough urban living offers opportunities for various forms of contact with nature, not all urban residents have equal access to these opportunities ,23,24,25Unequal engagement with urban ecosystems has been highlighted as a global problem in the United Nations Sustainable Development Goals, which aim to secure universal access for urban residents to green space by 2030 . Most ofSingapore provides an interesting case study in which to investigate relationships between people and nature, due to its context as a highly-developed and high-density tropical Asian city. We conducted a survey of 1000 Singapore residents to analyse relationships between demographic factors and (1) the frequency of visitation to different ecosystem types, and (2) the frequency of engagement with different nature-related activities.2. Despite its small land area and rapid urbanisation over the past 60 years [Singapore  is a highly urbanised island nation with a population of approximately 5.6 million residents  on a sma60 years , Singapo60 years . There a60 years , in addi60 years .The survey was conducted online from 4 to 15 September 2018 through the engagement of an online survey company . The approximate time to complete the survey was 20 minutes. Participants from across Singapore were randomly invited to participate in the survey. Only complete responses were counted and the survey remained open until a total of 1000 responses were collected. The survey company contacted members of the public who had previously agreed to join a general pool of participants. The survey fixed quotas for sex and age classes, targeting an equal number of respondents in each class (two sex classes and 14 age classes). The quota for sex was met, giving equal representation of male and female respondents. However, it was not possible to obtain sufficient respondents for all age classes, with the older age classes under-represented . The surThe majority of the survey focused on understanding the respondents’ engagement with nature-related activities and use of outdoor spaces. The frequency of visitation to outdoor spaces was quantified across a typology of eight outdoor space types, based on the common types of protected nature areas, public parks, and outdoor spaces built into housing developments ,43 Tabl. The freThe minimum Euclidean distance from the respondent’s home location to each outdoor space type was calculated as an indicator of accessibility. Accessibility can be indicated by various metrics, such as self-reported travel time or distance, or path distance along the transport network ,35. Howedata.gov.sg), downloaded on the 2nd of February 2019  as implemented in the “ordinal” package for R ,53. CLMs2 = 12, df = 9, p = 0.21; [2 = 0.07, df = 1, p = 0.79; [2 = 312.8, df = 13, p < 0.001; [2 = 49.3, df = 4, p < 0.001; 2 = 232.77, df = 4, p-value < 0.001).The pool of respondents approximately represented the ethnic diversity of Singapore’s population, with 73% stating they were Chinese, 11% Malay, 7% Indian, and 9% other races. The distribution of ethnicity of respondents was not significantly different from the 2010 census values . The su = 0.79; ). The ag< 0.001; ). Older In general, visitation rates to natural and semi-natural outdoor spaces were relatively low, with more than half of respondents visiting a nature reserve or other natural space only once a year at most . Rates wThe relationships between visitation frequency and personal characteristics were similar across all ecosystem types . People There was substantial variation in the frequency of engagement with different nature- related activities . Some acThe relationships between engagement frequency and personal characteristics were similar across all types of nature-related activity . People Nature reserves and other natural areas were visited less frequently than local neighbourhood parks, open spaces and park connectors. A difference in the frequency of visits to outdoor spaces may be due to the perceived attractiveness and ease of access to these outdoor spaces . The attThe frequency of visitation to outdoor spaces is also affected by the effort required to travel to them, with shorter travel distances encouraging more frequent use ,34,67. OPopular outdoor-related activities documented in this study included sitting, running, cycling, and art or photography. The choice of an individual to engage with a particular activity is highly personal, but people may be influenced by broader trends in society, and the relative opportunity to engage . The benYounger people were more likely to visit most types of outdoor space, and more likely to engage in most types of nature-related activities Tables  and 4. WThe findings of the present study are in partial agreement with work in other cities. For example, urban outdoor space use is commonly reported to be lower amongst older members of society ,35, althThe age range of most respondents in this study was between 18 and 50, meaning that most respondents were of working age. Over this range, it is possible that older respondents had less time available for visits to outdoor space or engagement in nature-related activities, due to considerable work and family commitments. A study from the UK found that 35–64 year olds were more likely than 16–34 year olds to cite being “too busy at work” as their reason for reduced visitation . Income A growing body of research suggests that engagement with nature brings benefits to urban residents in terms of health and well-being ,80,15, aThere are two key approaches through which we can increase visitation to outdoor spaces and engagement in outdoor-related activities; (1) by increasing motivations through education and public engagement programmes, and (2) by making nature more accessible through urban design . EducatiWhile public visitation to outdoor spaces is widely beneficial for people, it is not without associated impacts for wildlife and environmental quality ,93. HighThis study has shown unequal visitation to outdoor spaces and engagement with nature-related activities across demographic groups, giving rise to a potential inequity in experiences of nature. This inequity may translate to inequities in health and well-being, although the mechanisms through which outdoor space use, of varying time spent in nature and quality, impacts health outcomes are still unclear, and require further research ,96,97,98Older, less educated, and less wealthy people living in Singapore are less actively engaged with urban nature. This inequity in nature engagement is not restricted to certain types of outdoor space or activities, but appears to be universal. Low levels of engagement with nature correspond to an ‘extinction’ of nature-based experiences , with poS1 Appendix(PDF)Click here for additional data file.


