Electroacupuncture has been widely used to treat functional constipation. But its efficiency has not been scientifically and methodically evaluated. The objective of this study is to evaluate the efficiency and safety of the electroacupuncture treatment for functional constipation in adults.This protocol of systematic review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P). We will conduct the literature searching in the following electronic databases: the Cochrane Library, MEDLINE, EMBASE, Web of Science, Springer, the Chinese Science Citation Database (CSCD), China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), Wanfang, and the Chinese Scientific Journal Database (VIP). The time limit for retrieving studies is from establishment to July 2020 for each database. All published randomized controlled trials (RTCs) related to this review will be included. Review Manager (V.5.3.5) will be implemented for the assessment of bias risk and data analyses. The selection of the studies, data abstraction, and validations will be performed independently by 2 researchers.This review will assess the clinical efficacy and safety, as well as the acupoints characteristics of electroacupuncture on functional constipation (FC) in adults.This review will summarize the current evidence of electroacupuncture on FC outcomes and provide guidance for clinicians and patients to select electroacupuncture for FC in adults.This protocol of systematic review has been registered on PROSPERO website (No. CRD42019146715). The direct cost of constipation ranges from $1912 to $7522 per year per patient. Nowadays, electroacupuncture has been widely used clinically by doctors of traditional Chinese Medicine, gastroenterology department to treat FC with satisfied efficacy.–18 However, no relevant review or protocol has been published to date. Therefore, it is necessary to conduct evidence-based review to evaluate the efficacy and safety of electroacupuncture for FC in adults. It is urgently needed to accomplish this review.Electroacupuncture therapy is an external therapy used in traditional Chinese medicine. By adding external electrical stimulation to traditional acupuncture, the stimulus gets doubled and the therapeutic efficacy gets enhanced accordingly. It is an emerging therapy that combines acupuncture with electrical stimulation.2https://www.crd.york.ac.uk/prospero/#myprospero. The protocol will be strictly developed under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) and Cochrane Handbook for Systematic Reviews of Interventions.The protocol for this review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019146715) on 16 December, 2019. Available online: 2.12.1.1As the randomized controlled trials (RCTs) are reliable and feasible, RCTs will only be included. After the research, published clinical trials which reported the efficacy and safety on electroacupuncture for FC will be included. Literature of animal research, case reports, reviews, meta-analyses, retrospective studies, and non-RCTs will be excluded.2.1.2Patients aged ≥18 years and diagnosed with FC according to ROME II, III, or IV criteria will be included, without limits on gender, age, race, nationality, and medical units.2.1.3We will include the studies using electroacupuncture as the sole intervention in the experimental group, while we have no restrictions on intervention in the control group. Studies involving electroacupuncture combined with other therapies will be included if the other therapies are used equally in both THE experimental and control groups.2.1.4The main outcomes of this review include the mean weekly complete spontaneous bowel movements (CSBMs). Additional outcomes of this review include mean weekly spontaneous bowel movements (SBMs), mean scores for stool consistency and straining of SBMs, and Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL score).2.22.2.1The electronic databases of the Cochrane Library, MEDLINE, EMBASE, Web of Science, Springer, the Chinese Science Citation Database (CSCD), China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), Wanfang, and the Chinese Scientific Journal Database (VIP) will be searched from the establishment to July 1st, 2020. All published RCTs on this subject will be included. Exemplary search strategy of MEDLINE is listed in Table Relevant keywords were used to create search strategies, as listed in Table The MEDLINE search strategy in Table 2.32.3.1Two reviewers (NL and XA), who will be told the aim and process of the system review, will select the trials and studies independently according to the criteria for inclusion by reading the titles and abstracts; if necessary, the full text will be read for further assessment. The discrepancies in the process will be discussed and solved using RHW. Details of the research choices are shown and exclusive studies will be listed and explained. The process of study selection will be presented in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram Fig. . To ensu2.3.2An electronic form will be established via Excel to extract substantial contents, and then filled by 2 reviewers independently. Information was extracted from the qualified articles by using a standardized data extraction form as follows: authors’ name, year of publication, country, study design, age and gender of patients, intervention, sample size, outcomes, adverse events, and follow-up. Disagreements will be solved by group discussion or consulting seniors. However, if we fail to reach a consensus, the authors of trials will be contacted for further details and verification.2.3.3If any data information is not sufficient in the included trials, we will try to contact the first or corresponding author by email or phone, requesting adequate information and details of the studies included to retrieve missing or insufficient trial data. However, if the author is not available or sufficient information cannot be obtained, we will have a group discussion and analysis based on the current information. Meanwhile, the potential impact of missing data will be taken into account, and a relative discussion will be presented in the result section.2.3.4Two independent authors assess the risk of bias of each included article according to the Cochrane Handbook for Systematic Reviews of Interventions. The methodological quality will be evaluated from the following domains: random sequence generation, allocation concealment, blinding of participants and therapists, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. The judgements on these items will be categorized as “low risk of bias,” “high risk of bias,” or“ unclear risk of bias.” Discrepancies will be resolved by negotiation or by consulting other reviewers.2.3.5Dichotomous data and continuous variables are included in the outcomes of interest, and we will use the risk ratio (RR) to express dichotomous data and use mean difference (MD) to assess differences in the continuous outcomes between the groups. Although different methods for the measurement of outcomes are used in different trials, we will choose standardized mean difference (SMD) if they have the same outcomes. The corresponding 95% confidence interval (CI) for each parameter will be calculated between the electroacupuncture treated group and the control group. We will choose a descriptive review if quantitative synthesis is not appropriate.2.3.6P < .5 will be defined as statistically significant between studies. The heterogeneity of studies will be evaluated by I2 statistic. The following criteria will be used: I2 < 50% will be deemed as low heterogeneity; I2 between 50% and 75% will be considered as moderate heterogeneity; I2 > 75% will be considered as high heterogeneity.The research will be performed with RevMan5.3.5 software. 2.3.7When heterogeneity is high, we will perform a subgroup analysis based on different controls, intervention time, treatment frequency, follow-up duration, and outcome measurements. We will also tabulate the adverse reactions and then perform an evaluation.2.3.8If possible, a sensitivity analysis will be performed to verify the robustness of the review conclusions. The impact of methodological quality, sample size, and missing data will be assessed. In addition, the analysis will be repeated after the exclusion of low methodological quality studies.3FC is one source of distress. This disease has brought physical, psychological, and economic burdens to many people in many countries and has brought great suffering. It has aroused more and more concern all over the world. Electroacupuncture (EA), derived from the integration of traditional acupuncture and modern electrical stimulation, is another type of acupuncture. Now, EA has become more and more widely used in FC because it is a relatively straightforward, safe, and cheap therapy compared with other conventional therapies. But at the present, there is no systematic evaluation report on its therapeutic effectiveness and safety for the treatment of FC.The protocol of this systematic review study aims to assess the efficacy, safety, and cost benefits of acupuncture in the treatment of FC in adults. Meanwhile, we have tried our best to search and found that no relevant systematic review and meta-analysis concerning this topic has been reported in the last 5 years, and we will integrate the latest and most comprehensive clinical evidence in this field, hoping to offer a greater variety of treatment options for patients with FC and inspire more peer experts and doctors to carry out as many relevant studies as possible in the future.Conceptualization: Na Li, Ruihui Wang.Data curation: Na Li, Xia Ai, Xinrong Guo, Juan Liu, Dong Wang, Lei Sun, Rongchao Zhang.Investigation: Xinrong Guo.Methodology: Na Li, Xia Ai.Validation: Ruihui Wang.Visualization: Na Li.Writing – original draft: Na Li, Xia Ai.Writing – review & editing: Na Li, Ruihui Wang, Lei Sun.