Studies have reported that patient-related factors significantly impact the risk of Chemotherapy-Induced Nausea and Vomiting (CINV). The objective of this study was to analyze those risk factors of CINV through a systematic literature review.We searched MEDLINE to identify articles that addressed patient-related risk factors of CINV through clinical studies.A total of 49 articles were selected for this study. A total of 28 patient-related risk-factors that significantly impact the risk of CINV were documented. Three factors are demographically related, 17 factors are intrinsic in nature and innate to patient's physiology or influenced by physiology, and eight factors are extrinsic in nature. At least five studies identified seven risk factors with notable summary odds ratio: history of nausea/vomiting , female sex , expectancy of CINV , younger age , anxiety , history of morning sickness , and low alcohol intake .Oncologists can use these factors prior to the initiation of a chemotherapy regimen to identify patients at risk for CINV, in order to focus on more comprehensive antiemetic treatment options for those high-risk patients. This may enable better outcomes and avoid complications. Chemotherapy is a core component of nearly every cancer treatment plan. Several patient-related factors affect the risk of CINV. However, none of the guidelines considers those factors except the NCCN guidelines suggesting that regimens be chosen based on the drug with highest emetic risk as well as patient-specific risk factors . As seenThere is a lack of comprehensive review of the literature and meta-analysis for summarizing the patient-related risk factors of CINV. Warr  summarizThe objective of this study was to identify patient-related factors that significantly impact the risk of CINV by conducting a systematic review of the literature. The reporting of this systematic review follows the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” guideline .In June 2019, we used PubMed to search the MEDLINE database for eligible articles. The search terms are related to the following terms: antiemetics, CINV and risk factors. We used a comprehensive search strategy to ensure retrieval of all relevant documents in MEDLINE. The inclusion criteria include: (1) studies that reported patient-related risk factors of CINV, (2) any kind of clinical studies including prospective, retrospective, clinical trial, cross-sectional, cross-over, and case-control studies, (3) studies that do not provide any concomitant cancer treatment such as radiotherapy or surgery, and (4) adult patient population. We excluded any articles not written in English.The study selection was performed in two steps. In the first step, we read the titles and abstracts of the citations by the search query to screen the articles based on the inclusion/exclusion criteria. In the second step, we read the full text of the citations selected by the first step. The search criteria did not limit by publication date; the earliest eligible article was published in 1989.We abstracted information from the eligible full-text articles. www.r-project.org). DerSimonian-Laird estimate . We were able to extract odds ratio from 17 studies . Eight studies defined low alcohol intake on the basis of the number of standard drinks per week; the thresholds were < 4 drinks  (n = 1),A total of 25 studies analyzed the history of nausea/vomiting including history of nausea/vomiting (unspecified), history of CINV, prior CINV, and history of pregnancy related nausea/vomiting. Six studies reported that patients experiencing CINV during the prior chemotherapy treatment cycle are at higher risk of CINV during their current cycle . Also, four studies reported that the patients with history of CINV at an earlier treatment were at higher risk of CINV . Two studies found that female patients experiencing severe nausea/vomiting during their prior pregnancies are at higher risk of CINV . Three studies reported history of nausea/vomiting as unspecified and found significant impact on CINV . The summary odds ratio for all of the studies was estimated to be 3.13 (95% CI 2.40–4.07) as shown in Six studies  found that patients who experienced morning sickness were at higher risk of CINV . We compModerate to high anxiety was found to be a risk factor of CINV in six studies (p < 0.05), out of 12 studies that analyzed that variable. Most of the studies determined the level of anxiety using a Likert scale  or a 0–100-mm visual analog scale (VAS). We computed odds ratio from four studies. Three studies out of the four studies considered anxiety as a categorical variable  and estimated summary odds ratio was 2.57 (95% CI 1.94–3.40) as shown in Patients who expect nausea/vomiting after their chemotherapy, regardless of previous experience, are more likely to experience CINV. This attribute was analyzed in 10 studies, out of which seven studies confirmed the hypothesis (p < 0.05). Odds ratios were extracted from six studies. Five studies out of the six studies treated this variable as categorical (yes or no) and estimated summary odds ratio was 2.61 (95% CI 1.69–4.02), as shown in This variable was analyzed in seven studies, of which, two studies  demonstrTwo out of seven studies showed that existing comorbidities  reduce the risk of CINV    and geniPS, as estimated by the Eastern Cooperative Oncology Group (ECOG) PS scale, is graded at six levels from 0 to 5, where a value greater than one indicates poor PS . This variable was analyzed in nine studies, out of which four studies reported that poor PS is a risk factor of CINV . The oveFive studies analyzed the impact of race on CINV, of which two studies demonstrated that patients from certain races are at higher risk of CINV. Two studies demonstrated that the use of nonprescription drugs at home before chemotherapy, for nausea and vomiting control, significantly increased the risk of CINV . Both stThree out of 25 studies reported that the history of motion sickness is a risk factor of CINV . Motion There are five stages in cancer: stage 0, I, II, III, and IV. The variable “cancer stage” was analyzed in eight studies but only one study reported that patients with early stages of cancer (stages I and II) are at higher risk of CINV during the acute phase  ; the reaFour studies conducted in Japan by Substance-P and 5-HIAA/creatinine are two neurotransmitter measurements that are measured from blood and urine sample respectively. Social functioning is a variable within the health-related quality-of-life (HQL) indicator. Tumor burden/load is indicative of the amount of cancer in the body. 2 are at higher risk of CINV .BMI was analysed in five studies. In a study with gynecologic cancer by A total of 17 patient-related factors were found to be insignificantly associated to the prediction of CINV in any study. These factors are history of previous chemo (n=6), depression, (n=2), education (n=2), marital status (n=1), religion (n=1), weight (n=1), frequency of chemotherapy cycle (n=1), number of risk factors (n=1), drowsiness (n=1), neuroticism (n=1), autonomic perception (n=1), menopause (n=1), defecations (bowel movement) (n=1), history of radiotherapy (n=1), opioid use (n=1), social jetlag (n=1), ascites (n=1), opioid use (n=1), and time since diagnosis (n=1).A significant amount of research has been performed to identify patient-related risk factors of CINV. We have identified 49 studies through a systematic literature review. These studies analyzed a total of 47 patient-related variables. Among them, 28 factors were found to have a significant positive impact on the risk of CINV. Three factors are demographic-related: younger patients, female sex, and Asian race. A total of 17 factors are innate to patient's physiology or influenced by physiology, and may alter the pathophysiology of CINV ; these factors include history of CINV or pregnancy-related nausea/vomiting, anxiety, expectancy of CINV, absence of comorbidities, cancer type , history of morning sickness, poor PS, history of motion sickness, early stage of cancer, lower number of hours of sleep before chemotherapy, recent surgery within the past three months, a higher ratio of neurotransmitter measurements, nausea/vomiting before chemotherapy, larger tumor burden, recurrent cancer, higher symptom distress score, and BMI. Seven factors may influence the pathophysiology of CINV and are external in nature . These factors include low alcohol intake, patients at earlier cycles (≤ 3) of chemotherapy, use of nonprescription drugs at home for emesis control before chemotherapy, no food intake before chemotherapy, nonsmoking habit, having private insurance, low social functioning, and working status.None of the studies considered all the 47 variables together in their studies. The average number of variables included per study was 6.55 with a minimum of 1 and a maximum of 16 (median = 5 and standard deviation = 3.69). The average number of significant risk factors that were reported per study was 2.67 with a minimum of 0 and a maximum of 7 (median = 2 and standard deviation = 1.87). The maximum number of patient-related risk factors that were reported by a single study was 7 (n=3)  followedThe significance of this study is threefold. First, the current CINV guidelines that are basically based on emetic risks of chemotherapies can be considerably augmented using the findings from this review study  so that oncologists can consider these factors when they predict CINV. Second, the findings of the study can be used to discover associations among