Lifestyle choices reflect the beliefs that individuals attribute to aspects of life. This construct can be assessed with the Individual Lifestyle Profile (PEVI) questionnaire, which measures elements of Nutrition, Physical Activity, Preventive Behaviors, Social Relationships and Stress Management.The objective of this study was to estimate the psychometric properties of the PEVI applied to a sample of Brazilian university students, identifying the prevalence of each lifestyle component according to participants’ age, sex, weight status, course area/field and economic stratum and to estimate the contribution of these characteristics on physical and psychological lifestyle.2/df), Comparative Fit Index (CFI), Tucker-Lewis Index (TLI) and Root Mean Square Error of Approximation (RMSEA). First-order and second-order models  were tested. Prevalences of lifestyle components were calculated and compared by participants’ age, sex, weight status, course area/field and economic stratum. A hypothetical causal structural model was elaborated to investigate the impact of sample characteristics on physical and psychological lifestyles. This model was evaluated considering the global fit to the data  and the hypothetical causal trajectories (β) (α = 5%).The PEVI data was analyzed by confirmatory factor analysis, using the indexes chi-square per degrees of freedom ratio  and second-order  models. There was a higher prevalence of unfavorable physical and psychological lifestyle choices among females, among underweight and obese individuals, in older students and in those with lower economic strata. Moreover, negative behaviors in physical lifestyle were more prevalent in students from human/social/exact sciences and worse psychological lifestyle was observed among health sciences students. These results were confirmed by a structural model.A sample of 1,303 students was used. The mean age was 20.9 (standard deviation = 2.8) years, 66.8% of participants were females, 63.4% had weights in the normal range and 73.7% were students of the social and exact sciences. The PEVI data showed an adequate fit for both the first- (χThe PEVI data presented validity and reliability. Negative lifestyle choices had high prevalence among students. Moreover, individual characteristics had different impact on physical and psychological lifestyle choices. Lifestyle can be defined as a set of choices and actions reflecting one’s overall beliefs, values and attitudes towards life . These aStudies  indicateFANTASTIC” ) )  are someAlthough the PEVI (which has a five-pointed star as a symbol) has been employed in lifestyle studies, the instrument was originally developed with educational and clinical awareness purposes . In addi95%): [71.3–71.7])) and physical activity (62.8% (CI95%: [62.6–63.0])), which reinforces the concerns regarding the long term effects in the population.The PEVI has already been used in various contexts, such as among physical education professors  and univCharacteristics such as sex and weight status can also contribute to lifestyle choices . AccordiSeveral studies on health-related issues select samples from the health sciences student population . As futuThe objective of the present study was to estimate the PEVI’s psychometric properties when applied to a sample of Brazilian university students, identify the prevalence of each lifestyle component according to age, sex, weight status, course area/field and economic stratum and estimate the contribution of these characteristics on physical and psychological lifestyles.This was a cross-sectional observational study with a non-probabilistic convenience sample. Students between the ages of 18 and 40 years enrolled in undergraduate courses at a Brazilian public university were invited to participate.A minimum sample size was estimated according to Data related to sex, age, university course area/field and the time of day classes are held , weight, height and economic stratum were also collected. The participants’ body mass index (BMI) was estimated from their self-reported weight and height and cross-referenced with the World Health Organization  proposalData collection was performed in classrooms during normal class, after scheduling and authorization by the class professor. Before filling out the instrument, students were informed of the purpose of the research and made aware that participation was voluntary and anonymous. The students who agreed to participate signed the Informed Consent Form, and filled out demographic data and PEVI questionnaires. The study was approved by the Ethics Committee for Human Research of the School of Pharmaceutical Sciences of UNESP at the Araraquara campus (CAAE: 63553516.4.0000.5426).The PEVI was originally developed in Portuguese by Nahas, Barros and Francalacci  to evaluThe overall score is calculated by averaging the responses given to the items in each factor. Studies have evaluated the prevalence of adequate and inappropriate behaviors for each factor based on the scores  . Nahas, The PEVI’s psychometric properties have been assessed only through exploratory factor analysis . HoweverDescriptive statistic and shape measures (skewness and kurtosis) were performed. A normal distribution was considered when absolute values of skewness and kurtosis were lower than 3 and 7, respectively .2/df), Comparative Fit Index (CFI), Tucker-Lewis Index (TLI) and Root Mean Square Error of Approximation (RMSEA). The fit was considered adequate when χ2/df ≤ 5.0, CFI and TLI ≥ 0.90 and RMSEA ≤ 0.10 (p < 0.001) were also analyzed  with a robust weighted least squares method adjusted for mean and variance (WLSMV). The fit of the model to the data was evaluated using the chi-square per degrees of freedom ratio   and considered appropriate if ≥0.50 . Discrimj (rij2) .The reliability of the instrument was estimated from the Composite Reliability (ω)  and the n = 635) was applicable to an independent sample of the same population  using invariance analysis  for each PEVI component factor, as well as for the second-order model, according to sex, weight status, course area/field, age and economic stratum. It should be noted that for age range, prevalence of the lifestyle choices of individuals with 30 years or more was not presented in results because the sample size was small (n = 25).After confirming the PEVI’s validity and the reliability to the sample, the mean scores of the Nutrition, Physical Activity, Preventive Behavior, Social Relationship and Stress Management dimensions were calculated. The mean scores of the Physical and Psychological Lifestyle dimensions (for the second-order model) were also calculated. Based on scores, subjects were grouped according to the lifestyle division of the original proposal  into fav2/df ≤ 5.00, CFI and TLI ≥ 0.90 and RMSEA ≤ 0.10  was adopted. When necessary, the model was refined by stepwise regression using the backward elimination method considering non-statistical significance of some trajectories (p > 0.05).To investigate the impact of sample characteristics on physical and psychological lifestyles, a hypothetical causal structural model was constructed using structural equation modeling. In this model, the physical and psychological lifestyles components were considered dependent variables and sample characteristics were inserted as independent variables in the model. The models were analyzed in two stages. In the first stage, the global fit to the data was verified using the reference values χA ≤ 0.10 . In the A total of 1,357 students agreed to participate, but only 1,303 fully completed the PEVI (response rate = 96.0%) and were included in the final sample.2 . Additional demographic information of the sample is presented in The mean age of the participants was 20.9 years  and 66.8% were females. The mean BMI was 23.3 kg/mMost participants were enrolled in humanities and social sciences courses, in the first and second years of the course (62.8%), attended classes during the day (morning/afternoon/full-time periods—65.3%), belonged to economic strata A or B (83.5%) , and had normal weight (63.4%).The descriptive statistics of participants’ answers to the PEVI’s items in the test and validation samples are shown in No significant deviation from the normal distribution was observed for any of the PEVI items, underscoring the appropriate psychometric sensitivity of the items.The PEVI model fitted to the data, considering the confirmatory analysis of the “Test” and “Validation” samples. Moreover, strict invariance was found according to the CFI test (ΔCFI) between independent samples. These results are presented in The original PEVI model presented an overall adequate fit to the sample, however, convergent validity and reliability were not optimal. Model refinement was performed and the items with low factor loading were deleted. After refinement , validity and reliability estimates of the Preventive Behaviors factor were reduced. Considering that the fit of the overall model to the data was adequate and that the refinement did not improve convergent and discriminant validity and reliability estimates, the original theoretical proposal by Nahas, Barros and Francalacci  was mainThe total prevalence of individuals grouped according to negative, intermediate and positive options of the first and second-order lifestyle models and according to sex, course area/field, weight status, age and economic stratum is shown in A greater number of individuals grouped in the Negative lifestyle choices was found across the total sample when evaluating the Nutrition and Physical Activity dimensions. In relation to the other aspects, most participants demonstrated favorable lifestyle choices/positive behaviors. When considering the second-order aspects/model, there was a higher prevalence of people with a negative lifestyle for the Physical aspect and positive for the Psychological aspect.A greater number of females with unfavorable lifestyle choices in Physical Activity, Social Relationships and Stress Management was observed. For males, a higher prevalence of unfavorable lifestyle choices was found in the Nutrition and Preventive Behavior dimensions. For the second-order model, there was a higher prevalence of females with negative lifestyle for the Physical and Psychological aspects compared to males.Regarding the course area/field, a negative behavior was more prevalent in Nutrition and Preventive Behaviors among humanities, social and exact sciences students. In turn, among health sciences students, a higher prevalence of negative lifestyles related to Physical Activity, Social Relationships and Stress Management was found. For the second-order model, worse Physical lifestyle choices were found among humanities, social and exact sciences students and worse Psychological lifestyles were seen among health sciences students.The proportion of obese participants with unfavorable lifestyle choices across the Physical Activity, Social Relationships and Stress Management dimensions was significantly higher than participants with non-obese weight status. For the second-order model, a higher prevalence of underweight and obese individuals had a negative lifestyle for the Physical and Psychological aspects, respectively, compared to individuals with normal weight.Regarding age, a higher proportion of older students had negative lifestyles choices. Furthermore, a higher prevalence of individuals in economic strata C, D and E (people with lower purchasing power than people of A and B strata) also had negative lifestyles.2/df = 5.09, CFI = 0.88, TLI = 0.92 and RMSEA = 0.06); however, non-significant trajectories (p > 0.05) were found. After the stepwise procedure, the model achieved more adequate fit to sample ; regarding χ2/df index, it was influenced by sample size, and thus, it cannot be considered without other indexes to accept or reject model’s fit. Sex and age were significant for the physical lifestyle component and sex, course area/field and economic stratum were significant for the psychological component. The representation of the structural model is shown in The complete model  fitted marginally to the data  and positive choices for Psychological aspects of lifestyle . There was a higher prevalence of negative choices in both the Physical and Psychological components among females, underweight and obese individuals, in older students and in those with lower economic strata. Moreover, different deficits regarding lifestyle choices were observed according to course area/field.The theoretical model proposed for the PEVI demonstrated an adequate fit to data. The low convergent validity and reliability observed in some of the instrument’s factors can be justified by the low number of items per factor and the factor loading of the Preventive Behavior component . HoweverThe data obtained showed that the assessment of lifestyle from a hierarchical model is pertinent since the model presented adequate fit to the sample and reflected the original theoretical conception  of the i95% [69.1–69.5])) and Stress Management ) among college students was also high, which suggests that college students have a good psychological lifestyle. Perhaps the autonomy and enthusiasm related to the integration into the university environment may favor social interactions, exchange of experiences and leisure opportunities. Thus, to promote healthier lifestyles among these young people, professors and health professionals should focus on strategies to improve mainly the Physical dimensions of lifestyle choices.Students in general presented unfavorable lifestyle choices for the Nutrition and Physical Activity aspects, which might be related to their difficulty in managing the daily university routine , due to Similar to our study, the difference in prevalence of males and females with an unfavorable lifestyle in PEVI’s components was also observed in the study carried out by The low weight and obese subgroups had higher prevalence of unfavorable behaviors. The worse physical lifestyle choices among humanities/social and exact sciences students compared to health sciences students can be associated with the health-related content of health sciences courses . This acWe found that older individuals presented a better physical lifestyle. The present study does not establish causal relationships since it was a cross-sectional study. However, the presented findings are properly supported by validity and reliability estimates. Moreover, the performed analysis can be useful in the evaluation of lifestyle choices among Brazilian young adults. The generalizability of the results may be hampered by the non-probabilistic sampling. Additionally, we suggest that future studies be conducted in order to incorporate more psychosocial aspects , which can be related with lifestyle choices.The findings on lifestyle components in different subgroups provided information that may help the establishment of targeted preventive-educational interventions, such as nutritional education, physical activity information, and promotion of health-related preventive behaviors and healthy pleasures.The PEVI questionnaire demonstrated validity and reliability in the evaluation of lifestyle among university students. Females, underweight and obese individuals, older students and individuals with lower economic strata had significantly more unfavorable lifestyles both in the physical and psychological aspects. The physical and psychological negative lifestyles also differed according to students’ course area/field. These findings may guide the planning and implementation of health promotion interventions, designed to foster the adoption of healthier lifestyles, considering the inherent characteristics of university students.10.7717/peerj.9830/supp-1Supplemental Information 1Each chunk in R file represents one analysis.Click here for additional data file.10.7717/peerj.9830/supp-2Supplemental Information 2Raw data related to students’ characteristics and answers of PEVIClick here for additional data file.10.7717/peerj.9830/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.9830/supp-4Supplemental Information 4Click here for additional data file.


The associations between maternal use of antidepressant during pregnancy and preterm birth (PTB) has been the subject of much discussion and controversy. The aim of the present study was to systematically review the association between antidepressant use during pregnancy and the risk of PTB, especially in depressed women.June 30, 2019, supplemented with a manual search of the reference lists, to identify original research regarding PTB rates in women taking antidepressants during pregnancy. A random-effects model was used to calculate the summarized relative risks (RRs) and 95% confidence intervals (CIs). The potential for publication bias was examined through Begg' s and Egger' s tests.A computerized search was conducted in PubMed, PsycINFO, and Embase before A total of 2,279 articles were reviewed, 23 of which were selected. The risk of PTB was increased in women with depression [1.58 (1.23−2.04)] and in the general pregnant female population [1.35 (1.11−1.63)] who used antidepressants during pregnancy. Similar results were observed in depressed women treated with selective serotonin reuptake inhibitors (SSRIs) during pregnancy [1.46 (1.32−1.61)]. There was no significantly increased risk of PTB observed with SSRI use in the general pregnant female population [1.25 (1.00−1.57)], and the heterogeneity of these studies was high.The results of this meta-analysis indicate maternal antidepressant use is associated with a significantly increased risk of PTB in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with antidepressant during pregnancy. Preterm birth (PTB), defined as delivery prior to 37 weeks of gestation, is regarded as a global public health concern, since it is the leading cause of infant mortality worldwide . In compMany factors are thought to contribute to the increased PTB rate, including a higher mean maternal age, more frequent use of assisted reproductive technologies and a resulting increase in multiple gestations, and higher rates of preterm inductions and cesarean deliveries . InteresTherefore, in the present study, a meta-analysis of all available studies was conducted to quantitate the strength of the relationship between antidepressant use during pregnancy and PTB especially in depressed women.June 30, 2019. The search queries used are listed in The PubMed, PsycINFO, and Embase databases were searched for related articles published before Eligibility criteria were defined as: (1) articles available in English with the full text provided; (2) studies conducted in humans; (3) prospective cohort studies; (4) antidepressant use as the study exposure and PTB as the study outcome; (5) antidepressant use during pregnancy; (6) no psychotropic drug use in the control group; and (7) reported risk ratio or adequate data for the calculation of an effect size as a relative risk (RR) between antidepressant use and PTB.The study quality of eligible articles was assessed by two reviewers (X-YM and X-RX), who subsequently extracted data from each selected article including the study design, sample size, data source, criteria for inclusion/exclusion, definition of exposure, definition of outcome, outcomes with risk estimates and 95% confidence intervals (CIs), and adjusted confounders. The two reviewers extracted data independently and any disagreements were resolved by discussion with a third reviewer (QC), when necessary.For one study  that chaThe two reviewers independently performed a quality assessment using the Newcastle−Ottawa scale (NOS)  for cohoI2 value represents the percentage of total variation across studies due to heterogeneity rather than chance  was used for all statistical analyses. The mean effect size approach was used to pool estimates, which has been applied in other studies . The effn chance . Values n chance . A two-tg's test .If more than eight studies were available, potential sources of heterogeneity were explored by conducting subgroup analyses according to the following parameters: geographic location (Europe vs. North America or other regions) and adjustment for potential confounders (adjusted vs. unadjusted) including maternal age, ethnicity, maternal education, tobacco use, alcohol consumption, BMI during pregnancy, and parity. Heterogeneity between subgroups was evaluated by meta-regression analysis. To determine the influence of individual studies on each analysis of the estimated RR, sensitivity analysis was conducted that recalculated the pooled effect by omitting one study at a time. The population was divided into four groups: antidepressant use in the general pregnant female population, antidepressant use in pregnant women with depression, SSRI use in the general pregnant female population, and SSRI use in pregnant women with depression.A total of 2,278 potentially eligible articles were identified in PubMed, PsycINFO, and Embase. One additional study was added following a manual search of the reference lists. Following removal of 528 duplicate articles, the titles and abstracts were screened, and 1,577 irrelevant articles were removed. A total of 174 full-text articles were assessed for eligibility, and 23 (published between 2004 and 2019) were ultimately included in the present analysis. A flow diagram of study identification is shown in All prospective cohort studies assessing antidepressant exposure during pregnancy were included. Eight studies  were conAnalysis of the included studies using Newcastle−Ottawa criteria indicated that 21 studies were at a low risk and two studies  were at I2 = 75.8%, P < 0.001, Sixteen studies  in the gI2 = 9.7%, P = 0.365, Seven studies  in the pI2 = 85.6%, P < 0.001, Nine studies  in the gI2 = 0.0%, P = 0.432, Only four studies  in the pTo the best of our knowledge, this is the first meta-analysis of the impact of antidepressant use during pregnancy on PTB in depressed women. Our study focused not only on depressed pregnant women but also on the general pregnant female population, with 23 prospective cohort studies finally being selected. It was found that the risk of PTB was increased in depressed women treated with SSRIs during pregnancy. Similar results were observed in women with depression and in the general pregnant female population who used antidepressants during pregnancy. There was no significantly increased risk of PTB