those patient-related factors. While it is important to identify individual patient-related factors, the more important research would be to discover how those individual factors are associated with one another in terms of the risk of CINV. Third, this review may lay the foundation for improved CINV prediction models. Currently, CINV prediction models based on antiemetics and patient-related factors are unsatisfactory . This inThe study has some limitations and challenges. We might miss a few relevant studies. Retrieving all relevant documents is technically infeasible for all literature review studies, which is a well-known factor in the information retrieval field. In order to collect as many relevant studies as possible, we adopted a “broad” search strategy at the cost of precision. The studies included in this systematic review had various methodological designs and various statistical measures. Other variations include different phases  of CINV, various cycles of chemotherapy. One of the major challenges in this study was that all articles do not include the results for all phases  of CINV. As a result, in order to synthesize the analysis results of studies with different designs into one summary effect size for the entire phase, we used all the reported odds ratios for each phase and applied the random effect model instead of the fixed effect model. We excluded the pharmacogenomics studies. Pharmacogenomics was not within the scope of this study because the pharmacogenomics studies of CINV are sparse and limited. A review conducted by This systematic review study has identified and summarized patient-related factors scattered over various studies that significantly impact the risk of CINV. The identification of patients at high risk for CINV based on key risk factors prior to the initiation of a chemotherapy regimen is imperative. Oncologists may be able to selectively focus on more comprehensive antiemetic treatments on high risk patients. Although there are 28 significant risk factors, most studies used only two or three significant factors as well as many nonsignificant factors. Therefore, future studies are needed that include as many significant risk factors as possible to see how, in combination, they may affect the risk of CINV.AM contributed in conceptualization, design, validation, formal analysis, investigation, data curation, writing the original draft, reviewing, editing, and project administration. AH contributed in conceptualization, methodology, investigation, reviewing, editing, and supervision. BL contributed in investigation, reviewing, and editing. IY contributed in conceptualization, design, reviewing, editing, supervision, and project administration.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.


The high recurrence rate of atrial fibrillation (AF) after recovering sinus rhythm has always been a clinical problem. Despite the established and widespread use of antiarrhythmic drugs, which one is better for maintaining sinus rhythm is still controversial. This study aims to summarize the randomized controlled trials (RCTs) of amiodarone combined with beta blockers to maintain sinus rhythm in AF, and to determine an effective and safe intervention for the prevention of AF recurrence through network meta-analysis (NMA).A comprehensive search of the RCTs comparing amiodarone with different beta-blockers to maintain sinus rhythm of AF patients will be conducted from the inception to December 2019 in the Cochrane Library, PubMed, Web of Science, EMBASE, Chinese Biomedical Literature Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), and WanFang database. The primary outcomes will be the recurrence of AF and frequency of embolization complications. The secondary outcomes will be the symptom improvements and adverse events. Risk of bias assessment of the included RCTs will be conducted according to the Cochrane collaboration's risk of bias tool. Pairwise meta-analyses and Bayesian network meta-analyses will be performed for all related outcome measures. GRADE will be used to evaluate the quality of evidence.The results of this NMA will be published in a peer-reviewed journal.This NMA may provide more recommendations for patients and researchers, such as which treatment is better for a particular case of AF, and what may be the hotspots for the future studies.The protocol for this NMA has been registered on PROSPERO under the number CRD42020164438. The main complications of AF include stroke, thromboembolism, myocardial infarction, heart failure, cognitive decline, dementia, and renal impairment, and the main treatment are ventricular rate control, rhythm control, and anticoagulant therapy, which are supported by the American Heart Association, European Society of Cardiology, and Canadian