observed with SSRI use in the general pregnant female population.The focus of the present study was to explore the association between maternal use of antidepressants in depressed women during pregnancy and risk of PTB. Subgroup analysis shows that even though the use of antidepressants in the general pregnant female population significantly increased the risk of PTB, the heterogeneity was high, which may be due to the differences in population sources. There was a statistically significant difference in the European cohort study but not in the North American cohort study, which may be one of the sources of heterogeneity. Another reason for the high heterogeneity may be that there were confounding factors that influenced the conclusion. For this reason, a meta-regression analysis was conducted; when maternal age, tobacco use, and parity were defined, there was a statistically significant difference in the meta-regression, indicating that these may be confounding factors.P values were 0.27, 0.40, and 0.12, respectively, and the meta-regression was not statistically significant. Subsequently, the data were adjusted for certain confounding factors such as maternal age, ethnicity, maternal education, tobacco use, and alcohol consumption; however, the results were not ideal. Finally, a subgroup analysis of SSRI use in pregnant women with depression was performed, and it was found that the heterogeneity was 0%; therefore, a possible source of the high heterogeneity was not stipulating depression in the study population. However, there have only been four studies to date, and the present study suggests that future studies may be inclined to stipulate depression in the study population and to consider the effects of SSRIs or other antidepressants on preterm PTB, which is of great clinical significance.To further explore whether the heterogeneity originated from different drug types, subgroup analysis of SSRI use in the general pregnant female population was conducted, and it was found that the heterogeneity was elevated. A possible reason could be differences in the sources of the population. Firstly, according to geographic location, studies were divided into European, North American, and others; the P < 0.001); after limiting the population to depressed pregnant women, the OR was 1.79 (0.77−4.14). Moreover, a study by Currently, there exist four meta-analyses of the effects of antidepressant use on PTB (nearly 6 years) . The resThe present study describes a meta-analysis of 23 prospective cohort studies investigating the risk of PTB in women taking antidepressants during pregnancy, with additional analyses associated with a diagnosis of depression. The main strength is that it is a large meta-analysis including a large number of prospective cohort studies. Furthermore, to-date, evidence regarding associations between the use of antidepressant in depressed women and risk of PTB is limited. To the best of our knowledge, the present study is the first meta-analysis to investigate the associations between maternal antidepressant use in depressed women and the risk of PTB.Nevertheless, this study has several limitations, which should be considered when interpreting its findings. First, due to the limited number of included studies, the present study did not account for trimester exposure and either for duration of exposure in the analysis. Both factors may significantly modify the association between maternal use of antidepressant during pregnancy and PTB. The number of studies related to specific antidepressants are small for specific drugs  and did not allow for investigations into the dose-response. Second, heterogeneity was high among studies focusing on the associations between maternal antidepressant use in the general pregnant women and the risk of PTB. Our subgroup analysis suggested that the high heterogeneity might be attributed to differences in study locations and diagnosing of depression.The results of this meta-analysis highlights the association between maternal use of antidepressant during pregnancy and the risk of PTB. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with antidepressant during pregnancy.Y-HZ and QC designed and conducted the study. X-YM and X-XR collected, managed, and analyzed the data. QC, Q-JW, HS, and Y-HZ prepared, reviewed, and approved the manuscript. Y-HZ had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This work was supported by National Key R&D Program of China (No. 2017YFC0907403 to Y-HZ); Liaoning Revitalization Talents Program (No. XLYC1802095 to Y-HZ); Key R&D Program of Liaoning Province (No. 2019JH8/10300005 to Y-HZ); the Science and Technology Project of Liaoning Province (No. 2019JH6/10400002 to Y-HZ); Young Talents of Education Ministry of Liaoning Province (No. QN2019011 to HS). The other authors declare no conflicts of interest in relation to this study.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.


Expanding agribusiness in Northern Mexico has increased demand for workers from Southern Mexico, with hundreds of thousands migrating for work annually. Extreme temperatures, physical labor, and low fluid consumption place workers at risk for heat strain and dehydration, commonly underreported hazards in the agricultural industry. The objectives of this pilot study were to assess heat exposure and hydration status of a population of migratory agricultural workers in Northern Mexico throughout the grape harvest season. In addition to demographic information, environmental conditions, hydration status, and core body temperatures were collected. The majority listed Chiapas as their home state, nearly half spoke an Indigenous language, and none had completed high school. The wet-bulb globe temperature was significantly higher during the harvest and post-harvest seasons compared to the pre-harvest season. Across the different seasons, the majority were dehydrated post-shift, and mean core body temperature of workers was not significantly different. This project highlights the need for targeted interventions to improve hydration and prevent heat stress in this region. As the number of warm days is expected to rise each year worldwide, it will be increasingly important to engage in practices to protect vulnerable populations, such as migratory agriculture workers. Agricultural workers participate in strenuous tasks and experience an array of occupational risks and hazards. High humidity and extreme ambient temperatures coupled with heavy physical labor and low fluid consumption place individuals at risk for heat strain and dehydration, serious and commonly underreported hazards in the agricultural industry ,2,3,4,5.The Northwestern state of Sonora, Mexico comprises approximately 95% arid or semi-arid land characterized by lack of precipitation and high temperatures ,14. ExpaExposure to heat can cause a range of adverse health effects including damage to major organs and even death if the core temperature of the body exceeds 42 °C ,22,23,24To the best of our knowledge, no investigations to date have examined both exposure to heat stress and hydration status in migratory farmworker populations in Sonora, Mexico. Therefore, the objective of this pilot study was to assess the heat and hydration status of a vulnerable occupational group at different points during the growing season in Northern Mexico. Furthermore, this project aimed to describe the demographics and occupational history of a largely invisible population in order to provide effective recommendations and inform future study and intervention design.We conducted a cross-sectional study to evaluate heat exposure and hydration of farmworkers. Migratory farmworkers were recruited from a commercial grape farm near Hermosillo, Mexico in March, June, and August 2016 to capture the pre-harvest, harvest, and post-harvest seasons, respectively. During the pre-harvest season in March, workers trim and shape young grape plants to prepare the plants for optimal production. In the June harvest season, workers cut grape bunches from the plant and then weigh and package the fruit for sale. Post-harvest, in the month of August, workers complete a myriad of tasks, from clearing fields to driving tractors. The participants were recruited at the end of each workday with the assistance of the farm physician and engineering teams. A bilingual investigator screened potential participants in Spanish and obtained written consent for participation in the project. The sampling procedure was explained to participants in Spanish and all sampling equipment was shown to participants to ensure they were comfortable with the sampling methods. At the conclusion of the field study, each participant received a small monetary compensation. The individuals that participated in March were included in the June assessment. By August, the majority of workers from the original March cohort had returned to their home state or had transferred to a different farm. As such, a new group of participants was recruited in August. Before the initiation of the study, all participant and data-related methodology was approved by the University of Arizona Human Subjects Protection Program.In the months of June (harvest season) and August (post-harvest season), participants completed a questionnaire administered orally in Spanish at the conclusions of the workday. The questionnaire included questions regarding demographic information, work history, and worker-reported heat and hydration experiences including experiences from the day of sampling.Workers were given an ingestible core body sensor to swallow  and assigned a core body temperature monitor to wear around the waist to receive the sensor signals throughout the workday . The monitors were set to record temperatures every 10 s and were checked periodically throughout the workday by the investigators.eff). Following ACGIH guidelines, clothing, metabolic rate, and the natural wet-bulb temperature, globe temperature, and dry-bulb temperature of the environment were measured and incorporated in the Wet-Bulb Globe Temperature (WBGT) calculation to assess workers’ heat exposure. WBGT measurements were taken in the sun and in the shade using a handheld electronic heat stress monitoring device periodically throughout the day , recorded in a field notebook, and later transcribed into an electronic spreadsheet. The handheld WBGT device was carried by the investigators through the fields to ensure that measurements were taken in the immediate work areas during the workday. Observations about metabolic rate and clothing were recorded. To estimate the metabolic rate, observations of individual worker arm movement, leg movement, working speed, trunk movement, pushing and lifting, tool usage, and lateral and vertical movement were recorded. The metabolic rate, measured in watts (W), was then estimated using the ACGIH Table for Metabolic Rate Categories and the Representative Metabolic Rate with Example Activities . ClothinPost-shift and morning void urine samples were collected, refrigerated on-site, and transported in ice chests to the University of Arizona within 24 h. Urine specific gravity was measured using a pocket refractometer  by placing one drop of each participant’s urine onto a calibrated refractometer and recording the digital readout. Specific gravity from 1.020 to 1.029 was categorized as mildly dehydrated and 1.030 and above categorized as clinically dehydrated ,39,40. Core body temperature data was downloaded using HQ Inc. CorTrak Software and trimmed to exclude biologically implausible numbers that would indicate a body temperature lower than extreme hypothermia or higher than hyperthermia . The percentage of time during the workday that the core body temperature was between 37 to 38 °C and over 38 °C was calculated . Descripn = 25 (89.2%)), nearly half spoke an Indigenous language in addition to Spanish (n = 12 (42.9%)), most were between the ages of 18 and 24 (n = 17 (60.7%)), and none had completed high school (n = 17 (60.7%)), working at the current farm for three to five months (n = 15 (53.6%)), were contracted by the season (n = 20 (71.4%)), paid by the day (n = 17 (60.7%)), and worked 10 h per day, seven days per week (n = 13 (46.4%) and n = 15 ((53.6%), respectively)  . The WBGT was measured and recorded at multiple points during each sampling day in March, June, and August. Measurements were taken in both the sun and shade, as workers were continually moving in and out of the shade provided by the grape vines. The workers wore standard work pants, long sleeve shirts, caps, and some wore an additional sweater or jacket layer on their top half. To assess metabolic rate, observations of work activities and work intensity were recorded. In March, the pre-harvest season, the research team observed the workers moving very quickly through the rows of grape vines, trimming and shaping the plant with arms in front of the body, oftentimes stooping low to reach branches or reaching high overhead. The workers frequently ran between rows. As such, the metabolic rate ranged from 300 to 415 W, or moderate to heavy following the ACGIH Metabolic Rate Categories and the Representative Metabolic Rate with Example Activities. The minimum, mean, and maximum WBGT, both in and out of direct sunlight, for March were 13.9 °C, 16.6 °C, and 20 °C, respectively. For all clothing ensembles and metabolic rate combinations, the workers were either below or reaching the ACGIH TLV Action Limit for Heat Stress . eff to the metabolic rate in During the harvest month of June, the research team observed that each worker was responsible for walking down a row of grape vines, cutting off ripe bunches, stacking approximately 10 bunches into a box, and carrying the box to a packaging station. Each worker individually packaged their collected bunches and returned to the row to cut more bunches once packaging was complete. The pace of this work was light to normal. Several workers were responsible for collecting packaged products in wheelbarrows or carts and transporting them to a large trailer nearby. To represent the work completed in June, a metabolic rate range of 180–300 W was used.. A comparison of the WBGTeff reached the ACGIH Action Limit, with mean and maximum temperatures reaching and exceeding the TLV, depending on the clothing ensemble (p < 0.01). During the month of August, which was considered the post-harvest season, the research team observed the workers completing a variety of tasks, including: shoveling manure, operating open cab tractors, trimming new grape vines, and other maintenance around the farm as needed. While the fieldwork was very slow paced and required only small movements of the arms and legs, those shoveling were working at a heavy metabolic rate. All WBGTensemble . The minAs shown in p = 0.26).The core body temperature of 24 workers was measured, with measurements for eight workers in each month . Approxieff below the ACGIH Action Limit after incorporating the WBGT and clothing ensemble. During the harvest season in June, worker metabolic rates ranged from 180 to 300 W, surpassing the ACGIH Action Limit and ACGIH TLV with some WBGT and clothing combinations. In August, the post-harvest season, worker metabolic rates ranged from 180 to 415 W, exceeding the ACGIH Action Limit and ACGIH TLV with some WBGT combinations. Hydration status was largely inadequate by the majority of workers during all months. In the most extreme example, over 40% of post-shift urine specific gravities during the month of June were over the threshold for clinically determined dehydration, and almost all others (57%) were considered mildly dehydrated. The levels of dehydration are surprising given the difference in environmental conditions during the three sampling periods, with March, June, and August WBGT measurements averaging WBGTs of 16.6 °C, 26.4 °C, and 26.4 °C, respectively. Workers’ core body temperatures spent little time over the ACGIH TLV of 38 °C during the three sampling events, but did spend at least 80% of the workday between 37 °C and 38 °C.The findings from this study suggest that dehydration and heat stress are important and interconnected health outcomes in table grape workers in Sonora, as dehydration status of the body can moderate the response of the body to heat. Workers wore standard work pants, long sleeve shirts, caps, and some wore an additional sweater or jacket layer on their top half during the workday. The metabolic rate ranged from 300 to 415 W in the pre-harvest season during the month of March, with the WBGTThis project was made possible by the outreach and communication efforts of the University of Arizona and Sonoran research partners over the past seven years. The ability to complete this type of work requires many years of trust and communication to take place; ideally, this farm can set an example for other agricultural entities in Mexico with regards to working and living conditions. It is important to note that the findings from this project are applicable on both sides of the U.S.–Mexico border, as the population, working conditions, migratory status, and climate are very similar. However, the workers included in this study were considerably younger than agricultural workers in studies that have taken place in the U.S. ,44,45. The research on migrant and seasonal farmworkers that make agricultural production possible in Northern Mexico is limited, especially regarding heat and hydration. This project highlights the need for concentrated efforts to improve hydration regardless of season, further investigate the practice of paying workers by the pound or piece, and implementation of heat stress prevention practices in the agricultural industry. This will require communication and cooperation between farm owners, medical teams, social workers, community health workers, and middle management. Future work should ensure that vocabulary used in written documents is appropriate given the level of education, consider translating into an Indigenous language, and have historical context for Chiapas and internal migration. The use of trained community health workers, usually farmworkers themselves, to communicate environmental and occupational health and hazards has been successfully utilized in agricultural worker populations and may be useful in improving hydration and heat stress outcomes . n = 48) were dehydrated [Dehydration is commonly reported in agricultural and other physically demanding occupational settings. A study of hydration status at a Costa Rican sugarcane field found that 50% of workers , and continuous recording of core body temperature. Heat stress, especially during summer months, is a major concern for agricultural populations completing physically demanding work. WBGT measurements in an observational study of 105 sugarcane workers in Costa Rica surpassed the U.S. Occupational Safety and Health Administration recommendations for avoiding heat stress by 9:15 a.m. . In a 20It is important to note that the on-site dormitories the workers sleep in are single-layer cinderblock structures, with two to three cinderblock sleeping bunks stacked vertically. Previous projects carried out by the research team revealed an average of eight square feet per person of floor space in the dormitories. The crowded dormitories rely on natural ventilation for airflow, including open doors and large cutouts near the top of the structures. During a summer 2015 housing assessment conducted by the research team, the temperature inside the dormitories exceeded 32 °C during the day, which may prevent workers from adequately cooling down when they are inside the dormitories overnight and when they are not working during the day . There were several limitations of this project that should be recognized to inform future endeavors. As with many other pilot projects, the small sample size limits the statistical power of any comparisons that are made. For recruitment purposes, we relied heavily on the assistance of the farm doctors and engineering teams to recruit participants for the study, making the sample recruitment partially driven by convenience. Additionally, some of the recruitment took place by word of mouth from worker to worker. This may have biased the type of workers that were included in the study. The heat assessment may have been strengthened by the following: measuring heart rate throughout the day to be able to calculate the PSI; asking about caffeine, diuretics, acetaminophen, and alcohol consumption; and measuring workers’ pre- and post-shift body weight. As mentioned previously, the metabolic rate and clothing ensemble estimations used in the WBGT calculation rely on subjective observations made by the research team; future endeavors should include an objective measure of energy expenditure, such as a continuously monitoring accelerometer or heart rate monitor. Unfortunately, we did not include the rate of temperature rise and response to rest in this manuscript as individual workers were not observed the entire duration of wearing the sensor. Therefore, we did not have a concrete record of their periods of rest and work. We hope to include this data collection and analysis in future endeavors. In all, this pilot study has helped uncover necessary measures and precautions that will be useful in future work.eff in the harvest and post-harvest seasons exceeded the ACGIH TLV for heat stress. The percentage of time workers’ core body temperatures were over the ACGIH TLV of 38 °C was minimal for most workers during the pre-harvest, harvest, and post-harvest seasons. However, core body temperatures between 37 °C and 38 °C made up over 80% of the workdays. As the number of warm days is expected to increase each year, it will be increasingly important to engage in preventive practices to protect vulnerable populations, such as migratory and seasonal agricultural workers. This project gives insight into the demographics, work practices, and occupational exposures of a potentially vulnerable and underserved population. Dehydration was measured (urine S.G. >1.020) in the urine of the majority of workers during all seasons, the mean urinary S.G.s of March post-shift, June post-shift, and August post-shift were 1.25, 1.025, and 1.02, respectively. The estimated WBGT