Cardiovascular Society. Rhythm control as a primary therapy can reduce the risk of thromboembolism and the usage of anticoagulant drugs, and improve the left ventricular function, the hemodynamics, patient symptoms, and their quality of life.Atrial fibrillation (AF) is the most common clinical arrhythmia. As the population ages, its morbidity and mortality are on the rise,,9 The overall rate of AF recurrence without treatment is high. In the patients who have converted to sinus rhythm, only 20% to 30% could remain in sinus rhythm 1 year later.,11 Rhythm control in the early stage of AF is helpful to delay the progression and reduce the occurrence of AF-related complications, which can be regarded as the first choice for the treatment of recent-onset AF patients, paroxysmal AF patients, failed ventricular rate control patients, and the young patients who cannot tolerate AF symptoms.,14A major problem in the treatment of AF is the high recurrence rate. The risk of recurrence depends on age, AF duration, and the existence and severity of underlying heart disease.; compared with Class I antiarrhythmic drugs, it has fewer adverse reactions. Beta-blockers are less effective than Class I or Class II antiarrhythmic agents in maintaining sinus rhythm, but their long-term adverse effects are significantly less than Class I or Class II antiarrhythmic agents. Therefore, amiodarone combined with beta-blockers are often used clinically to maintain sinus rhythm.,17 However, current guidelines,6,7 do not uniformly agree upon the recommendation of antidysrhythmic agents for maintenance sinus rhythm in AF, and drug preference in clinical practice also varies internationally.,19 Previous systematic reviews and meta-analyses,21 are limited by trials with different antiarrhythmic drugs and different treatment duration were pooled together; except for maintaining sinus rhythm, other results were not evaluated; and head-to-head drug comparisons are insufficient. Therefore, we intend to conduct a network meta-analysis (NMA) to compare and rank the efficacy and safety of amiodarone combined with different types of beta-blockers for maintaining sinus rhythm in AF patients.Long-term antiarrhythmic therapy has been widely used to prevent the recurrence of AF. Amiodarone is more effective than other antiarrhythmic drugs in maintaining sinus rhythm22.1 The protocol for this systematic review has been registered in PROSPERO with number CRD 42020164438.We will perform this systematic review and NMA according to the Preferred Reporting Items for Systematic Reviews and Network Meta-Analysis (PRISMA-NMA) statement.2.2We will do a comprehensive search of the Cochrane Library, PubMed, Web of Science, EMBASE, Chinese Biomedical Literature Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), and WanFang database from the inception to December 2019. In addition, we will search the bibliography of the included studies, as well as previous relevant systematic reviews, to look for other studies that may not be found by our database search. The search strategy will be adjusted according to the characteristics of different databases. Table 2.32.3.1RCTs about amiodarone combined with beta-blockers  for the maintenance of sinus rhythm of AF will be included without language restriction.2.3.2Adults (>18 years) who have any type of AF and in whom sinus rhythm had been restored.2.3.3The included studies should randomly assign patients to the intervention group and the control group. The intervention group should receive long-term oral treatment with amiodarone combined with a certain β-blocker at an appropriate dose and aim at preventing the recurrence of AF and maintaining sinus rhythm.2.3.4The control group will be given amiodarone alone, or a placebo.2.3.5Primary outcomes are as follows:(1)The recurrence of AF  will be measured by electrocardiogram or 24 hours dynamic electrocardiogram.(2)The frequency of embolization complications .Secondary outcomes are as follows:(1)Symptom improvements, including palpitations, chest tightness, dizziness, blackness, fatigue, and other symptoms.