Quantitatively, three measurement methods, namely VOLPARA, Hand Delineation (HD) and ImageJ (IJ) were used to calculate breast density using the same set of cases, however, for VOLPARA only mammographic cases (n = 122) with full raw digital data were included. The agreement level between methods was analysed using weighted kappa test. Agreement between UK and USA radiologists and VOLPARA varied from moderate (κw = 0.589) to substantial (κw = 0.639), respectively. The levels of agreement between USA, UK radiologists, VOLPARA with IJ were substantial , and with HD the levels of agreement varied from moderate to substantial , respectively. This study found that there is variability between subjective and objective MBD assessment methods, internationally. These results will add to the evidence base, emphasising the need for consistent, simple and time-efficient MBD assessment methods. Additionally, the quickest method to assess density is the subjective assessment, followed by VOLPARA, which is compatible with a busy clinical setting. Moreover, the use of a more limited two-scale system improves agreement levels and could help minimise any potential country bias.In order to find a consistent, simple and time-efficient method of assessing mammographic breast density (MBD), different methods of assessing density comparing subjective, quantitative, semi-subjective and semi-quantitative methods were investigated. Subjective MBD of anonymized mammographic cases ( Mammographic breast density (MBD) represents the amount of fat and fibroglandular tissue, which is a mixture of fibrous tissue, glandular tissue, collagen and epithelial cells that line the ducts of the breast ,2. IncreSeveral methods of breast density classification have been developed, both subjective and quantitative ,7,8. StuYaffe, in 2008, described several other quantitative methods to measure and classify breast density subjectively or objectively . These iAlternatively, fully automated methods incorporate 3D measurements of dense areas, providing a more comprehensive assessment of the volume of dense breast tissue, which has been shown to be an indicator of increased risk of breast cancer ,18,19.Currently, there are a number of fully automated methods that quantitatively and objectively measure breast density ,21. One Many studies found an inter-rater variability between the subjective assessment and fully automated method in categorizing breast density ,24,25,26Furthermore, Ko et al. proposed reducing the BI-RAD’S and VOLPARA classification scale from four categories to just two, in order to minimize variations when categorizing MBD . The metBreast density notification legislation launched in many USA states from 2013 . AdditioMBD outcomes assist in defining an individualized patient imaging pathway for follow up imaging with the least amount of radiation exposure for the radio-sensitive breast tissues. Additionally, MBD is important for each patient’s breast cancer risk. A consistent categorization system has the potential to help reduce potential variations in breast density assessment . Such vaAn exemption from full ethical approval was granted by the University College Dublin, Human Research Ethics Committee (HREC). .Permissions were granted by the American Board of Radiology (ABR), AZ, USA, for their examiners and by the British Society of Breast Radiology (BSBR), Hertfordshire, UK, for their respective member attendees to be both recruited voluntarily as participants to undertake this study. Both participants were recruited via local advertising. USA and UK participants’ years of experience reporting mammographic cases were recorded. Additionally, UK participants confirmed that they all were breast radiologists.n = 250), comprised 180 cases and 70 repeated cases. These cases were collected as part of previous research, from 18 centres in a national breast screening programme, with full patient consent. Each mammography case included “Right and Left; Mediolateral-Oblique and Cranial-Caudal”. The researcher (2+ years mammography experience) and a lead researcher and expert in mammography (5+ years), using consensus agreement along with the ACR-BI-RADS Atlas 4th edition selected and categorised the cases using BI-RADS. The cases were selected based on the following criteria: cases with the least artefacts, lesions causing deviation from the norm, technical errors and amount of asymmetry of breast size and MBD (left vs. right). However, one patient image per set did include a distractor for a challenge. The cases were randomly split up into five groups of 50 mammographic cases, including 36 cases and 14 repeated cases. Fully anonymised digital mammographic cases  with full raw digital data were included [To facilitate the automated density analyser  to automatically measure density, only those mammographic cases (included . The cat2) maximum, 0.35 cd/m2 minimum and for the second screen: , for UK screen: .The target population consisted of breast radiologists from both USA and UK who were purposively sampled at two educational events, following voluntary recruitment. Datasets were displayed on secondary reporting monitors using two computer screens, each one with 20” full viewable diagonal area, with landscape and portrait display modes, called ’ViewSonic ViewPanel, VP201mb  with 1200 × 1600 pixel resolution for USA participants and a TOBII 23” TFT  with 1920 × 1080 pixels screen resolution, for UK participants. The luminance level of each monitor for both cohorts was first checked using the Digital Imaging and Communications in Medicine (DICOM). Part 14: Grayscale Standard Display Function (GSDF) using VeriLUM calibration software and pod (ImageSmiths) to ensure all screens met the standard range ,38. The All participants were asked to simply record their subjective MBD score using the Breast Imaging Reporting and Data System (BI-RADS) 4th edition  , for eacByng et al.,  and Boyd2 max, 0.41 cd/m2 min and 529.1 cd/m2 max, 0.63 cd/m2 min respectively. The area of the breast of each mammographic image for each projection  was quantified by selecting the contrast and density toolbar to adjust the contrast and density to enhance the skin edge of the breast. Then, the freehand area calculation tool was selected from the menu, to draw a semi-circular boundary around the area of the breast using a computer mouse pad and polygon generating a measurement in mm2. The measurements of the delineation of the breast area for the MLO images were done by tracing individually around the area of the whole breast excluding the pectoral muscle, see Using GE Centricity RA 600  image software. The images were displayed on two side-by-side Barco  Coronis 3 Mega Pixel (MFGD-3420) screens, with luminance levels of 402.6 cd/m2, see To measure dense breast tissue, the same steps were followed, by adjusting the contrast and density to enhance the fibroglandular tissue and using a computer mouse pad and polygon to draw around the area of interest. The measurement was generated in mm2 then multiplied by the depth of the breast on the mammogram image in order to calculate the whole volume of breast tissue versus the volume of dense breast tissue. The ratio of the density was thus calculated in a semi-subjective manner. Both area measurements were converted to cmThis assessment method uses an automated thresholding procedure that separates the interest area (dense tissue) from the background. The dense portion of the breast was segmented via IJ freeware software for Portable Network Graphics images, which is a built-in design extended by Fiji plugin a 3rd party Java modules . This so3), volumetric MBD (%), all by analysing the values in the density map. Then the volumetric density is calculated from these data, ranging from 0% to 40%. The information from MLO and CC images are averaged, and then the density information is given per breast. Following that, the density category is provided for each patient. To obtain percentage density, total fibroglandular tissue volume is divided by total breast volume. The percentage density is graded as following: BI-RADS1 (<4.5%), BI-RADS 2 (≥4.5% and <7.5%), BI-RADS 3 (≥7.5% and <15.5%) and BI-RADS 4 (≥15.5%) [The test set of patient digital mammography cases were saved as raw data DICOM images and then uploaded into a fully automated volumetric analysis, VOLPARA  density assessment software for quantitative assessment of MBD. Image analysis begins by locating a reference point in the breast, mainly close to the chest wall which contains fatty tissue. Following that, the x-ray attenuation is calculated for each pixel. A density map is created by calculating the attenuation degree in a pixel, the x-ray source and the tissue composition located between the pixel. VOLPARA computes the volume of the fibroglandular tissue and the breast (both in cm(≥15.5%) . The fin(≥15.5%) . The MBD(≥15.5%) ,47, whicThe average length of time for HD, IJ and VOLPARA was measured using a digital stopwatch . A random stratified sample of eight cases (two cases from each BI-RADS category) was selected for both the HD and IJ methods. Meanwhile, the time taken by VOLPARA to provide the BI-RADS for nine cases saved on one compact disc (CD) was measured. Finally, the length of time for the subjective BI-RADS categorization was calculated using ZILTRON software instant reporting and feedback of the length of time taken by each radiologist to move from one image to the next image for the five sets of cases. In addition, the time was calculated individually for the cases with and without distractors, as reported by the UK radiologists.For the HD method: the average time was calculated for all BI-RADS except for the two BI-RADS 1 cases, as they were fatty breasts. This time was calculated by adding the drawing time taken for each image for the outer surface to the time taken for outlining the dense area. Times were taken for each of the four projections for each patient, and the average time was calculated.To investigate further possible adaptations to the existing BI-RADS method, subjective BI-RADS ratings from radiologists in each country (USA and UK) and objective VOLPARA grades were additionally amended using just two categories (high vs. low). This was achieved by combining BI-RADS 1 and 2 together (Low Density), with BI-RADS 3 and 4 (High Density) as a second category.Further analysis was performed on the data collected for the cases with distractors from both cohorts. However, the USA radiologists, unlike the UK radiologists, rarely used or commented on this question; this will be explored in the discussion. Each answer from UK radiologists was counted and datasets created by the number of radiologists, thereby representing opinions from 1350 reads. An example is set C, which contains 50 cases read by six radiologists, yielding 300 reads. This procedure was used with all datasets.n = 56) and cases without distractors (n = 66) would have an influence on the level of agreement between the subjective BI-RADS decision of UK radiologists and the automated software (VOLPARA) categorisation.Additionally, further analysis was performed to explore whether cases with distractors (The levels of agreement between the radiologists from both countries (USA and UK) assessing MBD were compared separately to VOLPARA using Weighted Kappa test (κw)  for the categorical items . AdditioIntra-class Correlation Coefficient (ICC)  ,50 was cThe Spearman Correlation Coefficient (r) was calculated following the Li et al.,  study meKruskal–Wallis non-parametric ANOVA (Chi-Square Test) was used to determine whether there is a significant difference between the time taken for each mammographic density assessment method, including UK radiologists’ and VOLPARA ,52.A total of 25 USA breast imaging expert radiologists with >8 years’ experience, post radiology board certification, as well as 24 UK breast imaging experts, participated, with half of the cohort having >8 years’ experience and only 12% having ≤1 years’ experience post radiology board certification.p < 0.001). For the UK radiologists the average ICC measure was 0.927 with a 95% confidence interval from 0.821 to 0.975  = 15.194, p < 0.001).The intra-class correlation coefficient agreement for intra-rater reliability for the radiologists in both countries on the repeated cases within all five sets was high (ICC > 0.9): the average ICC measure for USA radiologists being 0.973 with a 95% confidence interval from 0.966 to 0.978  = 36.974, p < 0.001), while, with ImageJ was almost perfect agreement .The findings for the quality control tests are: the level of agreement between the researcher’s subjective BI-RADS categorisation and VOLPARA and Hand Delineation was substantial . The level of agreement using weighted Kappa between Hand Delineation and ImageJ, is substantial with κw = 0.699, , was found.When the correlation was tested between ImageJ and Hand Delineation assessment for breast density, a strong, positive association between the two subjects (p < 0.001) and UK radiologists .Using the modified two grade scale the agreement levels increased to substantial agreement between VOLPARA and USA radiologists , with visual assessment of the MBD taking an average of 14 s (range: 7–33 s), VOLPARA takes approximately 57 sec for each patient, with HD and IJ methods taking an average time of 320 sec (range: 198–453 s) and 131 sec (range: 83–168 s), respectively.Examination of the time difference between each method showed that there was a significant difference between each method (n = 24), according to the number of reads. Of the original total of 250 mammographic cases, 92 mammographic cases with distractors were included. However, results show that different decisions were taken by each radiologist (p < 0.001), meanwhile, the agreement level for the cases without any distractors was moderate . The average time for the subjective categorization for cases with distractors was 12 s (range: 7–23), and 16 s (range: 9–33 s) for those without any distractors, however, the time difference was not significant (p > 0.05). Furthermore, VOLPARA takes approximately 57 s for each patient, whether the image is with or without any distractors.When the agreement level for the BI-RADS categorization between UK radiologists and VOLPARA for cases with distractors was calculated, the agreement was substantial , it was found that this method has a substantial agreement with the American radiologists. However, a moderate agreement was found with the British radiologists. The higher agreement between USA radiologists and VOLPARA might be expected, as VOLPARA software thresholds were determined by a USA expert group of radiologists . This diLee et al., , a KoreaSartor et al.,  in his sp < 0.001), which was similar to the USA radiologists. This may be because the researcher has been specifically trained to use BI-RADS, and categorised the cases with the aid of BI-RADS Atlas 4th edition. These results add to the evidence supporting the fact that, without the assistance of VOLPARA, the image readers will have a lower agreement. This emphasises the value of incorporating VOLPARA or other such similar automated systems into MBD assessment as they may positively impact on the radiologists’ agreement, as also proven by Schilling et al. [Subjective variations noted worldwide could lead to increases in both radiologist and patient uncertainty. Radiologists may fear over or underestimating MBD, while patients may fear the possibility of a cancer being missed. Such variation could also create difficulties in following a consolidated MBD categorization, thus making it more difficult to develop a specific imaging pathway, which is dependent on MBD, and unifying patient care ,59,60,61g et al. . Thus, tA further part of the study tested the agreement between the subjective analysis and VOLPARA on a more limited version of the current BI-RAD’S classification by reducing the scale to just two separate categories, to see whether differences in MBD interpretation could be reduced. The findings demonstrate that the level of agreement between the two cohorts’ subjective evaluation and VOLPARA showed more substantial agreement. Thus, the scale of two separate categories—low density and high density—is reliable and robust, and therefore could lead to reducing patient uncertainty, as well as potentially minimizing the costs associated with unnecessary imaging and additional procedures, and help in unifying the imaging pathway for patient cohorts.r = 0.809). This was expected and is in agreement with previous studies of Li et al., [Moving toward the area-based methods (HD and IJ), which assess MBD by segmenting two-dimensional mammographic images into dense and non-dense areas, and have been only partially automated ,63, when et al.,  and Couw et al., , as IJ wThe second limitation, as stated by Byng et al. , is thatOn the other hand, when the level of agreements between HD and IJ MBD assessment methods with VOLPARA were tested, moderate agreement was found between VOLPARA and HD (0.597) and IJ (0.603). The variation in agreement between VOLPARA and both HD and IJ is due to the fact that VOLPARA is a fully volumetric measurement, while both HD and IJ are area-based methods with visual computer assistance. The differences in the methodologies may have an impact on the final results, as area-based methods are highly user-dependent. The two-dimensional image of the compressed breast is segmented and the threshold is defined by the user. This increases the possibility of inter-observer variability ,16,63,65When agreements between HD and IJ breast density assessment methods with the BI-RADS subjective assessment were tested, the level of agreement between these two methods and the two cohorts was substantial. In general, this is higher than the agreement level between VOLPARA and the two cohorts. Possible explanations for this higher agreement include the fact that, as in volumetric methods, it is difficult to locate a reference point in the breast that only contains fatty tissues, either within an extremely dense breast or in a very small breast . This sop < 0.001) was higher than the agreement for the cases with no distractors , which was not expected, and this supports the need for further studies to explore visual processing reasoning. Furthermore, as shown in British radiologists when asked regarding potential distractors, reported lesions causing deviation from the norm as the greatest distractor, followed by the asymmetry of the MBD. Lee et al.,  found thThe authors acknowledge that this work has some limitations: the two-dimensional nature of IJ and HD methods does not take into consideration the thickness of dense tissue within the breast ,71. ThisThere is variability between breast density assessment methods, and that all methods are not in complete or even high agreement with each other. The level of agreement varied from moderate to substantial between VOLPARA with both cohorts. Despite the high agreement between HD, IJ and both cohorts, HD, IJ are user dependent, requires skills, training and are time consuming. Therefore, these are costly in relation to radiologists’ time and are impractical in a clinical setting. Moreover, subjective assessment is the quickest method to assess density, followed by VOLPARA, and both are appropriate in a busy clinical setting. In addition, the use of the limited two-scale system improves agreement levels, and thus could help in minimizing any potential country bias while providing a clear imaging pathway for patients. To date, there is no universal agreement as to which methods are best-suited to creating individual imaging pathways, therefore, further investigation is strongly recommended.


Low back pain is a common clinical chronic disease with symptoms of back soreness, numbness, and pain. The incidence of low back pain is high, and gradually increases with age. It is mainly middle-aged and has a high recurrence rate. It is considered to be one of the common diseases with the highest disability rate. The aim of this systematic review is to assess the effectiveness and safety of moxibustion therapy for low back pain.Two reviewers will electronically search the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL);PubMed; EMBASE; China National Knowledge Infrastructure (CNKI); Chinese Biomedical Literature Database (CBM); Chinese Scientific Journal Database (VIP database); and Wan–Fang Database from the inception, without restriction of publication status and languages. Additional searching including researches in progress, the reference lists and the citation lists of identified publications. Study selection, data extraction, and assessment of study quality will be performed independently by 2 reviewers. If it is appropriate for a meta-analysis, RevMan 5.4 statistical software will be used; otherwise, a descriptive analysis will be conducted. Data will be synthesized by either the fixed-effects or random-effects model according to a heterogeneity test. The results will be presented as risk ratio (RR) with 95% confidence intervals (CIs) for dichotomous data and weight mean difference (WMD) or standard mean difference (SMD) 95% CIs for continuous data.This study will provide a comprehensive review of the available evidence for the treatment of moxibustion with low back pain.The conclusions of our study will provide an evidence to judge whether moxibustion is an effective and safe intervention for patients with low back pain.INPLASY202080027. Low back pain is a common cause of restricted activities and affecting life. It is the most common musculoskeletal disease, with an incidence of up to 70% in adults. As of 2016, the global prevalence and incidence of low back pain reached 51104.8 and 250,277,000 respectively. In addition, in most parts of the world, low back pain is the main reason that restricts peoples activities, lacks work, and reduces productivity. The incidence of low back pain is high, and gradually increases with age. It is mainly middle-aged and has a high recurrence rate. It is considered to be one of the common diseases with the highest disability rate. Have a great impact on their daily work and life. The purpose of intervention for low back pain is to relieve pain and improve the state of restricted functional activity. Usually, the first choice is drug therapy and non-invasive treatment. The most commonly used to relieve pain syndrome are non-steroidal anti-inflammatory drugs (NSAIDs), but their long-term use may have side effects on the gastrointestinal tract, kidneys, and antiplatelets. Therefore, doctors and patients should be cautious in clinical treatment. ,10 Moxibustion, as