(2)Adverse events, as reported by the individual trials: cardiac arrest, ventricular dysrhythmia, atrial flutter with 1:1 atrioventricular conduction, hypotension, and bradycardia.2.4All the retrieved titles and abstracts will be read and selected by 3 authors  independently based on the inclusion and exclusion criteria. For the studies that initially meet the selection criteria, we will read the full text to determine their eligibility. In addition, the search of the references of the selected studies will be also conducted. The inconsistency between the 3 authors will be finalized by the corresponding author (YHH). The literature retrieval of this study will be conducted by the PRISMA flowchart, as shown in Figure Two authors (SS and GZY) will perform the data extraction independently. Standardized electronic data collection forms implemented by Microsoft Excel will be used to extract the following data: study design, diagnosis, number of participants, intervention types, outcomes, results, risk of bias assessment, and main conclusions.2.5 The risk of bias tool includes 6 domains of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. All divergences will be solved by consensus. Each study will be classified as high or low risk in each domain at the study level and outcome (conversion to sinus rhythm) level.The risk of bias of all included studies will be assessed independently by the Cochrane review handbook.2.62.6.12 test and I2 statistic. The sources of heterogeneity will be explored by subgroup analysis and sensitivity analyses.If there are 2 or more RCTs that meet the inclusion criteria and report the same outcomes in comparable populations, we will use a random effects model to conduct a pairwise meta-analysis for each treatment. The standard pairwise meta-analysis will be performed by Stata V.14.0 software. Risk ratio (RR) and 95% credibility interval (CI) will be used for dichotomous outcomes, mean differences, or standard mean differences (SMDs) with 95% CI will be used for continuous outcomes. Clinical and methodological heterogeneity of the trials will be assessed by the χ2.6.2 We will use node-split approach to contrast the direct evidence with the indirect evidence on each node of the network when we assess the evidence for consistency in the networks.Consistency check is one of the major assumptions that NMA relies on.2.6.3We will complete the NMA by using Stata V.14.0 and WinBUGS 1.4.3  are directly compared and which are indirectly compared through one or more general intermediaries. A complex statistical model will be built by a Bayesian software program, and the Markov Chains Monte Carlo simulation technique will be used to generate samples. The initial burn-in period will be set to 5000 iterations for convergence, then the posterior summaries will be set to a further 30,000 iterations. In addition, the surface under the cumulative ranking curve (SUCRA) will be presented as well to rank the probabilities of all prevention interventions for each outcome.Research Council Biostatistics Unit, Cambridge, UK).2.6.4We will perform subgroup analyses according to age (age ≤60 and >60 years), gender , AF types , and location . Furthermore, we will conduct a sensitivity analysis to check each study sequentially and combine the remaining studies to identify the impact of each study on the overall outcome.2.6.5 According to the GRADE working group recommendations, we will assess the evidence quality to estimate the AF treatment effect of NMA. We will present the direct and indirect treatment estimates and the NMA estimate for each comparison of the evidence network.In order to assess the treatment quality of NMA, the assessment of the direct, indirect, and mixed evidence is necessary, as well as quality ratings for direct and indirect comparisons.2.7It is not necessary for ethical approval because it is based on published studies. The protocol will be disseminated in a peer-reviewed journal or presented at a topic-related conference.3 amiodarone showed some advantages over the Class I and other Class III drugs with 1-year follow-up. Amiodarone is a multi-ion channel blocker with anti-arrhythmic effects. It reduces the autonomy and conductivity of autonomous cells by blocking the INa, IKr, and L-type calcium channels. It is more effective in preventing the recurrence of AF, and it does not produce obvious pre-arrhythmia and increase the mortality. However, amiodarone has significantly more adverse reactions than placebo, and it is well known that its adverse reactions frequency increase with time. Therefore, clinically, amiodarone is often used in conjunction with beta-blockers to increase efficacy and safety. To the best of our knowledge, this will be the first systematic review concerning this topic. Considering the importance of maintaining sinus rhythm in the treatment of AF, we hope this systematic review can provide the health care workers with more high-quality evidence to choose antiarrhythmic drugs, amiodarone, and β-blockers for patients with AF.This systematic review will provide updated evidence for amiodarone combined with beta blockers to maintain sinus heart rate in patients with AF. According to a Cochrane systematic review,Conceptualization: Shuqing Shi, Jingjing Shi.Data curation: Shuqing Shi, QiuleiJiaMethodology: Shuai Shi, Guozhen YuanProject administration: Yuanhui HuWriting – original draft: Shuqing Shi, Jingjing ShiWriting – review & editing: Shuqing Shi, Qiulei Jia.