a commonly used treatment method within the scope of traditional Chinese Medicine, has a good effect on the treatment of various types of pain diseases, and has been widely accepted and recognized worldwide.Low back pain refers to the long-term chronic strain of lumbar muscles, myofascial membranes, tendons, and cutaneous nerves, leading to aseptic inflammation, tissue congestion, edema, adhesion, fibrosis, and long-term development of cord-like nodules.1.2 Moxibustion therapy is an external treatment method, which is mainly made from a series of Chinese herbal medicines such as mugwort leaves. It uses moxibustion to generate warmth on the patients local skin, and then exerts a therapeutic effect.,13 The basic theory of traditional Chinese medicine believes that moxibustion has the effects of warming the meridians and dispelling cold, dispelling dampness and relieving pain. It can play an important role in preventing and treating diseases. So far, many systematic reviews have shown that moxibustion therapy in traditional Chinese medicine has a good effect on the treatment of painful diseases.,16 Our research group has repeatedly checked the literature and found that moxibustion has a certain effect on the treatment of low back pain in terms of clinical efficacy and alleviating the development of pain. Therefore, moxibustion may become an effective treatment to delay the progression of low back pain.This disease belongs to the categories of low back pain, arthralgia and so on in Chinese medicine. The internal causes are mostly due to liver and kidney deficiency, weak qi and blood, trauma or strain. The external causes are mostly feelings of wind, cold, dampness, and trauma, which lead to poor circulation of qi and blood, pain caused by impassability, blocked veins, and muscle pain after a long period of time.1.3 Modern medical research has confirmed that moxibustion has anti-inflammatory, expelling rheumatism, dredging collaterals and relieving pain, improving the body's immunity, and achieving the effect of treating both symptoms and root causes.–22In traditional Chinese medicine, moxibustion is considered to play a major role through warming and drug effects. In Western medicine, the mechanism of moxibustion is not clear.1.4 but there is a large difference between acupuncture and moxibustion, which requires additional evaluation. Therefore, we hope to conduct a systematic evaluation of the published literature, with the aim of exploring the efficacy and safety of moxibustion in the treatment of low back pain, and to draw more reliable conclusions through meta-analysis to provide concluding evidence for clinical practice.Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be very effective in the treatment of low back pain, but their side effects and adverse reactions are still a major problem for some patients.at the same time.A systematic evaluation and meta-analysis showed that acupuncture treatment myofascitis may be effective, 1.5To systematically evaluate the effectiveness and safety of moxibustion therapy for low back pain patients.2 It is registered on the International Prospective Register of Systematic Reviews. .This protocol was designed in accordance with the methodological guidelines for overviews provided by the Cochrane Handbook for Systematic Reviews of Interventions.2.12.1.1Randomized controlled trials (RCTs) will be included, without restrictions on publication status.2.1.2Adult patients with low back pain, regardless of sex, race, or educational and economic status.2.1.3Research using moxibustion or combined with other therapies, without limiting the treatment time and dose.2.1.4The control group's treatment is not limited, including no treatment, placebo, or any control considered for comparison in a single systematic review.2.1.5Primary outcomes: Visual Analogue Scale (VAS score).Secondary outcomes:1.Dysfunction index score (ODI score).33.13.1.1The following databases from the inception to July 2020 will be searched by 2 independent reviewers, without restriction to publication status and languages: the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; China National Knowledge Infrastructure (CNKI); Chinese Biomedical Literature Database (CBM); Chinese Scientific Journal Database (VIP database); and Wan–Fang Database. A search strategy for PunMed database, which is established according to the Cochrane handbook guidelines, is shown in Table 3.1.2http://www.clinicaltrials.gov) and the World Health Organization International clinical trials registry search portal . Additionally, the citation list will be retrieved in Web of Science. Besides, the reference lists of those studies meeting the inclusion criteria and relevant systematic reviews will also be identified for additional relevant studies.Besides, electronic sources for relevant researches in progress will also be searched, including Clinicaltrials.gov . Records selected from other sources will also be moved to the same database. Two reviewers (SYZ and GHT) will independently screen the titles, abstracts, and keywords of all retrieved studies and decide which trials meet the inclusion criteria. We will obtain the full text of all possibly relevant studies for further assessment. Excluded studies will be recorded with explanations. Any disagreements will be resolved by discussion between the 2 reviewers (SYZ and GHT) and the third author (JC) for arbitration when necessary. We will contact reviewers of trials for clarification when necessary. The study flow diagram is shown in Fig. 3.3A unified data extraction form will be designed by all of the reviewers and its applicability will be tested in a small scope of trials by 2 reviewers (ZYZ and LBL). They will then independently extract data in the following domains: general information, participants, methods, interventions, outcomes, results and other information. Any disagreement will be discussed between the 2 reviewers, and further disagreements will be arbitrated by the third author (JC).3.4The risk of bias will be assessed by 2 reviewers (XCZ and HG) with the Cochrane Collaborations tool for risk of bias assessment. The risk of bias in included studies will be evaluated according to the following aspects: sequence generation, allocation sequence concealment, blinding of participants and personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. The assessments will be classified into 3 levels: low risk, high risk, and unclear risk.3.5RevMan V.5.4 will be used for data analysis and quantitative data synthesis. For continuous data, we will use standard mean difference (SMD) to measure the treatment effect with 95% confidence intervals (CIs). For dichotomous data, a risk ratio (RR) with 95% CIs for analysis will be adopted.3.6Data from studies with parallel-group will be included for meta-analysis. For randomized cross-over trials, only the first phase data will be included. In these trials, participants are individually randomized to 2 intervention groups, and a single measurement of each outcome from each participant is collected and analyzed.3.7 For the data “missing at random”, only the available data will be analyzed. For the data “not missing at random”, we will displace the missing data with replacement values and a sensitivity analysis will be used to determine whether the results are inconsistent.We will try to contact the first or corresponding authors of the included studies by telephone or email to retrieve missing or insufficient trial data. If missing data are unavailable, we will make an assumption using the terms “missing at random” and “not missing at random” to represent different scenarios, which is recommended in the Cochrane Handbook.3.8I2 statistic value. To be concrete, a fixed effect model will be adopted if the heterogeneity is indicated as high (I2 < 50%); otherwise, a random effect model will be applied on the contrary.On the basis of the data analysis, random effect or fixed effect models will be employed according to the heterogeneity given by 3.9We will use funnel plots to detect reporting biases and small study effects. If more than 10 studies are included in the meta-analysis, we will conduct a test for funnel plot asymmetry using Egger method. All eligible trials will be included, regardless of their methodological quality.3.10The systematic review will be conducted with the use of RevMan 5.4. Taking account of the heterogeneity assessment, MD or RR with fixed or random effect model will be computed. Additionally, if heterogeneity is considered significant, the sensitivity or subgroup analysis will be generated to distinguish the source of it. When it comes to the situation that the data are insufficient for quantitative analysis, the review will only represent and summarize the evidence.3.11Sensitivity analysis will be conducted to validate the robustness of the primary results. We will exclude certain trials by a revaluation of methodological quality, study types, sample size, missing data or other possible factors. Careful interpretations will be employed for sensitivity analysis if differ substantially.3.12 Six domains will be assessed, containing risk of bias, consistency, directness, precision, publication bias and additional points. The assessments will be categorized into 4 levels: high, moderate, low, or very low.The Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group methodology will be applied for the quality of evidence for all outcomes.3.13If data are available, a subgroup analysis will be performed based on the type of moxibustion intervention  because this is the main factor causing heterogeneity.4–28Therefore, the key to treating this disease with Chinese medicine is to promote blood circulation, remove blood stasis and relieve pain. Acupuncture and moxibustion therapy can clear the blood, relieve nerve root compression, promote blood circulation in the waist, and eliminate edema by stimulating acupoints to relieve pain.,29 Though nonsteroidal anti-inflammatory drugs (NSAIDs) have been recommended to be the commonly used for the management of low back pain, the side effects burden is still concerned. Therefore, it is very meaningful to explore the effectiveness and safety of moxibustion in the treatment of low back pain.Low back pain is mainly due to the invasion of wind, cold and moisture, which makes the meridian blood in the muscles and muscles not smooth, and It is prone to long-term indoor office work, sedentary sitting, improper sitting and other people, causing chronic strain. Or the acute muscle injury caused by trauma is not effectively treated. The disease can cause pain in the patients muscle tissue, and long-term edema can cause local tissue ischemia and hypoxia, resulting in tissue fibrous adhesions.Conceptualization: Siyuan Zhu, Jun Xiong.Data curation: Siyuan Zhu, Jun Chen, Genhua Tang, Zhiying Zhong, LunBin Lu, Xingchen Zhou, Han Guo.Formal analysis: Siyuan Zhu, Jun Chen.Investigation: Jun Xiong, Genhua Tang, Zhiying Zhong, Hao Fan.Methodology: Siyuan Zhu, Jun Chen, LunBin Lu.Software: Siyuan Zhu, Jun Chen.Supervision: Jun Xiong, LunBin Lu, Hao Fan.Writing – original draft: Siyuan Zhu, Jun Xiong.Writing – review & editing: Jun Xiong, Jun Chen, Genhua Tang, LunBin Lu, Hao Fan.